Development and Psychopathology 30 (2018), 1269–1303

# Cambridge University Press 2017. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creative-
commons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
doi:10.1017/S0954579417001730

Prenatal influences on temperament development: The role

of environmental epigenetics

MARIA A. GARTSTEIN AND MICHAEL K. SKINNER

Washington State University

Abstract
This review summarizes current knowledge and outlines future directions relevant to questions concerning environmental epigenetics and the processes that
contribute to temperament development. Links between prenatal adversity, epigenetic programming, and early manifestations of temperament are important
in their own right, also informing our understanding of biological foundations for social–emotional development. In addition, infant temperament
attributes represent key etiological factors in the onset of developmental psychopathology, and studies elucidating their prenatal foundations expand our
understanding of developmental origins of health and disease. Prenatal adversity can take many forms, and this overview is focused on the environmental
effects of stress, toxicants, substance use/psychotropic medication, and nutrition. Dysregulation associated with attention-deficit/hyperactivity–disruptive
disorders was noted in the context of maternal substance use and toxicant exposures during gestation, as well as stress. Although these links can be made based
on the existing literature, currently few studies directly connect environmental influences, epigenetic programming, and changes in brain development/
behavior. The chain of events starting with environmental inputs and resulting in alterations to gene expression, physiology, and behavior of the organism is
driven by epigenetics. Epigenetics provides the molecular mechanism of how environmental factors impact development and subsequent health and
disease, including early brain and temperament development.

Environmental exposures can alter maternal physiology in a with exposure to stress, toxicants, substance use/psychotropic
manner that results in “programming” effects on the fetus. medication, and nutrition. Programming effects of these envi-
This programming is understood in terms of adaptations to ronmental factors linked with temperament development will
the prenatal environment, which may or may not be beneficial be considered in the present review, focused on the underly-
after birth. That is, the course of fetal development is altered ing biological mechanisms.
as a function of critical environmental conditions in a manner Fetal programming is thought to transform the structure
that shapes growth and health outcomes into adulthood. Ac- and function of tissues/organs, shaping physiological out-
cording to Hochberg et al. (2011) and others, offspring faces comes associated with adult disease. Biological processes
risk in the form of vulnerability to adversity and/or a lack or underling these programming effects represent a more re-
resilience if in utero programming is discordant with the post- cent emphasis, as DOHaD research has become increasingly
natal environment. This programming effect was first noted concerned with the role of epigenetic mechanisms that alter
in the context of undernutrition and is often referred to as gene expression (Hochberg et al., 2011). Understood to me-
Barker’s hypothesis. Barker and Osmond (1986) relied on diate the effects of environmental input on the developing
epidemiological data to ascertain that gestational undernu- organism by shaping gene expression, epigenetics has
trition was correlated with adult onset heart disease. Multiple been defined as “molecular factors/processes around the
investigations have since identified fetal programming con- DNA that regulate genome activity independent of DNA se-
tributions to adult disorders (e.g., Tobi et al., 2014), and in- quence, and are mitotically stable” (Skinner, 2014). Epige-
terest in developmental origins of health and disease (DOHaD; netic mechanisms play a critical role in fetal programming,
Wadhwa, Buss, Entringer, & Swanson, 2009) continues to providing the basis for either healthy outcomes or disruption
grow. This research encompasses prenatal effects associated of physical and mental health. Environmental epigenetics
encompasses a variety of environmental factors that serve
We thank Eric Nilsson for critical review of the manuscript and Heather John-
to establish and maintain epigenetic modifications, influ-
son for assistance in the preparation of the manuscript. This study was sup- encing gene expression and the resulting phenotype. Fetal
ported by a John Templeton Foundation grant and NIH grants (to M.K.S.). programming associated with maternal stress, toxicants,
Address correspondence and reprint requests to: Maria A. Gartstein, De- substance/psychotropic medication use, and nutrition re-
partment of Psychology, Washington State University, PO Box 4820, Pull- flects diverse biological pathways. All these exposures are
man, WA 99164-4820; E-mail: [email protected]; or Michael K. Skinner,
Center for Reproductive Biology, School of Biological Sciences, Washing-
nonetheless relevant to environmental epigenetics, as epige-
ton State University, PO Box 4236, Pullman, WA 99164-4236; E-mail: netic processes provide conduits for conferring their effects
[email protected]. to the gestating organism.
1269

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 1270 M. A. Gartstein and M. K. Skinner

Consequences of fetal programming in humans have been & Khosla, 1999; Reik, Collick, Norris, Barton, & Surani,
documented most widely for physical health/medical out- 1987). Critical to multiple developmental outcomes, DNA
comes (e.g., Roseboom et al., 2011), with behavioral effects methylation is also emerging as important for temperament
often examined in animal models (Babenko, Kovalchuk, & development (e.g., Fuemmeler et al., 2016).
Metz, 2015). Outcomes have not been typically framed as
temperament per se, but rather discussed in terms of stress
Histone modifications
reactivity, susceptibility to anxiety, or impulsivity, without
making links to this overarching theoretical framework. Histones represent the chief protein component of chromatin,
Connecting these disparate findings under the umbrella functioning as beads around which DNA winds, and is com-
of the psychobiological model of temperament makes it pressed into nucleosomes. Histones, and their various modifi-
possible to view these in terms of their implications for cations, or marks, play an important role in regulating gene ex-
social–emotional development and developmental psycho- pression. Covalent posttranslational modifications to histone
pathology, and to provide prevention/intervention related proteins including methylation, phosphorylation, acetylation,
recommendations. Understanding developmental origins of ubiquitylation, and sumoylation impact gene expression by al-
temperament via fetal programming potentiated through epi- tering chromatin structure and/or recruiting histone modifiers.
genetic mechanisms could make earlier preventative efforts Whereas some result in transcription activation, others have
possible. Considering prenatal effects of maternal stress, tox- a repressive effect, effectively shutting down transcription.
icant exposure, substance/psychotropic medication use, and Lysine acetylation, for example, results in more accessible
nutrition in the context of the environmental epigenetics chromatin and tends to be associated with active transcription.
framework provides an opportunity to compare resulting Conversely, deacetylases remove acetyl groups from the his-
offspring epigenetic and behavioral signatures. These expo- tones, allowing the DNA to be wrapped more tightly and repress-
sures often work in tandem (e.g., inadequate nutrition cou- ing transcription activity. Histone methylation effects depend
pled with stress), and advances in environmental epigenetics on the location and number of methyl groups involved, poten-
will inform whether similar epigenetic mechanisms, overlap- tially leading to activation or repression of gene expression
ping genomic regions, and/or interacting gene networks are (Barski et al., 2007). Exposure to adverse environments has
responsible for compound effects. been shown to result in alterations in histone acetylation and
This review begins with epigenetic mechanisms critical to methylation status in animals (Weaver et al., 2004). Specifi-
current research, and those likely to gain importance going cally, histone acetylation of the glucocorticoid receptor, nuclear
forward. Links between temperament and developmental receptor subfamily 3, group C, member 1 (NR3C1) gene differ-
psychopathology are addressed next. We then turn to environ- entiated offspring born to high and low licking and grooming
mental factors that shape the intrauterine milieu and fetal mothers along with DNA methylation.
development: stress, toxicant, substance use/psychotropic
medication, and nutritional exposures. Finally, evidence link-
Chromatin structure/remodeling
ing DNA methylation and temperament, and implications for
behavioral/emotional health are described, followed by con- A number of factors come into play as DNA is packaged into
clusions and recommendations for future research. progressively larger units, starting with the assembly of nucleo-
somes and concluding with mitotic condensation, resulting in
chromosomes. A variety of factors (e.g., stage of cell life) affect
Epigenetic Mechanisms
chromatin state, resulting in either euchromatin or heterochro-
A number of epigenetic mechanisms have been identified, in- matin. The euchromatin, “beads-on-a-string” structure makes
cluding DNA methylation, histone modifications, chromatic DNA more accessible, promoting transcription and gene
structure/remodeling, and noncoding RNAs (Figure 1). expression. The euchromatin state is associated with activating
histone marks and remodeling complex recruitment that
facilitate transcription factor binding. Heterochromatin, in
DNA methylation
contrast, represents a repressed state with respect to gene
DNA methylation occurs when a small (methyl) chemical expression, and is associated with repressive histone and
group is attached to the DNA base cytosine (C) in a cytosine DNA methylation.
nucleotide–phosphate–guanine nucleotide (CpG) sequence.
Covalent modification of DNA by methylation of cytosine res-
Noncoding RNAs
idues serves to alter transcription and genome activity. DNA
methylation is responsible for silencing of transposable ele- Noncoding RNAs include short microRNAs, Piwi-interact-
ments and pericentromeric repeats to ensure genome integrity ing RNAs, and long noncoding RNAs, regulating genes
(Chen, Tsujimoto, & Li, 2004; Kaneko-Ishino & Ishino, translation/transcription and chromatin stability (Zhou, Hu,
2010; Xu, Bai, Collins, & Ghishan, 1999), inactivation of & Lai, 2010). Noncoding RNAs can directly bind to promot-
the X-chromosome (Lock, Takagi, & Martin, 1987; Sado, ers and interfere with polymerases by mobilizing transcrip-
Okano, Li, & Sasaki, 2004), and genomic imprinting (Feil tionally repressive complexes conducive to heterochromatin

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 Environmental epigenetics and temperament 1271

Figure 1. Epigenetic mechanisms: DNA methylation, histone modification, and noncoding RNA. Methylation: DNA methylation is the
addition of a methyl group (M) to the DNA base cytosine (C) in a CpG sequence; CH3, the methyl group, is added to a carbon of the
cytosine ring via a covalent bond, resulting in 5-hydroxymethyl cytosine. Chromatic structure/remodeling: Chromatin structure in heterochro-
matin states, silencing transcriptional activities, euchromatin HAT catalyzes histone tails leading to active transcription. Histone modifications:

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 1272 M. A. Gartstein and M. K. Skinner

(Zaratiegui, Irvine, & Martienssen, 2007) and through Temperament Development and Symptoms
posttranscriptional binding (Filipowicz, Bhattacharyya, & of Psychopathology
Sonenberg, 2008). Noncoding RNAs are involved in a num-
ber of activities, with current evidence suggesting the largest We now turn to temperament research addressing negative
class may be that of chromatin modifiers (Horabin, 2013). emotionality, surgency/extraversion, regulatory capacity/ef-
Whereas some noncoding RNA actions are sequence depen- fortful control, and links with developmental psychopathol-
dent, and thus not epigenetic in nature, examples of sequence- ogy. The study of temperament has a long-standing history.
independent effects have been reported (Cao, 2014). Childhood research began with the work of Thomas and
Although a number of epigenetic mechanisms have been Chess (1977) focused on “difficult temperament,” which re-
documented, initial implementation in DOHaD research has flects high levels of negative affects, coupled with few man-
focused primarily on methylation. Additional epigenetic pro- ifestations of positive emotions and poor regulation. A num-
cesses will likely be implicated in the future, likely working ber of temperament definitions and frameworks have been
in concert, for example, as histone modifications contribute proposed, several emphasizing biological underpinnings.
to chromatin remodeling (Figure 1). Accumulating evidence The study of behavioral inhibition and exuberance, for exam-
from animal studies supports the important role of epigenetic ple, has linked approach and avoidance tendencies to an
mechanisms in shaping physiological maturation and behav- asymmetry in frontal brain activation (Hane, Fox, Henderson,
ioral development, conferring effects of various exposures & Marshall, 2008). The polyvagal theory (Porges, 2007) ad-
(e.g., Skinner, Anway, Savenkova, Gore, & Crews, 2008). dressed how physiological states support different classes of
The human literature lags behind and is subject to greater me- behavior (e.g., vagal withdrawal supports mobilization, fight,
thodological challenges. Nonetheless, epigenetic effects have and flight) and primary emotions are related to autonomic
been identified utilizing brain tissue and peripheral cells (Nier- functioning. Currently, Rothbart’s psychobiological model
atschker et al., 2014; Szyf & Bick, 2013). That is, signatures of (Rothbart & Derryberry, 1981), an integration of existing
environment triggers that lead to epigenetic/molecular changes temperament and personality frameworks with other relevant
in the brain can also be identified in peripheral tissues, because areas, such as neuroscience and comparative studies, repre-
of systemic consequences of exposure (Lester, Conradt, & sents the most widely referenced approach.
Marsit, 2016; Szyf & Bick, 2013), and afford identification According to the psychobiological model, temperament
in humans. Moreover, issues around cell specificity of epige- represents constitutionally based individual differences in
netic programming can be addressed by comparative studies, emotional and motor reactivity, as well as self-regulation, dem-
wherein human peripheral cell epigenetic signature is com- onstrating consistency across situations and relative stability
pared to a brain tissue signature obtained from animals, with over time (Rothbart & Derryberry, 1981). Emotional reactivity
the focus on conserved genomic regions and/or gene networks encompasses fear, anger, sadness, and positive emotions. Pro-
(Nieratschker et al., 2014). This environmental epigenetics re- cesses serving to modulate reactivity, including attentional fo-
view will focus on stress, toxicant, substance use/pharmaceuti- cus, shifting, and inhibitory control, provide the basis for self-
cal, and nutritional prenatal exposures. Pathways that involve regulation. The psychobiological approach identifies unique
maternal physiology and offspring brain development will be domains of temperament, mapping these onto underlying
discussed as the foundation for temperament and risk/protec- neurobehavioral systems, and outlines their developmental
tion with respect to psychopathology. Epigenetic mechanisms pathways and interactions. The term “constitutional” empha-
mediate environmental effects on temperament phenotypes. sizes the connection between temperament and biology.
Effects set in motion during gestation likely contribute to de- Historically, individual differences in temperament have
velopmental psychopathology by impacting temperament been linked to the constitution of the organism, as it was under-
growth and could also play a role as risky temperament profiles stood at the time. Although “constitutionally based” has been
transform into symptoms and disorders (e.g., infant fear/ typically interpreted as genetically driven, accumulating evi-
behavioral inhibition culminate in childhood social anxiety). dence suggests epigenetic processes make important contribu-
Temperament-related effects are likely to be especially salient tions and have been incorporated in the definition of tempera-
in early childhood, as behavioral attributes “come online.” ment more recently (Putnam & Gartstein, 2016). The

histone modifications occurs via different enzymes. Active modifications result in permissive effects promoting transcription. Repressive mod-
ification marks serve to halt transcriptional activity in the gene, resulting in closed heterochromatin. Histone deacetylation (HDACs) and acet-
ylation (HAT) represent repressive and permissive modification marks, respectively. Acetylation refers to an introduction of an acetyl functional
group (Ac) into a chemical compound, whereas deacetylation reflects the removal of an acetyl group. Noncoding RNAs: noncoding RNAs per-
form a variety of functions related to gene expression. Long noncoding RNAs (lnc RNAs) can interfere in transcription and affect chromatin
stability, also playing a role in translation. Noncoding RNAs can directly bind to promoters and interfere with polymerase II (PolII), one of three
nuclear, DNA-dependent RNA polymerases. Posttranscription, microRNAs (miRNAs) are able to regulate gene expression by editing, splicing,
and affecting stability of mRNA and protein synthesis. This figure is based on previous literature (Bagga, 2012; Suter, Takahashi, Grove, &
Aagaard, 2013; Wahlestedt, 2013).

