J Biosci (2021)46:34 Ó Indian Academy of Sciences

DOI: 10.1007/s12038-021-00153-7 (0123456789().,-volV)(0123456789().,-volV) Review

Prenatal effects on offspring brain and behavior: Mediators, alterations and dysregulated epigenetic mechanisms

1 1 1,2 SHAMS UL HAQ ,UNIS AHMAD BHAT and ARVIND KUMAR * 1CSIR– Centre for Cellular and Molecular Biology (CCMB), Uppal Road, Hyderabad 500 007, India 2Academy of Scientific and Innovative Research, Ghaziabad 201 002, India

*Corresponding author (Email, [email protected]) MS received 23 July 2020; accepted 17 February 2021

Prenatal environment significantly influences mammalian fetal development and adverse in utero conditions have life-long consequences for the offspring health. Research has revealed that a wide variety of prenatal stress factors lead to increased risk of vulnerability to neuropsychiatric disorders in the individuals. Multiple mediators are involved in stress transfer from mother to the developing , with stress hormone being a chief player. Further, the developmental programming effects of prenatal stress have been observed in the form of alterations in the offspring brain at different levels. This review covers stress transfer mediators such as cortisol, , maternal cytokines, reactive oxygen species (ROS) and the maternal microbiota, and their role in fetal programming. Prenatal stress leads to alterations in the offspring brain at multiple levels, from molecular and cellular to structural. These alterations eventually result in lasting phenotypic alterations such as in the offspring behavior and cognition. Different brain alterations induced by prenatal stress such as in neural pruning processes, neural circuit formation, brain structural connectivity and epigenetic systems reg- ulating neural gene expression are under focus in the second part of the review. The latter constitutes a key molecular mechanism involved in prenatal stress effects and has been discussed in more detail.

Keywords. in utero stress; fetal neural programming; remodeled circuitry; affective disorder; cognitive disorder; epigenetic regulation

1. Introduction alterations have potentially severe and long-lasting consequences (Pryce et al. 2005;Ra¨ikko¨nen and Peso- The importance of early life milieu right from gestation nen 2009; Shonkoff et al. 2009;Taylor2010). The in shaping the long-term health and disease outcome, causation of multidimensional and long lasting effects including psychiatric health, has been recognized for by prenatal determinants has been conceptually expres- quite some time. The epidemiological studies on indi- sed as fetal programming (Bale et al. 2010). How the viduals born during difficult times like wars, floods, programming outcome plays out depends on many famines, etc., and other human studies corroborate that factors such as the timing and duration of the exposure, conditions during gestation have lifelong consequences stimulus type and its intensity, etc. Environmental fac- (Charil et al. 2010; Watson et al. 1999; Weinstock tors are believed to impact fetal brain development in 2008). Animal studies have further established prenatal multiple ways leading to the programming effects (fig- factors as determinants of the physiological and behav- ure 1). This review will have two parts; the first one ioral outcomes in adult life (Weinstock 2017). The brain deals with diverse mediators of fetal programming circuitries undergoing development and maturation known so far, followed by the alterations in the affected during the critical prenatal periods are sensitive to dif- neural circuitries including epigenetic alterations, that ferent environmental stressors and the resultant lead to lasting programming consequences. http://www.ias.ac.in/jbiosci 34 Page 2 of 16 Shams Ul Haq et al.

Figure 1. Graphical summary of prenatal stress mediators and effects in mice. (A) Different mediators of prenatal stress to developing offspring. (B) Prenatal-stress-induced alteration of hippocampus pituitary adrenal (HPA) axis in offspring. (C–E) Prenatal-stress-induced structural and molecular changes in offspring brain. (F) Alteration in gut microbiome.