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 Environmental epigenetics and temperament 1273

psychobiological temperament framework applies across the for filtering sensory input, the executive network is engaged
life span, with reactive and regulatory domains developing es- in conflict resolution and selecting between alternative
pecially rapidly in early childhood. Temperament attributes are response options (Posner & Peterson, 2011).
understood to encompass physiological reactivity, including A growing body of research indicates that the risk for ex-
elements of the hypothalamus–adrenal–pituitary (HPA) axis ternalizing problems (conduct difficulties, hyperactivity, and
response and patterns of brain activation. These are generally impulsivity; Campbell, 1995; Kovacs & Devlin, 1998) is
measured along with behavioral markers, typically ascertained greatest for highly reactive children with pronounced negative
through direct observations, and in humans also via caregiver emotionality and/or surgency, coupled with deficits in atten-
report (Gartstein, Putnam, Aaron, & Rothbart, 2016). tion and regulatory functioning (Diaz et al., 2015; Gartstein &
Structurally, temperament encompasses negative emo- Fagot, 2003; Martel, Gremillion, & Roberts, 2012; Muris &
tionality, surgency/extraversion, and orienting regulation/ Ollendick, 2005). Internalizing difficulties that involve
effortful control. Distress proneness is the first to emerge personal distress and are affective in nature (e.g., depression/
(e.g., Putnam, Rothbart, & Gartstein, 2008; Rothbart, anxiety) can occur as a function of high negative emotionality
1989). At the same time, negative emotionality has strong and low surgency (Fowles, 1994; Lonigan et al., 2003; Murray
conceptual and empirical links to the adult personality trait & Kochanska, 2002), with nontemperament pathways also
of neuroticism (Evans & Rothbart, 2007). Fearful reactiv- relevant for depressive symptoms (Hammen, 2005).
ity/behavioral inhibition, a component of negative emotional- Thus, early manifestations of temperament not only are
ity, tends to occur in the context of relative right-hemisphere important as key components of social–emotional develop-
dominance (right dorsolateral prefrontal cortex and temporal ment but also are significant as early markers of psychopathol-
regions), associated with limbic system (i.e., amygdala, basal ogy risk (Figure 2). A number of explanations for the relation-
ganglia, and hypothalamus) activation (Davidson, 1998; Sut- ship between temperament and psychopathology have been
ton & Davidson, 1997). HPA axis functioning alterations proposed. Vulnerability and pathoplasty models generally as-
marked by higher cortisol were also noted for children sign temperament a causal role in psychopathology. Vulner-
demonstrating behavioral inhibition/fear (Perez-Edgar, ability explanations cast temperament as increasing the prob-
Schmidt, Henderson, Schulkin, & Fox, 2008). ability of symptom onset (e.g., Perez-Edgar et al., 2008). In
Surgency in infancy is largely manifested through display- contrast, temperament and psychopathology can have inde-
ing pleasure (e.g., smiling and laughing) and approach behav- pendent etiology in pathoplasty models, wherein temperament
iors (Gartstein & Rothbart, 2003; Rothbart, 1989), incorpor- (or personality) is viewed as impacting the course and/or severity
ating characteristics of activity and enthusiasm (Rothbart & of disorders (e.g., De Bolle, De Clercq, De Caluwe, & Verbeke,
Ahadi, 1994). Individuals higher in positive affect have the 2016). Alternative differential susceptibility (Belsky &
tendency to be engaged, rather than disengaged, with their Pluess, 2009) and biological sensitivity to context (Boyce
environment (Lonigan, Phillips, & Hooe, 2003), as approach & Ellis, 2005) models are relevant primarily to negative emo-
tendencies are potentiated by increased behavior activation tionality, viewed as a plasticity, rather than a vulnerability fac-
system input (Gray, 1994; Rothbart & Hwang, 2005). The tor. Thus, the differential susceptibility/biological sensitivity
corticolimbic–striatal–thalamic network that operates via do- to context models make “for better or for worse” predictions
paminergic projections from the ventral tegmental area to the with respect to negative emotionality. There is growing em-
subcortical and frontal cortical regions (Depue & Collins, pirical support for the positive response of those high in
1999) favors left frontal regions (Coan & Allen, 2004) and negative emotionality to good environments and interven-
provides the foundation for surgency/extraversion. In in- tions (e.g., Hentges, Davies, & Cicchetti, 2015), and new evi-
fancy, relative left frontal asymmetry was associated with ap- dence that negative affectivity primarily confers adjustment
proach behaviors, including positive vocalization and facial risk (e.g., Moran et al., 2016). Predictive links between tem-
expressions of joy (Diaz & Bell, 2012; Hane et al., 2008). perament and symptoms were also framed in terms of under-
Infant regulatory/attentional skills set the stage for the lying neurobiology. Whittle, Allen, Lubman, and Yucel
more flexible, frontally mediated effortful control (e.g., Gart- (2006) proposed a model focused on six brain structures:
stein, Bridgett, Young, Panksepp, & Power, 2013). The amygdala, hippocampus, nucleus accumbens, orbitofrontal
emergence of effortful control coincides with rapid develop- cortex, anterior cingulate cortex, and the dorsolateral prefron-
ment of the executive attention system, including the lateral tal cortex, describing joint effects for negative emotionality,
prefrontal cortex and anterior cingulate regions (Rothbart, surgency/extraversion, regulation, and related symptoms/dis-
Derryberry, & Posner, 1994; Rueda, 2012). This critical orders. Environmental epigenetics can elucidate biological
milestone involves a shift from reliance on the alerting atten- underpinnings of temperament development, in turn expand-
tion network, supported by parietal lobe areas and governed ing our understanding of developmental psychopathology
by the norepinephrine system, to a more flexible executive at- and DOHaD more broadly, as temperament attributes repre-
tention network. Anterior cingulate, basal ganglia, and areas sent key contributing factors.
of the prefrontal cortex are included in the executive attention Human and animal studies showing connections between
network, modulated by dopamine (Posner, Rothbart, Sheese, prenatal environmental exposures and temperament-related
& Voelker, 2012). Whereas the alerting system is responsible phenotypes suggest these exposures, and the cascades of

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 1274 M. A. Gartstein and M. K. Skinner

Figure 2. Links between temperament attributes and developmental psychopathology. Depicted are the most prominent relationships between
child temperament traits and broad symptom/behavior problem clusters (internalizing and externalizing). (–) A negative relationship and (- - -) a
less well-established relationship.

epigenetic effects that follow, impact how reactivity and reg- response results in downregulation of CRH and ACTH (Dep-
ulation “come online.” Studies addressing the impact of ma- permann, Storchak, Fallgatter, & Ehlis, 2014).
ternal stress response and HPA axis functioning make some A mechanism wherein information from the environment is
of the least ambiguous connections between prenatal expo- conferred to the offspring via maternal stress hormones during
sure and alteration in offspring temperament across species, gestation appears to be conserved across multiple species (Ta-
elucidating epigenetic processes that mediate prenatal envi- ble 1). For instance, predation risk was shown to cause female
ronment–postnatal behavior relationships. Evidence linking fish to produce larger eggs with higher concentrations of corti-
maternal stress during pregnancy and offspring HPA axis sol (Giesing, Suski, Warner, & Bell, 2011). Behavioral effects
dysregulation also suggests the latter likely manifests in reac- were also noted, as juveniles exposed to prenatal stress formed
tive and regulatory components of temperament, as well as denser shoals, an effective antipredator strategy. In hares, in
their contributions to symptoms/disorders (Figure 2). utero predator stress was positively correlated to offspring
physiological stress reactivity, compromising subsequent re-
productive fitness (Sheriff, Krebs, & Boonstra, 2009, 2010).
Environment Effects That Shape Intrauterine
High maternal cortisol concentrations were linked with nonvi-
Environment and Fetal Development
able births, smaller offspring size, increased cortisol reactivity,
As environmental epigenetics concerns itself with a spectrum vigilance, and anxiety-like behaviors. Prenatally stress-ex-
of exposures capable of exerting developmental effects, we posed hares also dispersed more effectively, promoting juve-
now describe these, and established links with behavioral nile survival at a cost of reproductive output, in an example
phenotypes relevant to temperament. Stress exposure has of the “increasing glucocorticoid concentrations to survive at
been one of the most widely studied prenatal adversities. the cost of reproduction” strategy (Sheriff et al., 2009).
Human and animal studies indicate behavioral consequences Stress-related prenatal effects reflect a “calculation” aimed
for the offspring typically involve fear/anxiety and/or at improving the odds of survival and are not uniformly mal-
behavioral/emotional dysregulation. adaptive. These adaptations are of interest precisely because
of an attempt to balance the needs of the developing organ-
ism: the need for optimal development along a species-
Stress: Mechanisms, Definitions, Critical
typical timeline versus faster development advantageous for
Developmental Periods, and Epigenetic Effects
immediate survival. The speeded-up gestation translates
into alterations in cellular structure/function. Short-term
Stress response: The neuroendocrine system
benefits (i.e., faster gestation and survival) are self-evident,
In response to stress, paraventricular nucleus of the hypothalamus yet adverse health consequences in the long term are also
produces corticotropin-releasing hormone (CRH). CRH stimu- likely. DOHaD research with humans suggests that gesta-
lates the anterior pituitary to synthesize proopiomelanocortin. tional adversity, presumably resulting in fetal development
Adrenocorticotropic hormone (ACTH), a peptide derived shortcuts, translates into compromised health in adulthood,
from proopiomelanocortin, is subsequently released into the including mental health (e.g., Froehlich et al., 2009; Rose-
bloodstream. ACTH induces the adrenal glands to produce boom, de Rooij, & Painter, 2006).
cortisol in humans (corticosterone in rodents), the end The range of prenatal adversity is notably broader in
product of the HPA axis, often labeled the stress hormone humans, including stressful or life-threatening situations
(Charmandari, Tsigos, & Chrousos, 2005). A negative and maternal reactivity to these circumstances (e.g., posttrau-
feedback loop is created as cortisol binds to glucocorticoid re- matic stress disorder [PTSD]), signaled to the fetus by
ceptors in the hippocampus. This modulation of the HPA axis maternal HPA axis response (Babenko et al., 2015). Certain

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 Environmental epigenetics and temperament 1275

Table 1. Maternal neuroendocrine system response: Examples of effects on offspring development in animal and human
studies

Significant Developmental/ Developmental

Exposure Behavioral Outcome Sample Characteristics Timing of Exposure Reference

Animal Studies

Predator Egg cortisol concentrations n ¼ 6–30 fish Pre–post egg formation: Giesing et al.
Density of shoaling Measured prehatching, average 25 days (2011)
in juveniles
Fecal cortisol concentrations n ¼ 12–14 hares Late gestation: last 15 days Sheriff et al. (2009)
Body mass/length Measured at 30 hr after birth
Nestling size n ¼ 137–162 (68–92 female) Before & during ovulation: Coslovsky &
Longer wing span Measured at 2, 8, & 14 days prior to laying eggs Richner (2011)

Human Studies

Pregnancy Gray matter volume, prefrontal N ¼ 35 (17 female) Midpregnancy: measured at Buss et al. (2010)
anxiety cortex Measured at 6 & 9 years 19, 25, & 31 weeks
Cognitive control/response N ¼ 49 (20 female) Entire pregnancy: measured Mennes et al.
inhibition Measured at 17 years at 12–22, 23–31, & 32–40 (2006)
Performance decrement with dual weeks
task demands
Alterations in the dorsal prefrontal
cortex region activation
All effects for 12–20 weeks only

Note: Sample characteristics are provided in a different manner for human and animal studies, because of differences in design and presentation format. The
number of participants per condition (n) is indicated for animal experimental investigations, whereas the overall number of participants (N ) is presented for
human correlational studies. Additional information concerning numbers of male versus female participants is also provided when both sexes were in-
cluded/specified. Developmental timing of exposure indicators varies across studies. For humans, the timing is provided in terms of the number of gestational
weeks. In animals these indicators are typically more specific, often presented in terms of the number of days. () Increases in offspring physical/structural and
functional characteristics; () decreases in offspring physical/structural and functional characteristics.

stressors can be considered normative, as these generally include cognitive and allostatic processes, vulnerabilities that
occur in the context of daily life. Even routine hassles can result from early experiences and impact adaptation (Maccari
become problematic, however, especially in concert with et al., 2016), yet research examining prenatal effects of stress
symptoms of depression and anxiety (Diego et al., 2006). has generally relied on unidimensional operational definitions.
Although the majority of maternal cortisol (80%–90%) in In fetal programming research, operationalizations of stress in-
the placenta is metabolized, higher concentrations of cortisol clude traumatic events (e.g., exposure to interpersonal violence
can disrupt this process, exposing the fetus to higher or natural disasters), psychosocial stress (e.g., daily hassles/
levels (Meyer, 1985). Increased maternal HPA axis activity stressful events), physiological stress reactivity (e.g., cortisol
and resultant cortisol production is thought to downregulate concentrations), and symptoms of anxiety and depression
placental corticosteroid 11-b-dehydrogenase isozyme 2 (Table 2). Multiple studies rely on broad definitions of stress,
(11b-HSD-2), which metabolizes cortisol into inactive for example, combining indicators of psychosocial stress and
cortisone (O’Donnell et al., 2012). This reduced ability to symptoms of psychopathology (e.g., anxiety and depression;
increase placental 11b-HSD-2 with an acute stressor is likely Nieratschker et al., 2014). Thus, the literature does not cur-
critical to intergenerational transmission. That is, women who rently provide the basis for making meaningful distinctions
do not present with elevated cortisol during pregnancy, dem- with respect to the type of stressor in terms of consequences
onstrating a “blunted” response to chronic stress (Keeshin, for the offspring. Another challenge in examining stress with
Strawn, Out, Granger, & Putnam, 2014; Yehuda & Seckl, human populations is that exposures are often confounded,
2011), can nonetheless transmit exceedingly high levels of such as psychosocial/sociodemographic stress being accompa-
cortisol to the fetus with 11b-HSD-2 downregulation. nied by maternal substance use. Confounding effects are
somewhat mitigated in quasi-experimental studies wherein
stress response/adaptation data are collected in the aftermath
Prenatal stress exposure: Evidence of behavioral/ of a disaster (Tees et al., 2010; Yong Ping et al., 2015). This
temperament risk approach takes advantage of events that impact large numbers
of individuals in a manner that is random with respect to poten-
Human conceptualizations of stress and empirical studies. tial confounds. However, stress in the aftermath of a disastrous
Highly conceptual definitions of human stress evolved to event does not impact all affected to the same extent, and indi-

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Table 2. Examples of in utero stress exposure effects: Temperament-related outcomes for human and animal studies

Significant Developmental/Behavioral Developmental

Exposure Outcome Sample Characteristics Timing of Exposure Reference

Human Studies
1276

Maternal Stress

911 Basal cortisol concentrations, especially N ¼ 38 (male & female) Entire pregnancy: measured Yehuda et al. (2005)
with 3rd trimester exposure Measured at 12 months postpartum
Hurricane Katrina Temperamental difficulty with perinatal N ¼ 288 (male & female) Entire pregnancy: measured Tees et al. (2010)
PTSD Measured at 2 and 12 at delivery
months
Iowa floods Cortisol reactivity/separation with N ¼ 94 (48 female) Entire pregnancy: measured Yong Ping et al.
maternal prenatal stress Measured at 29–34 months within 3 months of delivery (2015)
Anxiety, depression Attenuation (flattening) of diurnal N ¼ 58 (29 female) Entire pregnancy: measured van den Bergh et al.
cortisol profile with anxiety at 12–22 Measured at 14–15 years at 12–22, (2008)
weeks 23–32, & 32–40 weeks
Emotional stress, general Fearful reactivity to novelty with N ¼ 102 (45 female) Entire pregnancy: measured Möhler et al. (2006)
psychopathology emotional stress across pregnancy Measured at 4 months at 2 weeks postpartum
Anxiety Regulatory capacity/orienting N ¼ 90 (44 female) Early–mid pregnancy: van den Heuvel
Measured at 10 months measured at 20 weeks et al. (2016)
Stress, anxiety depression, Negative emotionality, with 3rd N ¼ 247 (male & female) Entire pregnancy: measured Davis et al. (2007)
HPA-axis response trimester maternal cortisol Measured at 2 months at 18–20, 24–26, & 30–32
Negative emotionality with prenatal weeks
anxiety/depression scores across
pregnancy
Stress, anxiety, depression Temperamental difficulty with prenatal N ¼ 107 (male & female) Entire pregnancy: measured Della Vedova et al.
depression, not anxiety Measured at 3 months at 28–36 weeks, postpartum (2006)
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Stress, anxiety depression, Cortisol reactivity/painful event with N ¼ 116 (55 female) Entire pregnancy: measured Davis et al. (2007)
HPA-axis response maternal cortisol late 2nd/3rd trimester Measured at 24 hr after at 15, 19, 25, 31, & 36
Behavioral recovery with maternal birth weeks
cortisol early 2nd trimester, stress across
pregnancy
Stress, anxiety, depression Negative emotionality & fear N ¼ 282 (126 female) Entire pregnancy: measured Nolvi et al. (2016)
Falling reactivity/recover from distress Measured at 6 months at 14, 24, & 34 weeks
Trauma (lifetime/prenatal), Behavioral recovery/social stressor with N ¼ 23 (12 females) Majority of pregnancy & Bosquet Enlow et al.
PTSD, depression maternal traumatization (controlling for Measured at 6 months postnatal period: measured (2011)
symptoms) at 6 months

Animal Studies

Stress

Foot shock Anxiety-like behavior n ¼ 11–28 mice/condition Midgestation: E12 Golub et al. (2016)
(5–14 females)
Measured at PND9
Forced swim & observing Anxiety-like behavior n ¼ 10 rats/condition Mid–late gestation: E6–16 Nazeri et al. (2015)
forced swim (females) (5 females)
PND40
Observing foot shock Anxiety/depression-like behavior n ¼ 6 rats/condition (males Mid–late gestation: Abe et al. (2007)
Basal corticosterone only) E13–20
Measured at PND60 & 120
1277

Dexamethasone Corticosterone reactivity n ¼ 6–13 monkeys/ Mid–late gestation: 22 deVries et al. (2007)
administration condition weeks–birth
Measured at 12–14 months

Note: Sample characteristics are provided in a different manner for human and animal studies, beause of differences in design and presentation format. For human correlational studies, the overall number of par-
ticipants (N ) is presented, whereas the number of participants per condition (n) is indicated for animal experimental investigations. Additional information concerning numbers of male versus female participants is
provided, when both sexes were included/specified. Developmental timing of exposure indicators vary across studies. For humans, the timing is generally provided in terms of the number of gestational weeks,
whereas in animals these indicators are typically more specific, counting embryonic days. () Increases in temperament-related behaviors/displays and/or stress exposure; () decreases in temperament-related be-
haviors/displays and/or stress; HPA, hypothalamus–pituitary–adrenal; PTSD, posttraumatic stress disorder; E, embryonic day; PND, postnatal day.
 1278 M. A. Gartstein and M. K. Skinner

viduals subject to prior socioeconomic or psychosocial stress have noted consistent links between exposure to prenatal
likely fare worse. stress and compromised neurodevelopment (e.g., neurogen-
In one study making use of this quasi-experimental design, esis; Antonelli, Pallares, Ceccatelli, & Spulber, 2016; Fatima,
women exposed to the World Trade Center attacks during preg- Srivastav, & Mondal, 2017). Stress-related fetal program-
nancy were followed, along with their offspring. This research ming research in humans is limited by its correlational nature
focused on PTSD and physiological stress reactivity in the and reliance on quasi-experimental designs that inherently
wake of this human-made disaster (Yehuda, 2002; Yehuda lack internal validity afforded by the animal models, with
et al., 2005). Maternal PTSD symptoms were associated with the latter serving to further inform these connections.
lower infant cortisol concentrations, with most pronounced ef-
fects in their third trimester (Yehuda et al., 2005). Toddlers
whose mothers were exposed to Iowa floods during pregnancy Animal models of prenatal stress exposure. Investigations of
demonstrated increased cortisol reactivity to a separation. prenatal stress effects in animals provide an opportunity to di-
Higher subjective distress was linked with greater HPA axis rectly manipulate key parameters (i.e., frequency, severity,
reactivity for girls only, and more pronounced effects were and duration) of stress induction procedures, such as exposure
associated with later term exposure (Yong Ping et al., 2015). to novel environments, subcutaneous injections of saline,
Prenatal stress effects were also noted earlier in gestation, restraint, and predator proximity. Injections of synthetic
with higher self-reported maternal anxiety at 12–22 weeks glucocorticoids have also been utilized to induce conditions
predicting child HPA axis alterations. Female offspring only that parallel high levels of physiological stress reactivity.
exhibited depression in association with hyporeactivity (Van These exposures impact the developing fetus, altering off-
den Bergh, Van Calster, Smits, Van Huffel, & Lagae, 2008). spring neurobiology and behaviors into adulthood (Table 2).
In the short term, stress is expected to produce an increased A widely used restraint stress procedure resulted in anxi-
HPA axis response that translates into higher cortisol concen- ety-like behavior (decreased time spent in open arms of the
trations, yet the HPA axis downregulates after chronic periods elevated plus maze) for prenatally stressed males, with down-
of elevated stress (Gunnar & Vazquez, 2001). Child stress regulation of glucocorticoid receptors described as a potential
reactivity is associated with negative emotionality (e.g., fear/ mechanism behind these effects and long-term HPA axis
behavioral inhibition; Perez-Edgar et al., 2008), which can alterations (Maccari et al., 2003). Another prenatal stress
be measured via behavioral and physiological indicators paradigm involves the use of electric shock as an analogue
(e.g., cortisol), and has been examined in conjunction with a for human trauma exposure (Golub, Kaufman, Campbell,
spectrum of maternal prenatal symptoms. Li, & Donald, 2006). Prenatally stress-exposed offspring
A number of studies indicated associations between mater- demonstrated increased duration and frequency of ultrasonic
nal anxiety and depression during pregnancy and infant calls (sign of distress) during separation from mothers and
negative emotionality as well as dysregulation. Mothers spent less time in open arms of the elevated plus maze, com-
with higher prenatal emotional stress were more likely to pared to controls. Another stress induction manipulation re-
have infants lower in fearfulness (Mohler, Parzer, Brunner, lies on a forced swim test in the physical stress condition,
Wiebel, & Resch, 2006). This diminished fear was inter- with the psychological stress group observing those experi-
preted as potential behavioral risk, possibly contributing to encing physically stressful conditions. Female, but not
externalizing disorders, such as attention-deficit/hyperactiv- male, rat offspring exposed to both stress conditions demon-
ity disorder (ADHD; Mohler et al., 2006). Maternal anxiety strated a decreased number of entrances into open arms of the
during pregnancy was associated with poor infant self-regu- elevated plus maze indicative of anxiety, relative to controls
lation, likely setting the stage for later behavioral and (Nazeri et al., 2015). Abe at al. (2007) induced psychological
emotional difficulties (van den Heuvel, Johannes, Henrichs, stress in pregnant rats during the last trimester of gestation by
& Van den Bergh, 2015). In the Davis et al. (2007) study, pre- having animals observe an electric shock administration
natal anxiety and depression averaged across pregnancy were procedure. In comparison with control animals, exposed
both significantly correlated with infant negative reactivity. male offspring showed enhanced emotionality in an open
Della Vedova (2014) obtained somewhat divergent results field test, depression-like behavior in a forced swim test,
controlling for socioeconomic and partner/relationship fac- and increased HPA axis activity (higher basal plasma
tors in predicting difficult temperament, a construct reflecting corticosterone levels). In nonhuman primates, administration
high negative emotionality. Prenatal depression and state of dexamethasone resulted in an exaggerated corticosterone
anxiety in the postnatal periods emerged as independent response to a mild stressor (blood sampling) for the offspring
predictors (Della Vedova, 2014). of mothers who received the highest dose (de Vries et al.,
Whereas late-term effects of stress exposure are thought to 2007). In this paradigm, there is no environmental exposure
interfere with critical steps in fetal HPA axis development, to stress per se; however, the synthetic glucocorticoid admin-
early gestation effects likely result from cortisol impacting istration is intended to mimic stress exposure effects, specif-
cell migration and interacting with additional pathways ically HPA axis reactivity. Although this approach in a sense
(e.g., serotonin signaling pathway) involved in brain develop- provides a “short cut” eliminating the need for an exposure
ment (Beijers, Buitelaar, & de Weerth, 2014). Recent reviews manipulation, it does not reflect complexities of the physio-

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 Environmental epigenetics and temperament 1279

logical stress response, which may also involve dampening of ker et al. (2014) examined the impact of prenatal stress on
HPA axis reactivity with prolonged exposure. methylation in human infants, monkeys, and rats, utilizing a
Thus, prenatal stress has been shown to significantly alter genome-wide approach and identifying conserved differen-
offspring development across human and animal studies, tially methylated genes. Across species, 30 genes were
with a range of physiological and behavioral effects. Whereas associated with differential methylation as a result of prenatal
animal studies suggest primarily anxiety-like behavioral ef- stress. The protein coding the microrchidia homolog (mouse)
fects, human outcomes were more varied, with some indication family CW-type zinc finger protein 1 gene (MORC1) was
of risk for externalizing symptoms (Mohler et al., 2006). Prom- emphasized as a candidate genetic marker of prenatal stress,
inent late-gestation effects were reported (e.g., Yehuda et al., due to its prior associations with major depressive disorder
2005) and suggest disruption of fetal HPA axis development, (Nieratschker et al., 2014). Thus, most human research to
yet early gestational impact of stress was noted as well (Golub date addressed methylation of candidate genes, and the only
et al., 2016). Crews (2010) argued neuronal and behavioral genome-wide study did not make any connections with
plasticity, or the genotype’s ability to produce variable pheno- behavioral outcomes, which remains to be accomplished in
types in response to environmental inputs, peaks during future investigations.
embryonic development. Thus, early and later term gestational
exposure to stress appears to impact behavioral phenotypes re- Animal studies. In animal studies, DNA methylation changes
lated to temperament, albeit via different developmental path- explained the influence of maternal prenatal stress on the
ways. Sex differences were documented (e.g., Nazeri et al., density of glucocorticoid receptors in the fetal brain (hippo-
2015); however, a consistent pattern has not emerged. Further campus in particular), thought to alter sensitivity to stress
study is required in part because females have not always been throughout the life of the offspring (Babenko et al., 2015;
included. Epigenetic mechanisms are critical to connections Weaver et al., 2004). Restraint stress during gestation resulted
between prenatal stress and subsequent behavioral/tempera- in altered CRH DNA methylation in the hypothalamus and
ment development. We now turn to the emerging literature increased anxiety-like behavior (e.g., decreased entries into
demonstrating epigenetic processes play a key role in the open maze arm; Xu, Sun, Gao, Cai, & Shi, 2014). Restraint
intergenerational transmission of stress-related risk, conferring stress during the last 10 days of gestation also resulted in
environmental adversity to the offspring. anxiety-like behavior for adult offspring and altered RLN
gene expression. Specifically, higher levels of DNA
methylation in the promoter region were associated with de-
Prenatal stress exposure: Epigenetic effects
creasing mRNA expression in the cortex following exposure.
Human studies. Consistent with the environmental epigenetics The latter is significant because RLN is responsible for the
perspective, multiple studies indicate that epigenetic processes, protein Reelin, which regulates brain development through
DNA methylation in particular, provide a critical bridge be- cytoskeleton modifications. Thus, DNA methylation appears
tween prenatal stress exposure, offspring brain development, to provide a critical bridge between prenatal stress, offspring
and shifts in physiology/behavior relevant to temperament. brain development, and shifts in physiology/behavior relevant
Maternal depression and anxiety during pregnancy were to temperament.
associated with increased infant methylation of NR3C1, which
predicted higher infant salivary cortisol stress response (Ober-
Toxicant Exposure: Pesticides and Environmental
lander et al., 2008). Maternal pregnancy-related anxiety was
Contaminants
also positively associated with infant NR3C1 methylation
(Hompes et al., 2013). There is some indication of sex A similar picture emerges for toxicant in utero programming,
differences in the NR3C1 stress-related methylation shifts. wherein epigenetic processes link exposure to temperament
Methylation levels were elevated as a function of prenatal stress outcomes. A variety of environmental contaminants, such
for female, but not male, infants, and increased methylation as lead, dichlorodiphenyltrichloroethane (DDT), polychlori-
was positively associated with fearfulness for females only nated biphenyls (PCBs), and bisphenol A (BPA), have been
(Ostlund et al., 2016). Methylation of the serotonin transporter investigated. As noted in a recent review, multiple animal
gene (solute carrier family C6, member 4 [SLC6A4]) was also studies and a more limited human literature suggest that pre-
affected by neonatal intensive care unit-related stress. Increased natal toxicant exposure alters neurodevelopment, setting the
methylation of the SLC6A4 gene was noted for preterm, com- stage for potentially risky temperament and symptoms/be-
pared to full-term, infants. SLC6A4 methylation status was neg- havior problems (Antonelli et al., 2016).
atively correlated with mother report of infant duration of ori-
enting and approach for the preterm infants only (Montirosso
Endocrine disruptors (BPA, Vinclozolin, DDT,
et al., 2016). However, NR3C1 and SLC6A4 are not the only
diethylstilbestrol [DES], PCB): Developmental effects
genomic conduits of prenatal stress effects, and a recent review
implicated altered expression of 31 genes in prenatal origins of Endocrine disruptors are exogenous substances capable of
anxiety-like behavior (Nieto, Patriquin, Nielsen, & Kosten, dysregulating the endocrine system primarily by binding to
2016). Perhaps in the most definitive study to date, Nieratsch- hormone receptors, disrupting cell signaling pathways, and