2. Mediators of fetal programming 2014). In addition, chronic maternal stress induced glucocorticoids in rodents has been shown to affect 2.1 Glucocorticoids – cortisol in humans structural and functional development of brain, viz., loss of dendritic spine density in PFC (Murmu et al. Exposure to adverse prenatal environment impacts the 2006) and hippocampal neurons (Martı´nez-Te´llez et al. proper development of neuroendocrine systems thereby 2009), and alterations in glutamatergic synaptic trans- altering the hypothalamic-pituitary-adrenal (HPA) axis mission in prefrontal cortical regions of brain. Psy- regulation for life (Barbazanges et al. 1996; Henry chosocial stress during causes the maternal et al. 1994; Maccari et al. 2003; Van den Bergh et al. HPA axis activation leading to the rise in circulating 2008; Welberg and Seckl 2001). Studies have revealed cortisol levels in the mother (Brunton and Russell that glucocorticoid cortisol (or corticosterone in 2010; Lim et al. 2014; Piquer et al. 2017). Cortisol can rodents) mediates long-term gestational stress effects cross the placental barrier and get access to developing on the developing offspring. Prenatal exposure to fetus (O’donnell et al. 2009; Zarrow et al. 1970). synthetic glucocorticoids or behavioral stress induced Under normal conditions cortisol levels in developing glucocorticoids is reported to reduce hippocampal fetus are 5–10 times lower compared to maternal levels neurogenesis in mice offspring (Noorlander et al. due to the enzymatic degradation by 11beta- Epigenetics of prenatal stress effect on offspring behavior Page 3 of 16 34 hydroxysteroid dehydrogenase type 2 (11b-HSD-2) in stress-induced maternal tryptophan can reach to fetus the placenta. This process normally inactivates about (Coˆte´ et al. 2007). This is no surprise considering the 80–90% of maternal cortisol (Glover et al. 2010; well characterized active transport mechanisms for O’donnell et al. 2009). Chronic prenatal stress disrupts amino acids, including tryptophan, in the placenta this protective arrangement as cortisol rises sharply which is of critical importance for healthy growth and which is worsened by the reduction in the 11b-HSD-2 development of fetus (Cleal and Lewis 2008). Also, expression and activity as found in animal models as increased maternal tryptophan levels resulting from well as humans (Glover et al. 2009; Mairesse et al. exposure to stress can act as a precursor for 5-HT 2007). Exposure of fetus to elevated cortisol levels synthesis in the placenta which is delivered to fetus disturbs the normal development of its HPA axis with affecting its brain developmental processes (Bonnin resetting of its negative feedback mechanism (Fujioka and Levitt 2011; Goeden et al. 2013; Rakers et al. et al. 1999; Henry et al. 1994; Weinstock et al. 1992). 2017; St-Pierre et al. 2016). Detailed mechanisms Consequently, there is permanent modulation of stress involved in this pathway of fetal programming remain axis reactivity with repercussions for adult life behav- to be understood. ioral, physiological and cognitive phenotypes (Bar- bazanges et al. 1996; Fatima et al. 2017; Salomon et al. 2011; Weinstock 2005; Zagron and Weinstock 2006). 2.3 Maternal cytokines Also, there are reports that suggest cortisol effects by stimulation of corticotrophin-releasing hormone (CRH) Stressful environment during gestation increases the release by placenta which can have negative conse- chances of infections with cytokines being very impor- quences for fetus including impairment in development tant players (Andersson et al. 2016;Entringeret al. of important brain regions (Kofman 2002; Raison and 2010;Rakerset al. 2017; Ratnayake et al. 2013). Miller 2003; Sandman et al. 2006). A dysregulated Studies on animal models suggest that cytokines can HPA axis in combination with undesired develop- transfer directly through placenta and modulate the fetal mental alterations in important brain regions can have immune system (Andersson et al. 2016; Dahlgren et al. strong pathophysiological role in later life (Barker 2001, 2006; Zaretsky et al. 2004). Excess cytokines in 1998), viz., increased vulnerability to depression and fetal circulation can thereby negatively affect its brain associated cortical aberrations in prenatal stress development. Cytokines also have additional lines of exposed individuals (Davis et al. 2020). action with certain cytokines enhancing reactive oxygen species (ROS) production (TNF-a,IL-1b and IFN-c) and others (TNF-a, IL-1 and IL-6) promoting gluco- 2.2 Serotonin (5-HT) and tryptophan corticoid release by the activation of HPA axis (Liu et al. 2000;Rakerset al. 2017; Silverman and Sternberg The neurotransmitter monoamine serotonin (5-hy- 2012; Weaver et al. 2012). It must be pointed out here droxytryptamine, 5-HT) is synthesized from its pre- that cytokines as determinant of fetal programming is cursor tryptophan by the action of tryptophan not yet fully clear and further investigations in this hydroxylase enzyme. 5-HT has been reported to be regard are in order. There are, however, reports indi- important not just in psychiatric and cognitive behavior cating placenta also acting as a source of cytokines with but lately in fetal programming as well (Bonnin and maternal stress induced pro-inflammatory gene expres- Levitt 2011; Goeden et al. 2013; Naughton et al. 2000; sion like that of IL-1b and IL-6 having programming Rakers et al. 2017; St-Pierre et al. 2016). Because of consequences for offspring (Bronson and Bale 2014; the important role of 5-HT in fetal brain wiring during Rakers et al. 2017). Evidence has been obtained espe- development, any alteration in fetal serotonergic cially with regard to prominent programming role of IL- homeostasis has long term programming consequences 6 (Coussons-Read et al. 2005; Dahlgren et al. 2001; for the offspring. Environmental stressors can poten- Samuelsson et al. 2006, 2004). tially alter the 5-HT metabolic pathway thereby con- tributing to these programming effects. Studies on rodent dams using various stress paradigms like 2.4 Reactive oxygen species, catecholamines restraint, foot shock, etc., have shown effect of stress and impaired utero-placental perfusion (UPP) on serotonin metabolism (Malyszko et al. 1994a, b; Peters 1990; Rakers et al. 2017; Weil-Fugazza and Generation of Reactive Oxygen Species (ROS) is Godefroy 1976). There are reports which indicate that inevitable part of oxygen metabolism. When the levels 34 Page 4 of 16 Shams Ul Haq et al. of ROS overwhelm the body’s antioxidant systems, parturition (Cilieborg et al. 2012). GBA as well as oxidative stress (OS) is the result with severe physio- other microbial communities like vaginal microbiota logical consequences (Rakers et al. 2017; Thompson are perturbed by environmental stressors including and Al-Hasan 2012). Psychosocial stress is one of the gestational stress (Ehrstro¨m et al. 2005; Jasˇarevic´ et al. many factors that can lead to this oxidative stress 2015a; Nansel et al. 2006). These alterations in the (Rakers et al. 2017). OS during gestation has been vaginal microbiota in turn affect the composition of found to have negative fetal consequences ranging microbiota that colonizes the fetal gut with potential from abortion to metabolic disorders potentially con- developmental consequences. In a human-based study, tributing to fetal programming for adult life (Jansson it was reported that maternal high stress levels and and Powell 2007; Rakers et al. 2017; Thompson and cortisol concentrations were associated with decreased Al-Hasan 2012; Turpin et al. 2015). Among other prevalence of bifidobacterial and lactobacilli in vagi- things, oxidative stress induces alterations in fetal nally delivered babies(Zijlmans et al. 2015). Micro- epigenome, thereby providing one of the mechanistic biota transplantation studies report the mediatory role bases for fetal programming including in HPA axis of vaginal microbiota from dams in transferring (Godfrey et al. 2007; Niu et al. 2015; Szumiel 2015). maternal stress effects (Jasˇarevic´ et al. 2018). The GBA ROS due to their high reactivity have short half-life modulations have been reported to influence the inci- which precludes the possibility of direct transfer from dence of neurological, psychiatric and autoimmuno- maternal side to fetus (Reth 2002). However, there are logical conditions (Foster and Neufeld 2013; Jasˇarevic´ studies that indicate interaction between oxidative et al. 2015a, 2018; Petra et al. 2015; Zerbo et al. 2015). systems of mother and fetus although detailed mecha- Currently, there is a lot of focus on this area of research nism of the same is unclear. Reports suggest that pre- promising newer insights in this respect. natal stress may indirectly induce OS by its effect on utero-placental perfusion (UPP) with negative conse- quences for brain organization and activity (Burton and 3. Outcome of prenatal stress in offspring Hung 2003; Dreiling et al. 2016; Rakers et al. 2015; Thakor et al. 2010). A similar indirect stress transfer Adverse prenatal environment through these varied can occur by maternal catecholamines, norepinephrine mediators of stress induces alterations in offspring (NE) and epinephrine (E); their effect on UPP brain at multiple levels – microscopic to macroscopic – adversely influencing fetal growth and development leading to long lasting programming consequences. (Levine et al. 2016; Rakers et al. 2015, 2017). Some of these alterations and the regulatory mecha- nisms involved are summarized here.