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Table 3. Examples of in utero toxicant exposure effects: Temperament-related outcomes in human and animal studies

Significant Developmental/ Developmental

Exposure Behavioral Outcome Sample Characteristics Timing of Exposure Reference
1280

Human Studies

BPA Emotional reactivity, aggressive (males) N ¼ 198 (111 female) Entire pregnancy: measured Perera et al. (2012)
Anxiety/depression, aggression (females) Measured at 3–5 years at about 34 weeks
ADHD at 4 years; stronger N ¼ 438 (206 female) 1st trimester & entire Casas et al. (2015)
effect for males & 3rd Measured at 1, 4, & 7 years pregnancy: measured at 12 &
trimester concentrations 32 weeks
DDT Total difficulties (emotional, conduct, N ¼ 270 (140 female) Entire gestation: measured at Sioen et al. (2013)
hyperactivity, & peer problems); females Measured at 7–8 years birth
only
DES Depression, anxiety N ¼ 660 (315 female) 1st–3rd trimesters: treatment Vessey et al. (1983)
Measured in adulthood 6–35 weeks
PCB Impulsivity N ¼ 293 (male & female)/n ¼ 173 Entire pregnancy: measured Stewart et al. (2005)
nonexposed; n ¼ 40 (lower, middle, & at birth
upper exposure groups)
Measured at 8 & 9.5 years
ADHD symptoms N ¼ 607 (288 female) Entire pregnancy: measured Sagiv et al. (2010)
Measured at 7–11 years at birth
Lead Anxious/depressed, withdrawn, sleep N ¼ 577 (males & females) Entire pregnancy: measured Factor-Litvak et al.
problems, somatic problems, aggressive, & Measured at 3 years at birth (1999)
destructive behavior
Adolescent delinquent & antisocial N ¼ 195 (males & female) Early pregnancy: 1st trimester Dietrich et al. (2001)
behaviors Measured 15–17 years
Hyperactivity, emotional problems (males N ¼ 270 (140 female) Entire pregnancy: measured Sioen et al. (2013)
only) Measured at 7–8 years at birth
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Activity at 12 months (stronger for males) N ¼ 206 (107 females) Entire gestation: measured at Vermeir & Viaene
Inattention, withdrawal Measured at 12, 24, & 36 months birth (2007)
Total problems at 24 & 36 months
Disrupted activity level (males only) n ¼ 6–9/condition (males & females) Periconceptional/postnatal: Leasure et al. (2008)
Measured at 1 year until PND10

Animal Studies

BPA Anxiety-like behaviors n ¼ 16–30 rats/condition (9–14 female) Entire gestation: administered Kundakovic et al.
(females)/males Measured at PND30–40 until birth (2013)
Chasing behavior (males)
Aggression
Vinclozolin Response extinction following n ¼ 14–20 rats/condition (7–10 female) Perinatal: E14–PND3 André & Markowski
reinforcement withdrawal (males) Measured at PND60–80 (2006)
Immature social play, hyperactivity-like n ¼ 12–22 rats/condition (6–11 female) Perinatal: E14–PND3 Colbert et al. (2005)
behaviors; effect stronger for males Measured at PND22 & 34
DES Aggression n ¼ 16–26 mice /condition (12–13 Midgestation: E11–17 Palanza et al. (1999)
female)
Measured at PND60–90
PCB Passive avoidance test deficits (males) n ¼ 10–12 rats/condition (5–6 female) Perinatal: E15–19, PND1–21 Colciago et al. (2009)
Measured at PND60
Mercury Responding during the reinforcement n ¼ 3–8 rats/condition (males & Periconceptional/postnatal: Reed et al. (2006)
omission trials females) until PND16
Measured in adulthood
1281

Note: Sample characteristics are provided in a different manner for human and animal studies, because of differences in design and presentation format. For human correlational studies, the overall number of par-
ticipants (N ) is presented, whereas the number of participants per condition (n) is indicated for animal experimental investigations. Additional information concerning numbers of male versus female participants is
provided, when both sexes were included/specified. Developmental timing of exposure indicators vary across studies. For humans, the timing is generally provided in terms of the number of gestational weeks,
although in some instances measures are just taken at birth, or not specified beyond a particular trimester or month. For animals, these indicators are more specific, counting embryonic or postnatal days. () Increases
in temperament-related behaviors/displays; () decreases in temperament-related behaviors; BPA, bisphenol A; ADHD, attention-deficit/hyperactivity disorder; DDT, dichlorodiphenyltrichloroethane; DES, die-
thylstilbestrol; PCB, polychlorinated biphenyls; E, embryonic day; PND, postnatal day.
 1282 M. A. Gartstein and M. K. Skinner

inhibiting hormone synthesis. These contaminants interfere to temperament: decreased novelty preference in infancy
with physical development, especially of the reproductive (Boucher, Bramoullé, Djebbari, & Fortin, 2014) and higher
and central nervous systems, which translates into alterations ADHD problems for school-age children (Sagiv et al., 2010).
in emotional functioning, attentional, and behavioral regula- Although most often examined in the context of physical
tion components of temperament. Epigenetic mechanisms development and cognitive functioning, associations with be-
are critical to the profound effects of endocrine disruptors havioral changes reflective of temperament were also noted
on developmental cascades, as exposure to these toxic agents for all of the considered contaminants.
introduces changes in gene expression (Manikkam, Guerrero-
Bosagna, Tracey, Haque, & Skinner, 2012). Existing studies Animal studies. The animal literature speaks to similar links
with humans indicate consistent links between gestational en- between toxicant exposures and behavioral/temperament out-
docrine disruptor exposure and behavioral shifts, albeit typi- comes, indicating that prenatal effects can be transgenera-
cally without addressing epigenetics. tional in nature. BPA exposure induced largely sexually di-
morphic behavioral changes in young adult mice (Table 3).
Human studies. Prenatal BPA exposure and child behavior Chasing behavior in males was reduced to levels similar to fe-
problems were linked, controlling for postnatal BPA effects, males. Anxiety-like behaviors in an open field increased in
with a sex-dependent pattern of results (Perera et al., 2012). females, decreasing in males, with elevations in aggression
Boys with greater exposure received elevated emotionally re- noted for both sexes as a result of prenatal BPA exposure
active and aggressive ratings (Table 3). Among girls, higher (Kundakovic et al., 2013).
exposure was associated with significantly lower anxious/de- André and Markowski (2006) examined learning behavior
pressed and aggressive scores. Casas et al. (2015) examined following perinatal exposure to vinclozolin, an endocrine dis-
programming effects of prenatal BPA exposure and reported ruptor with antiandrogenic effects. Acquisition of a rein-
increased ADHD symptoms at 4 years of age. forced response was not affected. However, males exposed
Stronger associations were observed for boys, compared to to vinclozolin perinatally did not demonstrate any response
girls, with greater third, rather than with first, trimester effects. extinction once food was no longer available, suggesting an
These results suggest sex-specific mechanisms of BPA expo- alteration in sensitivity to reward/approach. In addition, Col-
sure may in part be determined by the timing of prenatal effects. bert et al. (2005) demonstrated an effect of perinatal vinclozo-
DDT is arguably the most widely used agricultural insecti- lin exposure on social behaviors. Males exposed during ges-
cide, with adverse health effects. Technical grade DDT includes tation and lactation demonstrated an increase in social play
a number of impurities and its breakdown product dichlorodi- marked by more frequent initiation behavior, interpreted as
phenyldichloroethylene (DDE) is able to cross the placenta a sign of hyperactivity and developmental delay.
and pass into breast milk (You et al., 1999). We located one Behavioral consequences of DES exposure were charac-
study linking DDE exposure and emotional/behavioral indica- terized in animal studies investigating developmental effects,
tors. Sioen et al. (2013) reported a significant positive associa- also using this compound as a positive control. (Palanza, Par-
tion between prenatal DDE exposure and overall emotional/be- migiani, Liu, and vom Saal (1999) reported that prenatal ex-
havioral difficulties for 7- to 8-year-old girls, but not boys. posure to DDT and DES increased the frequency of same-sex
DES, an estrogenic drug, was wrongly administered to aggression for male and female mice, at low doses only.
millions of pregnant women (until 1971 in the United States) There was a difference in DDT and DES effects, as males ex-
in an effort to prevent spontaneous abortions and promote posed to the lowest DDT dose only exhibited less intense at-
healthy development (Swan & vom Saal, 2001). In humans, tacks than controls.
adverse effects of DES exposure were documented for the PCB exposure in rodents has been largely studied perina-
women as well their offspring (Giusti, Iwamoto, & Hatch, tally, with animals affected during lactation as well as gesta-
1995; Greenberg et al., 1984). Most relevant with respect to tion, because this time frame corresponds to a critical brain
temperament, adult offspring exposed to DES during most sex differentiation period (Colciago et al., 2009). Perinatal
of gestation were more likely to experience symptoms of de- PCB exposure was shown to result in a dimorphic pattern
pression and anxiety, along with other psychiatric concerns, of hypothalamic testosterone activating enzyme expression.
compared to those not exposed in utero (Vessey, Fairweather, A learning deficit on a passive avoidance test was also noted,
Norman-Smith, & Buckley, 1983). as exposed males failed to develop an increased latency to en-
PCBs are the most common among endocrine disruptors ter an area associated with a previously delivered foot shock
(Casati, Sendra, Sibilia, & Celotti, 2015) because of their ex- (Colciago et al., 2009). This apparent decrease in sensitivity
tensive use in dielectric and coolant fluids, no longer pro- to cues of danger represents an aspect of fearful reactivity
duced due to their toxicity and persistence. Chronic exposure and reflects PCB effects on temperament development.
to low levels of PCBs is of particular concern given evidence Prenatal endocrine disruptor exposure resulted in tempera-
of cumulative endocrine, metabolic, and behavioral effects ment development alterations, including increased anxiety-
(Casati et al., 2015; Colciago et al., 2009; Stewart et al., like and playful/aggressive behavior. There is also indication
2008). Disruption of neurodevelopment for prenatally ex- of sex differences. Learning paradigms are not directly ap-
posed offspring was associated with manifestations relevant plicable to temperament; however, sensitivity to cues of re-

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 Environmental epigenetics and temperament 1283

ward versus punishment can be a function of relative ap- learning in exposed animals, with human research showing
proach and avoidance activation. Both neurobehavioral sys- an increased risk for ADHD and behavior problems more
tems appear compromised by prenatal exposure to androgen broadly (Dietrich et al., 2001; Kundakovic et al., 2013; Pie-
disruptors. Before we consider epigenetic mediation of envi- drafita, Erceg, Cauli, & Felipo, 2008). This pattern of results
ronmental toxicant in utero effects, other contaminant expo- implicates reactivity (e.g., reward/approach orientation vs.
sures should be noted. fearfulness/behavioral inhibition) and regulation (i.e., deficits
in emotional/behavioral control), indicating temperament is
impacted by maternal contact with toxicants during gestation.
Lead and mercury prenatal exposure: Developmental
There is evidence that male offspring may be more affected
effects
(Andre & Markowski, 2006; Colciago et al., 2009), and lower
Human studies. In humans, prenatal exposure effects of lead concentrations of contaminants, as opposed to higher levels
have been demonstrated into adolescence, with more fre- of exposure, may be more detrimental in some instances (Lea-
quent/severe behavior problems, delinquent and antisocial sure et al., 2008; Palanza, Parmigiani, & vom Saal, 2001).
behaviors, considering multiple covariates (Dietrich, Ris, Critical shifts in the epigenome were shown to occur as a
Succop, Berger, & Bornschein, 2001). Sioen et al. (2013) re- function of prenatal environmental contaminant exposure.
ported a significant positive association between prenatal lead
exposure and hyperactivity for 7- to 8-year-old children, con-
Environmental contaminants: Epigenetic effects
trolling for other contaminants. Prenatal lead exposure effects
included increased activity and deficits in focused attention at Human studies. A recent review considered 23 studies linking
12 months, as well as greater behavioral difficulties in the tod- environmental contaminant exposure and offspring DNA
dler period (Vermeir & Viaene, 2002–2007). Lead exposure methylation changes to autism spectrum disorders (Keil &
was associated with compound effects, acting in concert with Lein, 2016). Consistent with the environmental epigenetics
prenatal substance use. Specifically, the risk for ADHD in- framework, methylation changes were described as mediating
creased for children prenatally exposed to nicotine along environmental risk and conferring these effects onto behav-
with lead (Froehlich et al., 2009). ioral phenotypes via alterations in gene expression and brain
Thus, in utero lead exposure in humans has been well char- development. Shifts in the methylome and brain development
acterized in terms of contributing to impulsivity/approach as- that result from in utero contaminant exposures and contrib-
pects of temperament and difficulties with attention/regulation. ute to risk for autism spectrum disorders can also be expected
to affect temperament.
Animal studies. Animal studies offer more conclusive links,
examining prenatal mercury as well as other contaminant ex- Animal studies. Animal studies provide additional insights
posures, noting potential sex differences and potency of low- into epigenetics bridging toxicant exposure in the womb
dose exposures. Perinatal methylmercury (derived from mer- and behavioral effects. Studies using BPA and vinclozolin
cury) exposure has been studied primarily in tandem with provide evidence of transgenerational inheritance via perma-
PCB, as these contaminants are typically traced to the same nent alterations in the epigenome of the germ line (Anway &
source (Newland & Paletz, 2000). Learning-related effects Skinner, 2008). Skinner et al. (2008) reported a sexually di-
of prenatal exposure have been the main focus of research, morphic disruption of transcription in the hippocampus and
with some findings relevant to temperament (Table 3). Spe- amygdala, and associated behavioral effects. Third-genera-
cifically, prenatal mercury exposure in rats resulted in ele- tion female rats from the vinclozolin-exposed line exhibited
vated rates of responding in an operant learning procedure, increased anxiety-like behaviors, whereas male rats displayed
even when selenium intended to ameliorate adverse effects a decrease. Crews et al. (2007) examined rat mate preference
of methylmercury was administered to the animals. High rates in a task that engaged multiple brain regions including amyg-
of responding during reinforcement omission trials indicated dala, hippocampus, cingulated cortex, and anterior hypotha-
prenatal mercury exposure enhanced the efficacy of reinforce- lamus. Third-generation vinclozolin lineage males were less
ment (Reed & Newland, 2007), potentially leading to mani- attractive to females, reflecting a differential mate preference.
festations of impulsivity and/or reward dependency relevant This study offers evidence of epigenetic transgenerational in-
to temperament. Male, but not female, mice demonstrated heritance with evolutionary implications, as exposure effects
decreased spontaneous motor activity, yet increased ampheta- translated into methylome shifts, in turn producing changes
mine-induced motor activity, and altered dopamine levels. critical to reproductive success.
With respect to prenatal lead exposure, related sequelae Luo et al. (2014) investigated histone modifications as the
were consistently more notable in animals assigned to the mediator of lead-related effects in rats, linking prenatal expo-
low-dose condition (Leasure et al., 2008). sure to ADHD-like behaviors. A dose–response relationship
The range of prenatal contaminant effects is extensive, was observed, as increased lead exposure resulted in greater lo-
with a number of behavioral consequences relevant to tem- comotor activity, an analogue of human hyperactivity. Histone
perament. Animal studies demonstrate fearful/anxious acetylation was significantly increased in the hippocampus as a
behaviors, disruptions of social behavior, and reinforcement result of chronic lead exposure, supporting the role of this epi-