2.5 Maternal microbiota 3.1 Alterations in neural pruning process An additional mediator of stress transfer that is gaining attention is maternal microbiota (Jasˇarevic´ et al. 2015b; As the life of an individual gets started, brain is actively O’Mahony et al. 2017). Host microbial population has at work with surplus of neurons and synaptic connec- influence on many physiological processes like tions. Over time excess neurons and connections are immune responses, CNS function, behavioral outcomes pruned as part of healthy brain development. Micro- and HPA Axis regulation (O’Mahony et al. 2015; glia, a non-neuronal glial cell type, has appeared as a Sherman et al. 2015; Sommer and Ba¨ckhed 2013). new actor in this pruning process with its activity Gut-Brain Axis (GBA) constitutes a bidirectional link influencing the synaptic architecture (Cunningham between the central and the enteric nervous systems. et al. 2013; Paolicelli et al. 2011; Schafer et al. 2012; This facilitates cross interaction between emotional and Sturrock 1981). They prune the excess synapses; cognitive centers of the brain with gastrointestinal (GI) engulf synaptic structures and clear cell debris (Harry tract. Evidence is accumulating that suggest the influ- 2013). Thus, microglia play crucial role in brain wiring ence of gut microbiota on these interactions (Mayer during development, contributing to refined neural 2011; O’Mahony et al. 2015; Petra et al. 2015; Sher- circuits. This microglia mediated pruning process quite man et al. 2015; Sommer and Ba¨ckhed 2013). A sterile likely employs more than one mechanism (Schafer fetal gut gets colonized by vertical transmission of et al. 2012). These include complement signaling microbiota in the vagina as fetus makes its way out cascade system and activity-dependent, selective from mother’s womb into the outside world during elimination mechanisms. In the latter case, MHC class I Epigenetics of prenatal stress effect on offspring behavior Page 5 of 16 34 proteins which have already been implicated in activ- factors inducing multitude of brain alterations ity-dependent synaptic pruning possibly play an (Sandman et al. 2011; Van den Bergh et al. 2018). upstream signaling role (Schafer et al. 2012). Recent Key brain regions like hippocampus, amygdalar evidence suggests that MHCI recruits myocyte nuclei, neocortex, etc., are impacted as a result (Buss enhancer factor-2 (MEF2) transcription factors in an et al. 2010;Daviset al. 2011; Lemaire et al. 2000; activity-dependent fashion through calcineurin signal- Pallare´s and Antonelli 2017;Sandmanet al. 2011). It ing pathway (Elmer et al. 2013). MEF2 controls the has been associated with structural alterations in brain expression of number of genes including those areas important in cognitive, emotional and language involved in synapse elimination (Flavell et al. processing functions. These include prefrontal cortex, 2006, 2008). This involves interplay with upstream medial temporal lobe memory system including hip- signaling events, small non-coding RNA such as pocampus, temporal parietal cortex network, amyg- microRNAs and other factors (Potthoff and Olson dala, cerebellum, etc. (Davis and Sandman 2010; 2007). MEF2 transcription factors in partnership with Mestres-Misse´ et al. 2008;Petersonet al. 2000). class IIa histone deacetylases (HDACs) also operate as Gestational stress is associated with microstructural MEF2-HDAC transcriptional repressor axis, a hub of changes in the white matter in amygdalar, prefrontal, multiple epigenetic regulatory networks (Gre´goire parietal and corticolimbic regions (Chen et al. 2015; et al. 2006;Luet al. 2000; Potthoff and Olson 2007). Qiu et al. 2013, 2015; Rifkin-Graboi et al. Prenatal stress has been reported to influence microglial 2013, 2015). It has been shown to result in reduced function by altering the brain microenvironment (Male grey matter volume in brain areas such as cortex, and Rezaie 2001;S´lusarczyk et al. 2015). Alterations medial temporal lobe, amygdala and cerebellum (Buss in microglial physiological activity, whether that is et al. 2010;ElMarrounet al. 2016; Favaro et al. inhibitory alteration or over activation, especially dur- 2015;Sandmanet al. 2015). Prenatal stress has long ing critical periods have negative consequences for lastingeffectondentategyrus(DG)neurogenesis proper circuit formation and neuronal development. with stressed offspring showing accelerated age-re- Many neurodevelopmental and psychiatric disorders lated reduction in cell proliferation and thus limiting including ASD and exhibit synaptic hippocampal plasticity (Lemaire et al. 2000, 2006). deficits potentially implicating microglial dysfunction Such structural abnormalities in the hippocampus give in their pathogenesis (de Cossı´o et al. 2017; Kim et al. rise to functional deficits in the affected individuals 2017; Paolicelli and Ferretti 2017; Roumier et al. such as impaired cognitive abilities. In the same vein, 2008). Abnormal MHCI-MEF2 signaling has been morphological changes like reduced hippocampal size implicated in mediating the synaptic and neural con- in schizophrenia and depression with associated cog- nectivity deficits in offspring, in mouse model of nitive deficits