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Table 4. Examples of in utero substance/psychotropic Medication exposure effects: Temperament-related outcomes in human and animal studies

Significant Developmental/ Developmental

Exposure Behavioral Outcome Sample Characteristics Timing of Exposure Reference

Human Studies

Alcohol Cortisol reactivity, heart rate, & negative N ¼ 55 (21 female) Entire pregnancy: measured at 28 Haley et al. (2006)
affect 5–7 months weeks, 6 months postpartum
Difficult temperament N ¼ 1330 (625 female) Early pregnancy (0–6 weeks): Alvik et al. (2011)
Measured at 6 months measured at 17 weeks
Emotional withdrawal, conception N ¼ 144 (67 female)/92 Perinatal/postpartum: measured at Molteno et al. (2014)
exposure only exposed about 24 weeks, 1 month
Activity level, prenatal exposure only Measured at 6.5 months postpartum
Nicotine Response in the anterior cingulate cortex N ¼ 178/38 exposed (104 Entire pregnancy: measured Holz et al. (2014)
during a conflict task engaging executive female) postpartum
functions Measured at 25 years
Temperamental anger N ¼ 611/366 exposed (370 Entire pregnancy: measured in 3rd Liu et al. (2011)
1284

female) trimester
Measured at 38-48 years
Cannabis Depression, 1st & 3rd trimester effects N ¼ 633 (317 female) 1st & 3rd trimesters: measured at Gray et al. (2005)
Measured at 10 years 3rd & 7th month prenatally
Aggression, females only N ¼ 4077 (2060 female)/88 Early pregnancy: measured in 1st El Marroun et al. (2011)
exposed trimester
Measured at 18 months
Cocaine Behavior problems only for reactive N ¼ 220 (112 females)/119 Entire pregnancy: measured 4–8 Eiden et al. (2011)
exposed children, with low maternal warmth exposed weeks postpartum
Measured at 7, 13, & 18
months
Hyperactivity, with any prenatal exposure; N ¼ 473 (50 females)/204 Entire pregnancy: measured Delaney-Black et al.
males only exposed throughout pregnancy & at birth (2004)
Measured at 6–7 years
SSRI Motor, social–emotional, & adaptive N ¼ 83 (59 females)/31 Entire pregnancy: measured at 36 Hanley et al. (2013)
behavior exposed weeks
Measured at 10 months
Early evening basal cortisol levels N ¼ 76 (42 female)/31 Entire pregnancy: measured at Oberlander et al. (2008)
exposed 2nd trimester & birth
Measured at 3 months
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Fetal motor activity at 15–19 & 27–29 N ¼ 263 (136 female)/133 Entire pregnancy: measured at Mulder et al. (2011)
weeks, standard/high doses only exposed 15–19 weeks & birth
Measured at 15–19,
27–29, & 38 weeks
Behavioral pain responses N ¼ 61 (males & females)/38 Entire pregnancy: measured at Oberlander et al. (2002)
Parasympathetic cardiac modulation exposed 2nd trimester & birth
Measured at 2nd day
Serum CBG levels, following vaginal N ¼ 65 (35 females)/exposed Entire pregnancy: measured at Pawluski et al. (2012)
delivery only n ¼ 25 2nd trimester & birth
CBG levels linked to diurnal change in Measured at birth
cortisol

Animal Studies

Alcohol ADHD-like behaviors (males) n ¼ 8 rats/condition (males Mid–late gestation: E8–20 Atalar et al. (2016)
only)
Measured at PND30–55
Aggressive play behavior (males) n ¼ 16 rats/condition (males Entire gestation: E1–PND1 Hamilton et al. (2014)
only)
Measured at PND90
1285

Anxiety-like behavior (males) n ¼ 6 rats/condition (males Late gestation, shortly after birth: Baculis et al. (2015)
only) 3rd trimester equivalent, PND3–5
Measured at PND36–50
CORT in restrain stress task (males) n ¼ 25–34 rats/condition Early gestation: E7 Wieczorek et al. (2015)
ACTH in restrain stress task (females) (12–17 female)
Anxiety-like behavior (males) Measured at PND60–120
Anxiety-like behavior (females)
Nicotine Hyperactivity/impulsivity n ¼ 55–58 (males only) Entire gestation: 3 weeks before Schneider et al. (2012)
Measured between PND25 & mating till birth
PND50
Self-administration of methamphetamine n ¼ 18–19 (10 females) Mid–late gestation: E8–21 Lacy et al. (2014)
Measured at PND90
Anxiety-like behavior N ¼ 5–6 (about half female) Perinatal: E15–PND18 Lee et al. (2016)
Impulsivity Measured at PND21–22
Cannabis USVs/distress (males) n ¼ 12–26 rats/condition Perinatal: E15–PND9 Trezza et al. (2008)
Social interaction (males) (males only)
Anxiety-like behavior (males) Measured at PND12, PND35,
& PND80
Cocaine Hyperphonation-like quality in USVs n ¼ 34–50 rats/condition Entire gestation: E1–20 Zeskind et al. (2014)
(17–25 female)
Measured at PND5
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Table 4 (cont.)

Significant Developmental/ Developmental

Exposure Behavioral Outcome Sample Characteristics Timing of Exposure Reference

USVs/distress, PND25 only n ¼ 18–26 mice/condition Mid–late gestation: E8–17 Kabir et al. (2014)
Social interaction, PND25 & PND35 only (males only)
Measured at PND25, PND35,
& PND45
Fear extinguishing n ¼ 8–9 mice/condition Mid–late gestation: E8–17 Kabir et al. (2013)
Freezing response (males only)
Measured in adult animals
Anxiety-like behavior n ¼ 10–12 rats/condition Mid–late gestation: E11–PND1 Olivier et al. (2011)
Social play, self-grooming (males only)
Measured at PND28–35 &
PND87–177
Aggressive behavior (males) n ¼ 20/condition Entire gestation: E1 until birth Svirsky et al. (2016)
1286

(10 females)
Measured at PND28–31 &
PND49–52
Anxiety & depression-like behavior n ¼ 16–17/condition Perinatal: E15–PND12 McAllister et al. (2012)
(females) (females only)
Measured at PND73–83
Impulsivity (males) n ¼ 22–31/condition (9–14 Perinatal: E1–PND 21 Lisboa et al. (2007)
Depression-like behavior (females) female)
PND30 & 70 (females)
PND40 & 70 (males)

Note: Sample characteristics are provided in a different manner for human and animal studies, because of differences in design and presentation format. For human correlational studies, the overall number of
participants (N ) is typically presented. When indicated, the number of participants in the exposed subsample (n) is also included. The number of participants per condition (n) is always indicated for animal
experimental investigations. Additional information concerning numbers of male versus female participants is provided when both sexes were included/specified. Developmental timing of exposure indicators
varies across studies. For humans, the timing is provided in terms of the number of gestational weeks, although in some instances measures are just taken at birth, or not specified beyond a particular trimester or
month. In animals these indicators are typically more specific, counting embryonic days or postnatal days. () Increases in temperament-related behaviors/displays; () decreases in temperament-related be-
haviors/displays; SSRI, selective serotonin reuptake inhibitor; CBG, corticosteroid-binding globulin; ADHD, attention-deficith/hyperactivity disorder; E, embryonic day; PND, postnatal day; CORT, cortico-
sterone; ATCH, adrenocorticotropin hormone; USV, ultrasonic vocalization.
 Environmental epigenetics and temperament 1287

genetic mechanism as a mediator between toxicant exposure Tobacco use during pregnancy was also implicated in ad-
and offspring symptoms. Thus, the Luo et al. (2014) investiga- verse offspring temperament outcomes. Holz et al. (2014) per-
tion suggests prenatal lead exposure alters a temperamental formed functional magnetic resonance imaging, examining
phenotype associated with developmental psychopathology, novelty seeking and lifetime ADHD symptoms for adults pre-
namely, activity level, via an epigenetic mechanism. Together, natally exposed to tobacco. Participants with a history of in
these studies are compelling in pointing to epigenetic mecha- utero exposure exhibited a weaker response in the anterior cin-
nisms as the primary vehicle of environmental exposure effects, gulate cortex to a conflict task engaging the executive attention
as changes in the epigenome alter gene expression, with subse- system, coupled with novelty seeking/approach tendencies. Liu
quent developmental shifts often related to temperament. et al. (2011) also studied adults prenatally exposed to maternal
tobacco use and demonstrated increased anger proneness.
The main psychoactive component of cannabis, D9 -tetrahy-
Substance Use and Effects of Psychotropic Medication drocannabinol, is able to cross the placenta during gestation
(Hutchings, Gamagaris, Miller, & Fico, 1989). According to
Turning to the substance use/psychotropic medication litera-
a recent review, chronic/heavy cannabis use during pregnancy
ture, again there is evidence that environmental exposures alter
appears to disrupt brain maturation, predisposing the offspring
the epigenome, disrupting brain development and inducing
to neurodevelopmental disorders (Alpar, Di Marzo, & Har-
temperament risk for later psychopathology. Epigenetic pro-
kany, 2016). Six- and 10-year-old children prenatally exposed
cesses are just now being studied in this context, yet maternal
to cannabis presented with more frequent/severe externalizing
substance use during pregnancy is known to markedly impact
symptoms, impulsivity and hyperactivity in particular (Gold-
offspring development, with public health implications
schmidt, Day, & Richardson, 2000). Chronic maternal mari-
prompting consumption warnings.
juana use in the first and third trimesters was associated with
offspring depression at 10 years of age (Gray, Day, Leech, &
Richardson, 2005). Sex differences were noted, as prenatally
Substance (alcohol, tobacco, marijuana, cocaine) use
exposed girls (but not boys) exhibited higher aggression and
Human studies. The hazards of prenatal substance use expo- inattention at 18 months of age (El Marroun et al., 2011).
sures are well documented. There is a wealth of human research Child behavior problems were examined in the aftermath
linking in utero exposures and offspring outcomes, including of prenatal cocaine exposure, with mixed results. Several
temperament, with some longitudinal studies following affec- studies reported significant associations between prenatal co-
ted children into adulthood. caine exposure and child behavior problems (Bada et al.,
Alcohol passes through the placenta, directly affecting the 2007; Richardson, Goldschmidt, & Willford, 2009), yet
developing fetus and impacting placental functioning (e.g., others did not find direct links (Delaney-Black et al., 2004;
Ahluwalia et al., 2000). Fetal brain development effects are Eiden, Granger, Schuetze, & Veira, 2011).
considerable, evidenced by population-based estimates indi- Thus, prenatal alcohol exposure clearly disrupts neurodeve-
cating that maternal alcohol use during pregnancy was associ- lopment in humans. Nicotine and marijuana programming ef-
ated with 2.84%–4.89% of intellectual disabilities cases fects have also been described. Finally, somewhat equivocal
(O’Leary et al., 2013). The range of effects caused by prenatal findings were reported with respect to maternal cocaine use
alcohol exposure in totality is referred to as fetal alcohol spec- during pregnancy.
trum disorders (FASD), associated with deficits in intelligence
and adaptive functioning, memory, language, attention/execu- Animal studies. Animal studies inform this literature, suggest-
tive functions, and motor skills (e.g., Mattson & Riley, 1998). ing similar differences in the level of developmental impact
Most relevant for this review, prenatal alcohol exposure was for the substances examined. Prenatal alcohol effects have
linked with temperament development (Table 4). Haley, Hand- been widely studied via animal models, intended to serve
maker, and Lowe (2006) evaluated infant HPA axis response as analogues for FASD (Table 4). Atalar, Uzbay, and Karakas
and heart rate indictors in the context of a social stressor: a Still (2016) demonstrated ADHD-like behaviors in rats following
Face paradigm. Percentage of prenatal drinking days from con- prenatal alcohol exposure throughout gestation. Exposed
ception to pregnancy recognition (extending several weeks pups required more sessions to reach criterion relative to the
into gastrulation) was related to increased infant cortisol reac- control group on a reversal learning task, because of difficulty
tivity, heart rate, and negative affect, controlling for maternal inhibiting a previously reinforced response in favor of an
depression and income. In a subsequent study, maternal unreinforced/inhibited response. Moderate levels of prenatal
weekly binge drinking (5 drinks) during the first 6 weeks exposure across pregnancy achieved through voluntary con-
of pregnancy predicted infant difficult temperament and sleep- sumption of ethanol resulted in offspring play behavior
ing problems, controlling for confounds (Alvik, Torgersen, changes (e.g., increased wrestling) reflective of aggression
Aalen, & Lindemann, 2011). Prenatally alcohol-exposed in- (Hamilton et al., 2014).
fants also exhibited increased emotional withdrawal and lower Increased anxiety-like behavior in rodents was demon-
activity level, especially those later diagnosed with FASD strated across multiple studies considering effects of prenatal
(Molteno, Jacobson, Carter, Dodge, & Jacobson, 2014). ethanol exposure. High ethanol doses (delivered in vapor)