indicate the etiological relevance of maternal immune activation (MIA) that induces phe- prenatal stress in these conditions (Fumagalli et al. notypes of spectrum disorder (ASD) and 2007). Prenatal stress has also been reported to induce schizophrenia (Elmer et al. 2013). Microglial alter- reductionintheCA1areadendriticarborizationinthe ations have also been associated with reduction in hippocampus (Barros et al. 2006; Pallare´s et al. 2013) trophic factor (BDNF/ IGF1) release as well as over- and CA3 area synapse number (Hayashi et al. 1998). production of pro-inflammatory cytokines IL-18 and Prenatal stress in different cortical regions induced TNFa (Paolicelli and Ferretti 2017;S´lusarczyk et al. dopamine and glutamate receptor subtype changes 2015). While the former leads to malformed neural (Berger et al. 2002), caused enduring reduction in circuits the latter causes neuronal excitability by dendritic arborizations and lowered dendritic spine increasing voltage-activated Na? currents (Klapal densities in the dorsal anterior cingulate (ACd) and et al. 2016; Parkhurst et al. 2013). These develop- orbitofrontal cortex (OFC) pyramidal neurons (Barros mental alterations in brain have long-lasting program- et al. 2006;Murmuet al. 2006;Pallare´s et al. 2013). ming effects with impact on physiology, behavior and Additionally, important intrinsic brain network con- cognition during adulthood. nectivity like those in default mode network, atten- tional networks and, the amygdala–thalamus networks are compromised (Van den Bergh et al. 2018). The 3.2 Alterations in brain structure and connectivity altered brain developmental patterns have program- ming consequences leading to different adult psy- Gestational environment appears to influence the tra- chopathologies including emotional and cognitive jectory of brain development with adverse prenatal disorders in the offspring. 34 Page 6 of 16 Shams Ul Haq et al. 3.3 Epigenetic alterations to some extent in humans have shown that the prenatal stress exposure influences the epigenetic processes in Epigenetic alterations constitute an important molecu- the placenta and different brain tissues, with key genes lar mechanism that mediates prenatal stress effects on like 11b-HSD-2 gene, glucocorticoid receptor (Nr3c1) fetal brain development and thereby contributes to the gene and brain-derived neurotrophic factor (Bdnf) long lasting programming effects (Babenko et al. 2015; gene, also altered (Kundakovic and Jaric 2017; Ober- Kundakovic and Jaric 2017). Epigenetic differences lander et al. 2008; Palma-Gudiel et al. 2015; Pen˜a et al. arising in brain during development in response to 2012; Roth et al. 2009). These and other early life environmental influences (Table 1) can remain epigenetic perturbations impact the development of stable over long time and in turn may mediate vul- endocrine systems and crucial brain structures with nerability to the occurrence of psychiatric disorders in consequences for long term mental health of the indi- later life. These epigenetic modifications are being vidual like induction of neurodevelopmental disorders. actively explored to understand phenotype to genotype differences in an individual’s behavioral response to 3.3.1 Prenatal-stress-induced alterations in DNA stressful conditions in later life. Epigenetic mechanisms methylation and histone modification machineries: like DNA methylation, histone modifications and non- Expression levels of important players in epigenetic coding RNA expression have crucial role in develop- regulatory machineries of DNA methylation (DNMT1 mental processes (Babenko et al. 2012, 2015). DNA and TET1) and histone modification (Histone methylation plays a critical role in a variety of devel- deacetylases HDAC1 and HDAC2) has been reported opmental processes in the embryo. In the brain, DNA to show alterations in response to gestational stress methytransferases DNMT1, DNMT3A are crucial for (Dong et al. 2015; Zheng et al. 2016). These changes processes like synaptic plasticity with mutations in epigenetic machinery lead to alterations in DNA impacting synaptogenesis, neurogenesis, and learning methylation and histone acetylation programs which as and memory (Feng et al. 2010; Hutnick et al. 2009). indicated above are related to altered expression of Other players in DNA methylation machinery have many relevant genes including the reported downreg- also been shown to be important in neurodevelop- ulation of BDNF. In the same context, prenatal stress mental processes with mutations leading to disorders. induced altered expression of SCZ-related glutamater- As an example, mutations in methyl binding protein gic and GABAergic pathway genes through epigenetic MeCP2 have been implicated in different neurodevel- mechanisms have been reported (Dong et al. 2015; opmental disorders like X-linked mental retardation, Matrisciano et al. 2013). Several rodent studies have severe neonatal encephalopathy, autism, and Rett syn- reported prenatal stress associated increase in cytosine drome (Goffin et al. 2012; Gonzales and LaSalle methylation at different promotors of Bdnf gene in 2010). Accumulating evidence suggests that the non- hippocampus and prefrontal cortex (Blaze et al. 2017; coding RNAs like miRNAs play an important role in Dong et al. 2015;Yeet al. 2018).Prenatal toxicological neuronal development and function (Krichevsky et al. exposure studies also show that environmental toxi- 2003; Schratt et al. 2006; Sun et al. 2013). Reports cants induce lasting behavioral changes in the offspring suggest their involvement in epigenetic regulation at through epigenetic mechanisms. For example, maternal multiple levels including control of de novo DNA exposure to methyl mercury induced long-term methylation and switching chromatin remodeling depression-like behavior in the offspring and is complexes (Sinkkonen et al. 2008;Yooet al. 2009). accompanied by diminished BDNF level in the dentate Placental miRNAs’ expression and DNA methylation gyrus. This involved enduring repressive changes in patterns are also believed to have important develop- Bdnf promoter region such as increased DNA methy- mental role with any aberrations affecting fetal brain lation and histone H3K27me3, and decrease in active development (Babenko et al. 2015). Similarly, histone H3 acetylation (Onishchenko et al. 2008). Along the modifications and chromatin remodeling have been same line, long-term neurobehavioral alterations reported to play an important role in brain develop- involving epigenetic mechanisms have been reported in mental processes including production of neurons and maternal immune activation (MIA) mouse models glial cells from precursor cells (Be´rube´ et al. 2005; (Basil et al. 2014; Labouesse et al. 2015; Richetto et al. Chelly and Mandel 2001; Fischer et al. 2007; Kondo 2017). Basil et al. reported that gestational exposure to and Raff 2004). All these epigenetic mechanisms viral mimetic Poly(I:C) induces DNA hypomethyla- potentially get perturbed by stressful environmental tion, global as well as in the hypothalamic Mecp2 factors during gestation. Studies in animal models and promoter region (Basil et al. 2014). In a study by Epigenetics of prenatal stress effect on offspring behavior Page 7 of 16 34 Table 1. Summary of prenatal-stress-induced epigenetic modifications

Labouesse et al., this Poly(I:C) maternal immune increased DNA methylation at Gilz gene promoter activation lead to downregulation of GABAergic genes positively correlates with development of PTSD like glutamic acid decarboxylase (Gad)1 and Gad2 phenotype in adult offspring after PTSD induction involving epigenetic modifications such as hyperme- procedures (Lebow et al. 2019) . Although several thylation at their promoters and increased methyl CpG- studies have documented prenatal-stress-induced DNA binding protein 2 (MeCP2) promoter binding methylation changes at promoters of several candidate (Labouesse et al. 2015). Behaviorally, the result was genes, similar results from genome wide association deficits in offsprings’ working memory and social studies are somewhat inconclusive. For example, a interaction. Richetto et al. reported developmental study based on influence of maternal depressive window-specific effects of MIA involving epigenetic symptoms during pregnancy on infant DNA methyla- machinery of DNA methylation (Richetto et al. 2017). tion from Norway population did not reveal significant These changes encompassed GABAergic differentia- associations (Wikenius et al. 2019). tion and signaling genes, Wnt signaling genes and A study by Benoit et al. (2015) using chronic neural development genes with their expression level unpredictable stress reported that prenatal stress indu- associated with methylation differences. Prenatal- ces repressive epigenetic changes in the hippocampus stress-induced aberrant epigenetic modifications can with prenatally stressed males exhibiting reduction in dysregulate transcriptional output of the affected gene acetylated histone H3K14 (AcH3) while as female which in turn predisposes the individual to the devel- offspring show a further decrease in AcH3 along with opment of psychiatric disorders in adulthood. CRF very elevated DNMT1 protein levels (Benoit et al. induced gestational stress in male mice increased DNA 2015). Similarly, prenatal stress induced mRNA and methylation at promoter region of glucocorticoid-in- protein expression of histone deacetylase 1 (HDAC1) duced leucine zipper Gilz gene in the amygdala that and HDAC2 in mice. Furthermore, at BDNF promoter inversely correlates with Gilz mRNA expression. This regions , a significant decrease in levels of acetylated 34 Page 8 of 16 Shams Ul Haq et al. histone H3 lysine 14 (AcH3K14) has been observed in gene Dazap1 in humans is a putative marker for prenatal stressed mice (Zheng et al. 2016). In a similar schizophrenia and bipolar affective disorder. Results study with restraint prenatal stress, the stress was from Hollins et al., 2014 also revealed significant associated with attenuated levels of H3K14Ac levels in alterations in offspring miRNA expression induced by median prefrontal cortex (Dong et al. 2015). Prenatal adverse gestational environment. Using poly I:C stress resulted in decreased levels of H3K9Ac at Tph2 maternal immune activation model they report miRNA gene promoter in hippocampus of male juvenile off- expression changes predominantly in the entorhinal spring. This decreased