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 1288 M. A. Gartstein and M. K. Skinner

during the rat equivalent to the human third trimester of preg- were not observed during follow-up testing and thus may
nancy resulted in anxiety-like behavior (Baculis, Diaz, & not be long term (Kabir et al., 2014). Kabir, Katzman, and
Valenzuela, 2015). Moreover, basolateral amygdala, gluta- Kosofsky (2013) evaluated the impact of prenatal cocaine ex-
matergic, and GABAergic synaptic transmission was impli- posure on rodent recall of extinguished cue-conditioned fear
cated in the observed behavioral alteration (Baculis et al., using foot shock and observed significant increases in freez-
2015). Maternal alcohol treatment limited to very early stages ing for prenatally exposed mice. According to Kabir et al.
of pregnancy (equivalent to the third week postfertilization in (2013), prenatal cocaine exposure could increase the risk
humans) also disrupted brain development (Godin, Poizat, for PTSD by disrupting fear cue learning.
Hickey, Maschat, & Humbert, 2010) and HPA axis function- These animal studies compliment the human literature, in-
ing in mice, increasing anxiety-related behaviors (Wieczorek, dicating profound neurodevelopmental effects as a result of in
Fish, O’Leary-Moore, Parnell, & Sulik, 2015). Sex differ- utero exposure to alcohol. Less prominent disruptions were
ences were noted: males showed elevated corticosterone fol- noted for prenatal cocaine administration; nonetheless, tem-
lowing an alcohol injection, whereas females displayed a perament alterations increasing the risk for psychopathology
blunted adrenocorticotropic response. Anxiety-like behavior were observed. Prenatal cannabinoid and nicotine exposures
declined in exposed female mice, whereas males demon- were also implicated in long-term effects on offspring emo-
strated heightened anxiety marked by decreased exploration tional functioning/temperament, potentially signaling life-
(Wieczorek et al., 2015). Altering the timing of alcohol ad- long mental health risk.
ministration resulted in different brain malformations and
variable patterns of behavioral disruption (Murawski, Moore,
Psychotropic medication/selective serotonin reuptake
Thomas, & Riley, 2015). Animal models suggest that even
inhibitor (SSRI) use
moderate levels of prenatal exposure lead to behavioral
changes that parallel human symptomatology (Valenzuela, Human studies. Prescribed psychotropic medications, SSRIs in
Morton, Diaz, & Topper, 2012). particular, have also been linked with adverse offspring devel-
In utero exposure to nicotine produced deleterious behav- opmental effects when administered during pregnancy. Prenatal
ioral effects in rats. Exposed males showed increased hyper- SSRI exposure has been linked with multiple fetal, neonatal,
activity (more frequent entries) and impulsivity (increased and infant behavioral disturbances (Table 4). For example,
anticipatory responses; Schneider, Bizarro, Asherson, & SSRI-exposed infants displayed decreased physiological and
Stolerman, 2012). Increased responding and larger doses of behavioral responses relevant to negative emotionality in the
self-administered methamphetamine were interpreted as context of a typical neonatal painful event (Oberlander et al.,
signs of neurobehavioral changes in the exposed offspring’ 2002). Altered neonatal cortisol levels were also reported (Paw-
motivational systems linked with reward and vulnerability luski, Brain, Underhill, Hammond, & Oberlander, 2012), con-
to substance use (Lacy, Morgan, & Harrod, 2014). Nicotine trolling for maternal symptoms. In light of these observations,
exposure resulted in anxiety-like and impulsive behaviors, re- Gur, Kim, and Epperson (2013) suggested that prenatal SSRI
ducing exploration and increasing instant reward choices exposure could buffer infants from increased HPA reactivity.
(Lee, Chung, & Noh, 2016). Temperament in SSRI-exposed and nonexposed children
Several studies provide evidence of increased hyperactiv- was compared. Nulman et al. (1997) did not identify signifi-
ity and altered emotionality following prenatal cannabinoid cant differences in temperament for children of mothers using
exposure, consistent with human research. Exposed rat pups SSRI medication during pregnancy (ages 16–86 months) and
emitted more frequent ultrasonic vocalizations (USVs) indic- those not exposed. However, temperament was only assessed
ative of distress and anxiety when removed from the nest directly among children younger than 24 months, with behav-
(Trezza, Cuomo, & Vanderschuren, 2008). Adult animals ior problems examined for older participants. Nulman et al.
also demonstrated anxiety-like behavior, spending more (2002) again failed to identify differences with a very small
time in the closed arms of the maze, compared to controls sample (n ¼ 18) of SSRI-exposed children, using similarly
(Trezza et al., 2008). Prenatal cannabinoid exposure is limited measures of temperament.
thought to alter offspring emotional functioning via seroto-
nergic and dopaminergic systems (Trezza et al., 2012). Animal studies. SSRI exposure has also been evaluated in an-
Zeskind and Stephens (2004) examined the impact on pre- imals, often with perinatal/neonatal administration (Table 4).
natal cocaine exposure on distress vocalizations in human in- Rodent studies demonstrate lifelong biobehavioral alterations
fants and rat pups. A shift in the acoustic structure of rodent following perinatal exposure, including disruption of the sero-
USVs subsequent to in utero cocaine exposure paralleled hy- tonin signaling pathway development (Maciag et al., 2006)
perphonation (high-pitched cry sound) observed in humans. and increased depression-like behavior in adulthood (Ansorge,
Prenatal cocaine exposure effects on social interactions and Zhou, Lira, Hen, & Gingrich, 2004; Olivier et al., 2011).
vocalizations were studied in mice (Kabir, Kennedy, Katz- Olivier at al. (2011) examined SSRI exposure from midges-
man, Lahvis, & Kosofsky, 2014). Exposed mice emitted tation till birth. Prenatally exposed animals responded with in-
more frequent USVs and demonstrated increased interactions creased anxiety, demonstrating greater latency to begin feeding
with other animals during initial evaluations. These effects in a novel setting and increased avoidance in a conditioned

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 Environmental epigenetics and temperament 1289

aversion test. Juvenile SSRI-treated animals engaged in fewer FASD in a comparative study, assessing methylation patterns
social play behaviors. Svirsky, Levy, and Avitsur (2016) also in children (3–6 years of age) and mice prenatally exposed to
noted prenatal SSRI exposure effects on social behavior, alcohol. A total of 269 DMR were reported, with 21 involved
with increased aggression for adult males, but not females. in regulation of clustered protocadherin genes responsible for
Smit-Rigter et al. (2012) provided evidence of a potential synaptic complexity in the developing brain (Kalmady &
mechanism for serotonergic developmental effects, as SSRI Venkatasubramanian, 2009). In their review of the literature,
exposure influenced dendritic complexity in the cortex, specif- Kobor and Weinberg (2011) described critical developmental
ically serotonin receptors linked with anxiety. windows for alcohol exposure epigenetic effects: prior to
McAllister, Kiryanova, and Dyck (2012) reported a de- conception on the paternal side and maternal alcohol con-
crease in anxiety-like behavior, as perinatally SSRI exposed sumption between fertilization and implantation.
mice spent less time in the closed arms in the elevated plus A number of studies considered the role of prenatal tobacco
maze. Depression-like behavior, reflected in longer latencies exposure in altering DNA methylation in humans. Tobacco ex-
to immobility in the forced swim test, declined as a result as ex- posure was linked with a decrease in methylation of Sat2, one
posure as well. However, perinatal SSRI exposure was also as- of the repetitive elements commonly used as a proxy for mea-
sociated with increased immobility (Lisboa, Oliveira, Costa, suring genomic DNA methylation changes (Flom et al., 2011).
Venancio, & Moreira, 2007). These discrepant results could Genome-wide methylation differences in cord blood cells of
be attributed to the SSRI delivery differences. SSRIs were ad- prenatally tobacco exposed and nonexposed infants were iden-
ministered orally in the McAllister et al. (2012) study and ex- tified (Ivorra et al., 2015). Significant differences for 31 CpG
pected to reach the offspring in relatively lower concentrations. sites associated with 25 genes were observed, adjusting for
Thus, the totality of human and animal research addressing multiple comparisons. Ladd-Acosta et al. (2016) also iden-
in utero exposure to maternal substance use indicates consider- tified a methylation signature of prenatal tobacco exposure
able impact on offspring emotional/behavioral functioning rel- via a machine learning classification model, reliably differen-
evant to temperament. Emotional withdrawal and lower activ- tiating exposed and nonexposed groups. Methylation specific
ity level in the context of prenatal alcohol exposure (Molteno to 26 sites was described as a potential biomarker of in utero
et al., 2014), as well as novelty seeking and ADHD symptoms tobacco exposure. Ivorra et al. (2015) concluded that DNA
for those prenatally exposed to tobacco (Holz et al., 2014), have methylation status at birth could serve as a marker of risk asso-
temperament implications. Cannabinoid exposure during ges- ciated with prenatal environmental adversity. However, future
tation was associated with adverse behavioral effects primarily studies are required to discern clinical significance of these epi-
related to the dopaminergic system (Alpar et al., 2016) involved genetic findings, as methylation changes identified in humans
in approach/positive affectivity and regulation/effortful control. thus far have not been linked with behavioral alterations.
Sex differences were noted, with increased aggression in SSRI- DNA methylation differences between prenatally exposed
exposed males (Svirsky et al., 2016). Exposure effects vary by to SSRIs and nonexposed neonates were recently reported. In
substance in terms of strength and consistency. Most detrimen- a genome-wide investigation, Gurnot et al. (2015) identified
tal outcomes were reported for prenatal alcohol use, followed cytochrome P450, family 2, subfamily E, polypeptide 1
by nicotine and marijuana, with less consistent effects for in (CYP2E1), the gene encoding an ethanol-metabolizing en-
utero exposure to cocaine and SSRIs. Additional data concern- zyme by the same name, as providing the greatest discrimina-
ing the timing of most pronounced prenatal effects is required, tion between SSRI-exposed and nonexposed neonates. The
yet maternal alcohol use creates adversities for offspring health/ role of prenatal SSRI exposure and SLC6A4 promoter
development throughout gestation. methylation status in shaping soothability, an early aspect
of temperamental regulation, was examined (Gartstein, Hoo-
kenson, et al., 2016). For SSRI-exposed infants only, more
Prenatal substance and psychotropic medication use:
advanced development of soothability was observed with
Epigenetic effects
higher SLC6A4 methylation levels.
Human studies. We now consider the extent to which epige-
netic processes are responsible for conferring prenatal sub- Animal studies. Animal studies inform regarding epigenetic
stance use exposure risk. Consistent with the environmental mechanisms as bridges between in utero substance use/expo-
epigenetics framework, prenatal maternal substance/medica- sure and offspring development, especially with respect to
tion use has been associated with offspring methylation epigenetic shifts impacting gene expression in the brain.
changes. Portales-Casamar et al. (2016) examined genome- Rodent models developed to understand the etiology of
wide DNA methylation patterns, identifying differentially FASD in humans enable links between analogue phenotypes
methylated regions (DMR) in buccal cells of children with to epigenetic mechanisms. Immediate and long-lasting altera-
FASD and typically developing controls. Of 658 DMR, 41 tions of DNA methylation and microRNAs, crucial for synap-
displayed differences in percentage methylation change tic plasticity and behavioral/emotional functioning, have been
.5%. Children were between 5 and 18 years of age; thus, reported. Marjonen et al. (2015) noted shifts in offspring
possible confounding postnatal variables were introduced. DNA methylation, gene expression, and brain structure fol-
Laufer et al. (2015) also identified DMR associated with lowing chronic moderate ethanol exposure in early gestation,

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Table 5. Examples of in utero nutrition exposure effects: Temperament-related outcomes in human and animal studies

Significant Developmental/Behavioral Developmental

Exposure Outcome Sample Characteristics Timing of Exposure Reference

Human Studies

Undernutrition Major affective disorder incidence N ¼ 163,282/41,847 exposed Entire pregnancy: measured at 1st, Brown et al. (2000)
1290

(bipolar & unipolar); 2nd & 3rd (77,056 female) 2nd, & 3rd trimester estimates from
trimester effects, stronger for men Measured in adulthood records
Anxiety N ¼ 819 (450 female) Entire pregnancy: measured at 1st, de Rooij et al. (2011)
Measured at about 58 years 2nd, & 3rd trimester; estimates
from records
Overnutrition/ Externalizing problems N ¼ 23,020 (male and female) Midpregnancy: measured at 16 to Jacka et al. (2013)
high-fat diet Measured at 1.5, 3, & 5 years 20 weeks
Temperamental surgency & N ¼ 48 (24 female) Entire pregnancy: measured at Gustafsson et al. (2016)
regulation Measured at 4 months 13–16, 24–27, and 34–37 weeks
Micronutrients Autonomous nervous system N ¼ 216 (109 female) Entire pregnancy: measured at Hernández-Martı́nez
Iron functioning, 1st & 2nd trimester Measured at 48–72 hr postpartum 10–15, 24–27, & 33–34 weeks et al. (2011)
Signs of stress

Animal Studies

Undernutrition Anxiety-like behavior n ¼ 5–6 rats/condition (males Periconceptional–postnatal/ Levay et al. (2008)
(males) only) lactation
Measured at PND63–70
Motivation to work for reward n ¼ 7–12 baboons/condition Perinatal: pregnancy recognition– Keenan et al. (2013)
Emotional arousal (3–8 females) lactation
Variable activity level Measured at about 3 years
Persistence/attention (females)
Overnutrition/ Anxiety-like behavior n ¼ 21–22 mice/condition (9–10 Periconceptional–postnatal/ Peleg-Reibstein et al.
high-fat diet female) lactation (2012)
Measured at PND90+
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Anxiety-like behavior n ¼ 20–24 rats/condition (10–14 Periconceptional–postnatal/ Sasaki et al. (2013)

Basal corticosterone & slower return females) lactation:
to baseline Measured at PND110 4 weeks prior to mating–PND21
Gestational corticosterone n ¼ 6 rats/condition (males only) Periconceptional–postnatal/ Rodriguez et al. (2012)
Anxiety-like behavior Measured at E19 & PND80 & lactation
110
Activity level n ¼ 7–8 (female only) piglets/ Periconceptional– Clouard et al. (2016)
condition postnatal/lactation:
Measured at 4, 5, 6, & 7 weeks 8 weeks prior to conception–8
weeks postpartum
Micronutrients
Vitamin D Impulsivity n ¼ 12–16 rats/condition (6–8 Periconceptional–birth Turner et al. (2013)
female)
Measured at 20 weeks
MK-801 induced hyperlocomotion n ¼ 32 rats (males only) Periconceptional–birth: late O’Loan et al. (2007)
(late & full deprivation only) Measured at PND70 (conception–birth); full (6 weeks
before conception–birth)
Anxiety (deprivation and excess) n ¼ 20–28 rats (10–14 female) Perinatal: mating–PND18 Pan et al. (2014)
PND40 only Measured at PND35–40 &
Activity (deprivation) PND40 only PND100–105
Iron Spontaneous activity n ¼ 12–14 monkeys (4–8 Prenatal: entire gestation Golub et al. (2006)
Inhibitory response females)
Measured at 4 months
Folate Anxiety-like behavior n ¼ 40 mice (20 females) Periconceptional–late gestation: Ferguson et al. (2005)
Measured at PND63–65 & 8 weeks before mating–E18
1291

PND68–83
Folic acid USVs/distress N ¼ 13–20 (7–9 females) Pre & postnatal: entire gestation– Barua et al. (2014)
Anxiety-like behavior Measured at PND2–6, 2–6 6 months
Hyperactivity months