acetylation at Tph2 promoter cortex (EC) left hemisphere with relevance to psychi- correlated with expression of depressive symptoms in atric pathologies (Hollins et al. 2014). Along the same juvenile male offspring along with attenuated mRNA lines, Wang et al. reported that a number of miRNAs levels of Tph2. Interestingly, HDAC inhibitor treatment show altered expression in fetal brain and Laufer et al. with trichostatin resulted in restoration of H3K9Ac at reported genome-wide DNA methylation, miRNA and tph2 gene in hippocampus along with amelioration of small nucleolar RNA (snoRNA) expression alterations depressive symptoms (Dang et al. 2018). Global levels in adult offspring brain in response to in utero ethanol of H3K9Ac, H3K4Me3, H3K9Me2 and H3K27Me3 exposure (Laufer et al. 2013; Wang et al. 2008). In the are dynamically regulated during brain development Laufer et al. study, a significant subset of altered non and have been reported to peak in hippocampus and coding RNAs mapped to three brain specific imprinted prefrontal cortex from postnatal day 0 to PND 6 as regions (Snrpn-Ube3a, Dlk1-Dio3 and Sfmbt2) that compared to embryonic 18.5. PND 0 to PND 6 time have been associated with neurodevelopmental disor- period is important as it corresponds to large scale ders previously. These regions were also found to changes in brain myelination, synaptogenesis and gli- exhibit DNA methylation alterations suggesting its ogenesis, etc. in rodents. Restraint Prenatal stress in possible role in co-regulation of these clusters (Laufer mice has been shown to increase H3K9Ac in frontal et al. 2013). It is being envisioned that maternal stress cortex and decrease H3K9Ac, H3K9Me2 and induces many miRNAs that diffuse to fetal blood and H3K27Me3 in hippocampus of male mice at PND6 ultimately affect several neurodevelopmental processes (Varma et al. 2017). A similar study has also reported in developing fetus via downregulation of key genes region and time specific perturbations of histone post involved in such processes. In this direction several translational modifications in mice, viz., prenatal stress differentially expressed miRNAs (miR-3589, miR-455, increased H3K9/14Ac levels at PND 0 in frontal cortex miR-130a, miR-134, miR-25, miR-495) have been and decreased H3K9Me3 at PND6 in hippocampus reported in fetal plasma collected from social defeat (Schneider et al. 2016). Another study in rats showed induced stressed mothers (Scott et al. 2020). Blood prenatal restraint stress leading to reduction in Reelin- miRNAs have a potential diagnostic value for evalua- positive neurons in cortical layer I accompanied with tion of early life stress and also in determination of risk reduced Reelin expression (Palacios-Garcı´a et al. for psychiatric disorders. Using unbiased miRNome 2015). These down-regulatory changes in Reelin analysis, Cattane et al. established a detailed prenatal- expression in PNS neurons were strongly associated stress-induced expression profile of miRNAs in blood with increased CpG DNA methylation levels at the of adults subjected to childhood trauma, hippocampus Reelin gene promoter and with higher offspring anxiety of rats’ offspring exposed to restraint prenatal stress and learning and memory problems. and human hippocampal neural progenitor cells. This study demonstrated that certain stress induced molec- 3.3.2 Prenatal-stress-induced alterations in small RNA ular dysregulations (e.g., miRNAs) are conserved expression: Recent reports have provided evidence for across various tissues and species as well. Integrated alteration in small RNA profiles associated with off- analysis of all the three data sets revealed miRNA spring brain pathology as a consequence of prenatal 125-1-3p as a single common downregulated miRNA environmental insults. Zucchi et al. reported that hun- and further several of its predicted targets (Bcl11b, dreds of miRNAs in the offspring brain show differ- Creb3l1, Hcn1, Ypel3) have been implicated in ential expression after gestational stress (Zucchi et al. schizophrenia (Cattane et al. 2019). 2013). Putative target genes of altered miRNAs include those involved in neurodevelopment, neurotransmis- 3.3.3 Prenatal-stress-induced epigenetic alterations sion and different neuropathologies. Inflammatory in placental 11b-HSD-2 expression and HPA axis: response related miRNAs (miR-323 and miR-98) were Maternal cortisol, as mentioned above, is a major upregulated as was miR-219 which along with its target mediator of maternal stress transfer and under stressful Epigenetics of prenatal stress effect on offspring behavior Page 9 of 16 34 conditions, developing fetus is exposed to its elevated significantly reduced by prenatal stress. In a genome levels. Chronic stress to mothers during gestation not wide occupancy analysis of O-GlcNAc by Chip-seq only raises their blood corticosteroids sharply but also experiments, it was observed that changes in occu- increases placental cortisol permeability via down- pancy of O-GlcNAc and H3K4Me3 at same genomic regulation of cortisol inactivating 11b-HSD-2 gene locus cooperatively affect the gene expression in pla- expression in placenta. Reduction in 11b-HSD-2 centa, viz., prenatal-stress-induced attenuations of expression in the placenta contributes to the increased O-GlcNAc and H3K4Me3 at Hsd17b3 (an enzyme fetal exposure to cortisol which in turn perturbs normal involved in conversion of androstenedione to testos- fetal brain development. Findings from Pena et al. terone) locus corelates with repression of this gene in 2012 suggest that prenatal-stress-induced repression of male prenatal stressed placentas as compared to control 11b-HSD-2 gene in placenta involve DNA methylation placenta (Howerton and Bale 2014). Sex differences in machinery (Pen˜a et al. 2012). They found prenatal O-linked N-acetylglucosamine transferase were shown stress was associated with reduced 11b-HSD-2 mRNA to mediate the effects of prenatal stress on neurode- expression, increased DNA methyltransferase3a velopmental programming as targeted trophoblast- (DNMT3a) mRNA levels, and hypermethylation at specific deletion of Ogt recapitulated the prenatal stress specific CpG sites of 11b-HSD-2 gene promoter in the phenotype (Howerton and Bale 2014). These studies placenta. Consistent with this, human studies have also suggest that placental Ogt function and the subsequent revealed prenatal stress correlation with 11b-HSD-2 trans-placental signals are critical for the developing hypermethylation (Monk et al. 2016) and down brain, and that Ogt sex differences may mediate the expression of 11b-HSD-2 mRNA in placenta higher vulnerability in male offspring to neurodevel- (O’Donnell et al. 2012). Mueller and Bale (2008) opmental disorders. One mechanism involved in this reported sex specific programming of prenatal stress varied vulnerability to prenatal stress is by determining which was related to gestational timing of stress sex-specific trophoblast gene expression patterns and exposure. Early prenatal stress resulted in depression regulation of the histone repressive mark, H3K27me3 like behavior in adult male offspring which was (Nugent et al. 2018). Male and female trophoblasts accompanied with epigenetic regulatory effects on were found to show differences in their epigenomic CRH and NR3C1 genes in amygdala and hippocampus programming due to varied placental Ogt dosage with respectively (Mueller and Bale 2008). There was trophoblast gene expression in females exhibiting more hypermethylation at the NR3C1 promoter region and baseline homogeneity. Higher levels of H3K27me3 correspondingly reduced expression of NR3C1 gene in leading to epigenetically more repressive chromatin hippocampus. They also reported hypomethylation at state in females provide them relative resilience against CpG cytosines of CRH gene promoter in hypothalamus transcriptional fluctuations due to prenatal insults and amygdala and elevated CRH expression levels in (Nugent et al. 2018). the amygdala. The study thus suggests epigenetic mechanistic link involving HPA axis for prenatal- 3.3.4 Prenatal-stress-induced epigenetic signatures: stress-induced lasting behavioral alterations. Further, Examples from human research: Events like Dutch the observed sex differences were found to show cor- Hunger Winter or the Holocaust have provided evi- relation with expression levels of number of placental dence that epigenetic mechanisms are associated with genes including DNMT1 (Mueller and Bale 2008). The long term programming in humans. Heijmans et al. human study in this regard by Oberlander and col- reported decreased methylation of CpG in insulin leagues reported maternal depressed mood being growth factor 2 [IGF2] gene, a gene important in associated with hypermethylation at specific CpG sites growth and metabolism, in blood samples of adults of NR3C1 in cord blood at birth which in turn was from mothers prenatally exposed to famine (Heijmans associated with elevated HPA stress reactivity early in et al. 2008). Similarly, Yehuda et al. have reported infancy (Oberlander et al. 2008). reduced cytosine methylation within FKBP5 gene Research from the Bale lab also uncovered placental region in blood samples of offspring of Holocaust O-linked N-acetylglucosamine transferase (Ogt) as a survivors that correlated with decreased wake-up cor- biomarker of prenatal stress exposure in mice, medi- tisol levels (Yehuda et al. 2016). Along the same lines, ating sex specific programming of prenatal stress project ice storm studies revealed genome-wide epi- (Howerton et al. 2013). The Ogt mRNA and protein genetic signatures in children exposed prenatally. There levels in the male placental tissue are nearly half of that was differential methylation of CpGs mostly in in females to begin with, which is then further immune function related genes that showed correlation 34 Page 10 of 16 Shams Ul Haq et al. with degree of objective hardship. The patterns were Junior and Senior Research Fellowship. UAB comparable in varied samples such as saliva, T cells acknowledges CSIR fellowship supports for doctoral and peripheral blood mononuclear cells (PBMCs) research and department of Biotechnology, India, for (Cao-Lei et al. 2014). These studies show program- senior research fellowship. ming at molecular levels in response to external stres- sors, which then determines offspring health outcomes in humans. References

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