Note: Sample characteristics are provided in a different manner for human and animal studies, because of differences in design and presentation format. For human correlational studies, the overall number of par-
ticipants (N ) is typically presented, whereas the number of participants per condition (n) is indicated for animal experimental investigations. Additional information concerning numbers of male versus female par-
ticipants is also provided when both sexes were included/specified. Developmental timing of exposure indicators varies across studies. For humans, the timing is provided in terms of the number of gestational weeks.
In animals these indicators often refer to whether the nutritional exposure was periconceptional, beginning around conception and including the postnatal/lactation period, or starting at pregnancy recognition, with a
number of studies providing specific weeks/days. () Increases in temperament-related behaviors/displays; () decreases in temperament-related behaviors/displays; E, embryonic day; PND, postnatal day; USV),
ultrasonic vocalization; MK-801, N-methyl-D-aspartate receptor (NMDA-R) antagonist.
 1292 M. A. Gartstein and M. K. Skinner

corresponding to the first 3–4 weeks of human pregnancy. Study is a population-based investigation with volunteers pre-
Gene expression analyses conducted with mouse hippocam- natally affected by undernutrition (Roseboom et al., 2006). In
pal tissue of ethanol-exposed adolescent offspring revealed utero undernutrition was predictive of psychopathology, inso-
altered expression of 23 genes and three microRNAs. How- far as the role of exposure in affective disorders was docu-
ever, no connections were made between gene expression mented based on a large-scale archival study (Table 5). Un-
changes and brain structure/function changes. dernutrition as a result of famine in middle or late gestation
Methylation of the insulin-like growth factor II (IGF-II), an resulted in a higher risk for hospitalization for unipolar and
imprinted gene with a role in memory consolidation and en- bipolar depression, with a stronger effect observed for men
hancement, was examined in the context of prenatal cocaine (Brown, van Os, Driessens, Hoek, & Susser, 2000). Famine
exposure with mice (Zhao et al., 2015). Offspring of mothers and undernutrition exposure early in gestation increased the
administered cocaine during pregnancy demonstrated in- risk for anxiety in adulthood (de Rooij et al., 2011). Males ex-
creased anxiety, along with impaired memory. Hippocampal posed to famine during early gestation were again affected to
IGF-II mRNA and protein expressions were significantly de- a greater extent, self-reporting more frequent/severe symp-
creased, likely contributing to the phenotypic changes (Zhao toms of anxiety and depression. This pattern of results is con-
et al., 2015). Prenatal administration of cocaine to mice was sistent with the evidence indicating males may be more vul-
also shown to alter genome-wide DNA methylation in the off- nerable to nutritional deprivation during certain periods of
spring hippocampal tissue (Novikova et al., 2008). Exposed fetal development because of faster growth relative to females
and nonexposed mice were differentiated by methylation of (Eriksson, Kajantie, Osmond, Thornburg, & Barker, 2010).
492 CpG islands, a number associated with repetitive elements Other cohorts exposed to undernutrition and nutritional inter-
(e.g., LINE, Alu; Novikova et al., 2008). ventions have been evaluated; however, behavioral/emotional
Epigenetic alterations associated with prenatal cannabis ex- outcomes were not addressed. Interest in fetal programming
posure have also been considered, albeit not as extensively. Di- related to overnutrition has grown as a result of the “obesity
Nieri et al. (2011) examined fetal brain tissue and reported de- epidemic.” Connections between excessive prenatal nutrition
creased dopamine receptor D2 (DRD2) mRNA expression in and behavioral/temperament outcomes are starting to emerge.
the human ventral striatum (nucleus accumbens). DRD2 Prenatal nutrition characterized as “unhealthy” (high in
mRNA levels were negatively associated with maternal report fat) was predictive of multiple emotional/behavioral prob-
of prenatal cannabis use. Morris, DiNieri, Szutorisz, and Hurd lems later in childhood (Jacka et al., 2013). Increased mater-
(2011) reviewed contributions of cannabis and tobacco nal intake of unhealthy foods (e.g., processed meat products)
exposures, as these in utero effects commonly co-occur in hu- during pregnancy predicted child externalizing problems at 5
mans. Consistent with the environmental epigenetics perspec- years of age, controlling for covariates including childhood
tive, a critical role of epigenetic mechanisms, methylation in diet. Most relevant to this review, Gustafsson, Kuzava, Wer-
particular, was noted in shaping offspring neurodevelopment. ner, and Monk (2016) reported associations between mater-
Thus, existing research provides evidence of gene expres- nal prenatal dietary fat intake and offspring temperament.
sion changes, modulated via methylation and noncoding Specifically, maternal total fat intake was linked with infant
RNA mechanisms sensitive to prenatal substance use. The ex- surgency and regulatory capacity at 4 months of age, so that
tent of epigenetic alterations may be related to the level of de- higher fat content translated into lower positive affectivity
velopmental disruption, with alcohol exposure expected to trig- and regulation indicative of temperament risk. Together,
ger greater gene expression changes. Multiple downstream human studies indicate temperament alterations and an
behavioral effects relevant to temperament have been noted. increased risk for behavior problems/symptoms as a conse-
However, in humans, connections between prenatal substance quence of prenatal exposure to under- and overnutrition.
use exposure, epigenetic changes, and alterations in tempera- Prenatal effects of multiple nutrients have been reported
ment development have not been made in a convincing manner. for child neurodevelopment (e.g., B vitamins, zinc, protein,
iodine, etc.; Georgieff, 2007) and can be expected to influ-
ence temperament as a result. For example, Hernández-Mar-
Nutrition: Undernutrition, overnutrition, and
tı́nez et al. (2011) reported that first- and second-trimester
micronutrients
iron deficiency predicted neonatal autonomous nervous sys-
Human studies. These links were somewhat better established tem functioning, including signs of stress reactivity. In a re-
in the context of studies addressing prenatal nutritional expo- cent review, poor nutrition during pregnancy was described
sures, in part because of an opportunity for a natural experi- as contributing to deficits in neurocognitive development
ment created by a World War II humanitarian disaster. Effects (e.g., sensory–perceptual skills, memory, an learning), espe-
of gestational undernutrition in humans have been studied cially in the context of maternal distress (Monk, Georgieff, &
most extensively following individuals who were prenatally Osterholm, 2013).
exposed to famine during the Dutch Hunger Winter (1944–
1945): a period of severe food shortage in the western region Animal studies. Connections between unhealthy in utero nutri-
of the Netherlands during the last winter of World War II tion and subsequent adverse behavioral/temperament
(Barua & Junaid, 2015). The Dutch Famine Birth Cohort outcomes for the exposed offspring are further supported by

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 Environmental epigenetics and temperament 1293

animal research. A variety of animal models have been utilized in nonhuman primates, with exposed offspring demonstrating
to examine fetal programming associated with nutritional fac- reduced activity. Ratings of “fearful” affect emerged as the
tors (Table 5), as these allow precisely timed diet manipula- most critical temperament descriptor differentiating prena-
tions inducing nutritional accesses and deficits. Levay et al. tally iron-deprived animals from controls (Golub et al.,
(2008) examined effects of moderate maternal calorie restric- 2006). In rodents, females exposed to zinc deprivation
tion in preconception and the perinatal period on adult off- throughout gestation exhibited higher levels of aggression,
spring anxiety-like behaviors. Preconception deprivation relative to females born to typically fed mothers and those
(50% caloric intake for 3 days) exerted the strongest effect exposed to overall undernutrition (Halas, Reynolds, & Sand-
with respect to most offspring anxiety-like behavior (e.g., less stead, 1977). Adult offspring perinatally exposed to vitamin
exploration in the open field). Nonhuman primates exposed D deficiency engaged in more frequent premature responses
to maternal undernutrition during gestation demonstrated on a learning task, relative to control animals, interpreted as
greater variability in activity level and less emotional arousal impulsivity induced by the deprivation (Turner et al.,
(Keenan et al., 2013). Females, but not males, showed lower 2013). Hyperlocomotion in rats following vitamin D defi-
levels of attention/persistence, ascertained based on computer- ciency was also reported. Full and late term, but not early ges-
ized task engagement and performance. Keenan et al. (2013) tational, deprivation resulted in this behavioral phenotype
concluded that prenatal diet interventions could be effective (O’Loan et al., 2007). Late gestation was described as the
in preventing common behavior problems in children. likely “critical window” for vitamin D deprivation, corre-
Preconceptional/perinatal maternal high-fat diet effects on sponding to midgestation in humans (Clancy, Darlington,
anxiety-related behaviors, as well as expression of GABAergic, & Finlay, 2001). Pan et al. (2014) considered effects of
serotonergic, and brain-derived neurotrophic factor (BDNF) re- both deficient and excessive perinatal levels of vitamin D, fol-
ceptors involved in anxiety and depression, were examined in lowing exposed offspring into adulthood. Exposure to vita-
mice. Offspring in the high-fat diet condition exhibited in- min D deficiency resulted in lower offspring activity and in-
creased anxiety-like behaviors, with expression alterations creased anxiety (e.g., fewer open arm entries). Vitamin D
noted in the hippocampus (i.e., increased BDNF and GABA re- excess was also linked with adverse effects, and Pan et al.
ceptors; Peleg-Raibstein, Luca, & Wolfrum, 2012). Adult off- (2014) suggested high concentrations may be toxic.
spring exposed to a perinatal high-fat diet showed increased ex- Folate deficiency during gestation was associated with
pression of corticosterone receptors in the amygdala and more frequent anxiety-related behavior in the elevated plus
inflammatory gene expression in the hippocampus and amyg- maze (Ferguson et al., 2005). At the same time, offspring ex-
dala. These changes were linked with increased anxiety behav- posed to high levels of folic acid exhibited increased USVs,
ior (e.g., less time in the open field; Sasaki, de Vega, St.-Cyr, anxiety, and hyperactivity-like behaviors (Barua et al.,
Pan, & McGowan, 2013). Males subjected to a high-fat diet 2014). This pattern of result prompted Barua et al. (2014)
through gestation and lactation demonstrated increased cortico- to recommend moderation in folic acid supplementation.
sterone serum levels. Anxiety-related effects were mixed, with Overall, behavioral effects as a result of prenatal under- and
offspring from the pregestation dietary intervention group overnutrition have been observed across human and animal
(mothers returned to a healthy diet) showing partial recovery studies, with some indication of sex differences (de Rooij
(Rodriguez et al., 2012). Substance-use related behavioral ef- et al., 2011; Keenan et al., 2013). Both sets of investigations
fects of prenatal high-fat exposure have been documented in implicated symptoms of anxiety, relevant to temperament as
rats (Karatayev et al., 2015). Exposed offspring engaged in fear/behavioral inhibition, represents a prominent risk factor.
more extensive nicotine and ethanol self-administration, Moreover, animal studies provide evidence of brain develop-
relevant to temperament because of associated impulsivity/ ment alterations (e.g., expression of receptors involved in an-
behavioral undercontrol. This connection between prenatal xiolytic medication effects). Behavioral/emotional dysregula-
high-fat diet exposure and offspring deficits in regulation was tion emerged as another consequence of prenatal nutritional
further supported by a recent review. Sullivan, Nousen, and adversity, with temperament-related outcomes implicated in
Chamlou (2014) noted that primary offspring outcomes of peri- studies addressing prenatal deficiencies/accesses of micronu-
natal high-fat diet programming involved behavioral/emotional trients. Impulsivity and activity-level increases were noted,
dysregulation, further suggesting serotonergic system suppres- with some indication of a critical window with respect to
sion as the likely mechanism. vitamin D effects. These effects are not surprising, as brain
The impact of a calorie-dense perinatal diet (high in satu- development is altered with under- and overnutrition, in part
rated fat, refined sugar, and cholesterol) on the development due to sensitivity to deficits or overabundance of specific nutri-
of piglets was examined (Clouard, Gerrits, Kemp, Val-Laillet, ents (Georgieff, 2007). Cunha et al. (2015) argued for the
& Bolhuis, 2016). Prenatal exposure resulted in decreased basal “similarities in the inequalities” model, as offspring prenatally
salivary cortisol levels, relative to controls. Animals exposed to exposed to both undernutrition and high-fat conditions demon-
the high-fat/sugar/cholesterol diet spent more time walking in strated similar effects (e.g., lower birth weight and decreased
their pens, with control group animals inactive longer. activity level), compared to controls. In a recent review, Lang-
Micronutrient deficiencies have been studied extensively ley-Evans (2015) suggested: “a limited number of common
in animals. Iron deficiency during gestation was examined mechanisms may link nutritional ‘stressors’ to development

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 1294 M. A. Gartstein and M. K. Skinner

changes that result in later disease.” Prenatal nutritional effects fearful/anxious behavior (Sullivan et al., 2010). Sex differ-
are both unique and co-acting with respect to maternal stress ences were noted in responses to threatening novel objects,
and mood, leading to alterations in the offspring dopaminergic as female high-fat exposed offspring exhibited increased anx-
and serotonergic systems (Sullivan, Smith, & Grove, 2011). iety, and males demonstrated higher levels of aggression.
Psychosocial stress is a known contributor to unhealthy eating Overall 78% of animals born to mothers subjected to a
during pregnancy (Hurley, Caulfield, Sacco, Costigan, & Di- chronic high-fat diet exhibited disordered behavior. Consis-
pietro, 2005) and can alter the manner in which nutrients are tent with the environmental epigenetics perspective, deficits
metabolized (e.g., accelerating protein breakdown), with fur- and accesses in prenatal nutrition were shown to result in epi-
ther negative consequences for the fetus (Monk et al., 2013). genetic shifts for the offspring, yet only a limited number of
As noted earlier, co-occurrence with additional exposures studies demonstrated links between these alternations and be-
(e.g., substance use) should be addressed in the future. havioral outcomes.
Connecting these overlapping environment exposures to their In summary, the totality of existing studies suggests
epigenetic signatures will be important going forward. important links between environmental exposures, epigenetic
alterations, and shifts in behavioral outcomes relevant to tem-
perament (e.g., fear/anxiety). However, connections among
Prenatal Nutritional Exposure in Humans and
these levels of analysis have not been made frequently, espe-
Animals: Epigenetic Mechanisms
cially in humans. In addition, questions remain regarding op-
The role of epigenetic processes in conferring effects of pre- timal developmental widows and sex differences in program-
natal nutrition are already being addressed and will be dis- ming effects. In terms of stress, human candidate gene studies
cussed next. Prenatal undernutrition exposure research in hu- suggest methylation of NR3C1 and SLC6A4 are critical to
mans provides further support for the environmental conferring prenatal effects for several temperament outcomes
epigenetics framework. Results indicate a variety of epige- (e.g., infant HPA axis reactivity; Montirosso et al., 2016;
netic changes, in some cases linked with disease-related phe- Oberlander et al., 2008; Ostlund et al., 2016). However, en-
notypes, but not behavior/temperament (Heijmans et al., thusiasm for these as potential markers of exposure effects
2008; Tobi et al., 2014). Periconceptional exposure to famine is dampened by the number of other genes implicated in
during the Dutch Hunger Winter was associated with a life- stress-related methylation shifts, as evidenced by a genome-
long methylation signature linked with physiological pheno- wide approach (Nieratschker et al., 2014). Toxicant studies
types. For example, methylation of DMR associated with the provide consistent evidence of environmental exposures
physical growth and insulin signaling gene (insulin receptor translating into epigenetic shifts. These alterations of the
[INSR]) was positively correlated with birth weight. Fatty epigenome affect developmental cascades relevant to
acid oxidation gene (carnitine palmitoyltransferase 1A temperament phenotypes (Keil & Lein, 2016; Skinner
[CPT1A]) methylation was positively correlated with low- et al., 2008). Among notable substance-use related findings,
density lipoprotein cholesterol levels, after adjusting for mul- Zhao et al. (2015) reported transcription alterations in the
tiple covariates (e.g., age and smoking; Tobi et al., 2014). hippocampus and increased anxiety-like behavior following
One study with humans utilized a genome-wide approach, prenatal cocaine exposure. Existing prenatal nutrition re-
demonstrating that micronutrient supplementation was asso- search indicates connections between methylation status
ciated with decreased methylation, interpreted as important and temperament, as expected based on the environmental
to “programming gene activity” later in life (Khulan et al., epigenetic framework. Nutrition affects maternal health/phys-
2012). Unfortunately, behavioral outcomes relevant to tem- iology, a key determinant of the intrauterine milieu, shaping
perament were not examined. the progression from environmental exposure to changes in
In a mouse model, perinatal exposure to a high-fat diet was offspring epigenome, brain, and temperament development.
linked with DNA hypomethylation along with alterations in
dopamine and opioid-related gene expression (Vucetic,
DNA Methylation and Temperament: Implications
Kimmel, Totoki, Hollenbeck, & Reyes, 2010). Micronutrient
for Behavioral/Emotional Health
deficits can also influence gene expression, as perinatal iron
deficiency was associated with altered mRNA expression in The course of prenatal development is altered by exposure to
the brain (Clardy et al., 2006). Konycheva et al. (2011) maternal stress, contact with toxicants, substance/psychotropic
examined prenatal methyl donor deficiency effects on off- medication use, and nutrition. These environmental factors
spring hippocampal methylation of candidate genes involved impact maternal physiology during gestation and program
in glucocorticoid metabolism and anxiety-related behaviors. the offspring. As anticipated by the environmental
Exposed animals demonstrated increased anxiety. However, epigenetics perspective, prenatal exposures appear to
methylation of candidate genes was not associated with any confer subsequent behavioral phenotypes via epigenetic
of these behavioral changes, suggesting the need for a ge- mechanisms. Brain development is sensitive to multiple expo-
nome-wide strategy. Nonhuman primates prenatally exposed sures during gestation, and this epigenetically driven fetal pro-
to a chronic maternal high-fat diet evidenced epigenetically gramming shapes regions/systems relevant to temperament.
driven serotonin signaling pathway alterations linked with Even subtle alterations in brain structure/function during fetal

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 Environmental epigenetics and temperament 1295

development can become magnified over time, producing evidence points to the importance of epigenetic processes as
lifelong deficits (Buss et al., 2012). Development of the amyg- mediators of prenatal effects, conferring environmental risk
dala and hippocampus, relevant to fear/avoidance and other onto temperament-related phenotypes. As indicated by the
temperament-related behaviors, was disrupted by prenatal environmental epigenetics perspective, a variety of environ-
stress (Barros, Myers, Van Driesche, & Tzagoloff, 2006), mental adversities impact maternal health/physiology, result-
environmental contaminants (Skinner et al., 2008), maternal ing in a cascade of epigenetic changes that shape central
alcohol use (Baculis et al., 2015), and a high-fat diet (Sasaki nervous system maturation and temperament, in turn, often
et al., 2013). Prenatal stress effects on the synthesis and trans- translating into similar phenotypes across exposures.
port of dopamine, as well as relevant receptors, were also Prenatal exposure to multiple adversities results in tem-
noted (Antonelli et al., 2016). Development of the dopaminer- perament profiles marked by high levels of fear/behavioral in-
gic system can be disrupted by prenatal lead and cannabinoid hibition and risk for anxiety, with these effects mediated by
exposure, as well as maternal nutritional state (DiNieri et al., epigenetic processes. On the animal side, exposure to prenatal
2011; Leasure et al., 2008; Sullivan et al., 2014). The dopami- stress resulted in a number of offspring “fearful” behaviors,
nergic system plays multiple roles relevant to temperament as such as higher levels of inhibition in response to foot shock,
it functions to prioritize stimuli or responses, facilitating decreased time spent in the center of an open field and in open
selection of alternatives in either a perceptual-cognitive or a arms of the elevated-plus maze, increased defensive with-
motor-behavioral context (Trofimova & Robbins, 2016). drawal, and conditioned fear (Dickerson, Lally, Gunnel, Bir-
The serotonin signaling pathway also pertains to temperament kle, & Salm, 2005; Griffin & Evans, 2003; Ward, Johnson,
given links to depression and anxiety associated with negative Salm, & Birkle, 2000). Epigenetic mechanisms were impli-
emotionality. Serotonergic effects were most pronounced in cated in the risk for increased fear/anxiety observed in the
studies examining in utero SSRI exposure (Smit-Rigter context of prenatal toxicant exposure (e.g., Skinner et al.,
et al., 2012). Changes in serotonin signaling were also ob- 2008) and for humans prenatally exposed to undernutrition
served in the context of prenatal restraint stress (Miyagawa, (de Rooij et al., 2011).
Tsuji, Fujimori, Saito, & Takeda, 2011). Compound effects With respect to depression, temperament risk primarily in-
of maternal diet, stress, and mood, as well as sleep and volves increased negative emotionality, along with decreased
exercise, can be expected to shape offspring serotonergic approach/positive affectivity (Lonigan, Carey, & Finch,
and dopaminergic neurotransmitter systems (Sullivan et al., 1994; Lonigan et al., 2003). This profile resulted from several
2011), and thus should be explored in future research. Overall, reviewed exposures shown to operate via epigenetic pro-
epigenetically mediated prenatal exposure effects on brain de- cesses. Alvik et al. (2011) demonstrated that maternal binge
velopment have considerable implications for temperament, drinking in early pregnancy predicted offspring temperament
especially stress reactivity, fear/anxiety, impulsivity, and marked by high negative affect, low regulatory capacity, and
attention/regulation. positive affectivity in infancy, which could bode future de-
Epigenetic mechanisms have been linked with behavioral pressive symptoms. Prenatal high-fat diet was associated
phenotypes relevant to temperament by multiple investiga- with lower infant surgency (Gustafsson et al., 2016), which
tions. In one such study, genome-wide DNA methylation could translate into long-term risk for depression given
and mRNA expression analyses were conducted with primate high negative emotionality. Prenatal stress and maternal
amygdala tissue collected from juveniles exhibiting a fearful high-fat diet were shown to disrupt serotonin neuronal devel-
temperament (freezing, increased levels of cortisol; Kalin & opment (Miyagawa et al., 2011; Peleg-Raibstein et al., 2012),
Shelton, 2003). Transcriptome analyses distinguished 22 likely contributing to temperament risk for depression.
genes with active expression changes, of which two gluta- In utero exposure to SSRIs was associated with offspring
mate receptor genes (glutamate ionotropic receptor NMDA serotonergic effects (Oberlander, 2012), although additional
type subunit 1 [GRIN1] and metabotropic glutamate receptor research is required to determine their long-term significance.
5 [GRM5]) play a role in fear and anxiety-like behaviors. Tentative conclusions can be drawn regarding disruptive
NR3C1 and SLC6A4 methylation has been linked with infant behaviors/disorders. General maternal anxiety during preg-
duration of orienting, approach, soothability, and fear, mea- nancy was associated with increased infant surgency, negative
sured via parent report (Gartstein, Hookenson, et al., 2016; affectivity, and poorer self-regulation (van den Heuvel et al.,
Montirosso et al., 2016; Ostlund et al., 2016). Methylation 2015), linked with risk for conduct disturbance. Offspring be-
of imprinted genes was also associated with infant tempera- havioral/emotional dysregulation reported following prenatal
ment: higher methylation of maternally expressed gene trauma-related exposures (i.e., trauma occurrence or maternal
intergenic (MEG3-IG) linked with greater surgency and of PTSD; Yong Ping et al., 2015) is also consistent with
the progression elevated gene 3 (PEG3) with higher levels temperament risk for disruptive behaviors. Studies that
of negative emotionality and externalizing problems (Fuem- measure offspring ADHD-like behaviors (Atalar et al., 2016;
meler et al., 2016). In adulthood, DNA methylation of the oxy- Holz et al., 2014; Luo et al., 2014; Sagiv et al., 2010) suggest
tocin structural gene (OXT) was associated with sociability and multiple prenatal toxicant and maternal substance use effects.
greater superior temporal sulcus activity during social– Luo et al. (2014) demonstrated histone modifications mediated
cognitive functional MRI tasks (Haas et al., 2016). Existing prenatal lead exposure effects on ADHD-like behavior in

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 1296 M. A. Gartstein and M. K. Skinner

juvenile rats, serving as a bridge between environmental community that differ in terms of psychosocial and/or
toxicant exposure and offspring symptomatology. physiological stress could provide comparisons with re-
Biologically speaking, phenotypes are considered benefi- spect to effects of the HPA axis activation. It would be
cial to the extent that these increase survival and subsequent possible to examine other environmental exposures, such
reproductive success. These need not be socially desirable or as healthy versus unhealthy prenatal nutrition, in a similar
health promoting in the long term (Frankenhuis, Panchana- fashion. This approach could elucidate reliable connec-
than, & Belsky, 2016). Children who experience adverse fetal tions between environmental adversity, maternal health,
programming effects likely present with temperament epigenetic mechanisms, and offspring behavioral out-
profiles aimed at increasing their immediate probability of comes with human participants, given appropriate statisti-
survival (e.g., greater reactivity/fearfulness), which may not cal control of covariates (e.g., postpartum variables).
align with caregivers’ and societal demands/expectations. Second, some conclusions can be made about develop-
These temperament trajectories speak to long-term risk, mental windows associated with stronger effects; however,
increasing the likelihood of developing psychopathology/ additional research is required to clarify these across species
behavior problems that typically emerge after the first year for different environmental exposures. Overall, earlier stages
of life. Alternatively, these phenotypes may be reflective of of prenatal development afford greater malleability of organ
increased sensitivity to context, with superior outcomes un- structure and function and are more “open” to environmental
der optimal environmental conditions. Selection pressures influences via epigenetic modifications (Crews, 2010). At the
may favor differential plasticity when environmental condi- same time, a number of reviewed exposure effects occurred
tions vary across time, with epigenetic mechanisms explain- later in gestation (e.g., Yehuda et al., 2005), presumably be-
ing “bet hedging” that leads to varying offspring plasticity cause this timing coincides with the maturation of brain re-
(Frankenhuis et al., 2016). As DOHaD research has already gions relevant to temperament. Comparative studies includ-
demonstrated, environmental epigenetic modifications im- ing animal and human participants with parallel exposure
mediately protective in adverse circumstances (e.g., inade- windows are likely to be especially informative, given diver-
quate prenatal nutrition and stress) result in a spectrum of gent sensitive period findings thus far.
risk-promoting developmental shifts relevant to temperament Third, interactions among different in utero exposure con-
and mental health in the long term (Hochberg et al., 2011). ditions should be examined more closely in future research, as
compound effects are likely relevant to temperament. Epige-
netic modifications invoked by different prenatal environ-
Conclusion
mental circumstances may have substantial overlap, leading
Considerable evidence points to the importance of in utero en- to diverse developmental and health risks. Comparative
vironmental exposures in shaping offspring temperament de- studies are likely to inform this effort. Multiple exposures
velopment, with epigenetic mechanisms conferring the risk, as can be manipulated with respect to dose, timing, and duration
indicated by the environmental epigenetics perspective. Greater with animals, in a manner that parallels human prenatal ef-
understanding of these connections is critical for advancing fects. For example, comparative research could address joint
DOHaD research and specifically for elucidating prenatal effects of prenatal stress and inadequate nutrition, as well as
origins of developmental psychopathology, which could lead maternal polysubstance use.
to more effective preventative efforts. Additional study is Fourth, the pattern emerging from existing studies suggests
required to make these connections for eventual use of epige- that males may be more vulnerable to physiological and behav-
netic information in targeted interventions. ioral effects of prenatal environmental exposures (Andre &
First, research that starts with environmental adversities Markowski, 2006; Colciago et al., 2009; Eriksson et al.,
and considers epigenetic alterations as well as brain/behavior 2010; Leasure et al., 2008). Sex differences are generally pre-
effects related to temperament has been limited to date. Inves- dicted in the direction of females exhibiting greater anxiety/
tigations that link all components of the developmental pro- depression and males presenting with higher aggression/
gression and levels of analysis are needed, especially with hu- impulsivity, with a number of studies providing support (Na-
mans. Animal studies provide an opportunity to directly zeri et al., 2015; Sullivan et al., 2010; Svirsky et al., 2016).
manipulate independent variables related to environmental However, males born to mothers exposed to psychological
exposure, ensuring internal validity, yet their external validity stress during pregnancy demonstrated more depression-like be-
with respect to human applications is necessarily limited. havior (Abe et al., 2007) and females increased in aggression
Thus, efforts with humans are required, translating animal following DET/DES and zinc deficiency in utero exposure
findings in a manner that provides support for generaliz- (Halas et al., 1977; Palanza et al., 1999). Interpretation of
ability. Future research could focus on links between epi- sex differences is complicated by the fact that a number of stud-
genetic mechanisms and temperament development in ies were conducted with male animals only (e.g., Abe et al.,
high- and low-risk populations. Despite a quasi-experi- 2007; Maccari et al., 2003). Nonetheless, existing evidence
mental design, multiple fetal programming pathways de- suggests fetal programming may have sexually dimorphic ef-
scribed in this review could be examined. For example, re- fects (Baillargeon, Keenan, & Cao, 2012; Hyde, Mezulis, &
cruiting samples of pregnant women from the same Abramson, 2008; Skinner et al., 2008). Thus, offspring sex

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 Environmental epigenetics and temperament 1297

should be considered as a moderator of links between prenatal tative treatment. A noninvasive biomarker (e.g., buccal cell
exposures, epigenetic shifts, and behavioral outcomes. methylation signature) could enable this intervention targeting
Fifth, potential transgenerational effects linked with epige- early in infancy, rather than awaiting behavioral testing at a la-
netic mechanisms addressed in this review (e.g., Skinner, ter time point. Thus, preventative programs could address par-
2014) highlight the need for additional study of etiology, as enting/parent–child interactions, modifiable contributors to
well as preventative efforts. It is critical to understand biolog- risk for psychopathology, before maladaptive patterns become
ical/developmental processes involved in the chain of events the norm. Research that identifies connections between expo-
that starts with prenatal environmental exposures. Subsequent sures, their epigenetic signatures, and behavioral outcomes is
changes in maternal health/physiology, offspring epigenome, needed to support this preventative approach. Temperamental
and gene expression result in temperament profiles that typi- precursors of symptoms/psychopathology offer advantages rel-
cally bode risk for symptoms/behavior problems. It will be ative to the study of full-blown disorders, as these temperament
important to determine if certain exposures result in epige- risk factors can be reliably measured in the first year of life.
netic shifts that afford plasticity, rather than risk. Studies Thus, fetal programming/epigenetic investigations with tem-
that make connections between methylation signatures of pre- perament outcomes will not require lengthy longitudinal ef-
natal environmental exposures and temperament profiles forts, although the latter are important as well. Environmental
linked to risk could facilitate screening and preventative inter- epigenetics can make a substantial contribution to the study of
ventions. Szyf, Tang, Hill, and Musci (2016) noted that DNA temperament development, informing our understanding of
methylation could be used as a biomarker for effects of pre- debilitating mental health symptoms/disorders, as well as ef-
natal exposures on individuals’ risk and a measure of treat- forts aimed at their prevention.
ment progress. Thus, screening/assessment applications
could be implemented once sufficient empirical evidence is
Supplementary Material
generated. Links between methylation patterns resulting from
in utero exposures and risky temperament phenotypes To view the supplementary material for this article, please
represent the first step to enable targeted selection for preven- visit https://doi.org/10.1017/S0954579417001730.

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