Epigenetic Transmission of the Impact of Early Stress Across Generations

“Environmental risk factors implicated in affective disorders that have been shown to program heritable behavioral traits in mice include fearful experiences in adulthood (Dias & Ressler, 2014) as well as early life stress (Bohacek et al., 2014; Franklin et al., 2010).”

“It has also been demonstrated that MS, like the LG-ABN model can produce transgenerational epigenetic effects, though, in contrast to the later model, some of the changes in DNA methylation appear to be passed on in the male germ line (Franklin et al., 2010).”

“the effects of life stresses [221] and resilient behaviors [203] can”

“As a specific example, mice that were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14 were differentially methylated in several candidate genes, including: MeCP2, CB1, and CRFR2 (44).”

“Another group demonstrated that chronic and unpredictable stress during early postnatal life causes depression and alters responsivity to aversive environments in adult mice [109].”

“Given that FST alone was significantly different in IVF-derived mice [118] together with previous findings that epigenetic changes in DNA methylation was observed moderately in offsprings of stress vulnerable mice [117] could suggest that each gene possibly contributes to a small part of the behavioural phenotype and…”

“The retention of genomic methylation patterns in sperm of exposed parents and brains of offspring may occur following generational stress (Franklin et al., 2010) or drug-exposure (Govorko et al., 2012).”

“…example, a number of studies in rats and mice report different emotional traits to be predominantly affected in males by diverse pre- and postnatal paradigms (Wigger and Neumann, 1999; Barna et al., 2003; Mueller and Bale, 2008; Franklin et al., 2010; Freund et al., 2013; Kundakovic et al., 2013).”

“This phenomenon has been reported to occur after in utero endocrine disruptor exposure (8), postnatal stress (9), alcohol exposure (10), and dietary changes (11).”

“…life experience and other environmental insults acquired in the parental generation may result in altered brain function and behavioral changes in subsequent generations (Weaver et al., 2004; Arai et al., 2009; Franklin et al., 2010; Bohacek et al., 2013; Dias and Ressler, 2014; Gapp et al., 2014).”

“In mice, unpredictable maternal separation combined with unpredictable maternal stress was shown to lead to a wide range of behavioral symptoms including depressive-like behaviors, social withdrawal, impaired social recognition, and reduced risk assessment [30, 48, 49].”

“…sexually dimorphic brain development (i.e., feminize male development) can carryover and produce the same reversal in the following generation (Franklin et al. 2010; Morgan and Bale 2011) demonstrates the potential for epi-marks laid down during very early development to influence androgen…”

“This not only alters the DNA methylation profile in the germline of the affected males, and their behavioural response to adverse environments, but it is also associated with modified brain gene expression in their offspring, even when these are raised under normal conditions [136].”

“DNA methylation profile in both the fathers’ sperm and the offspring cortex, including genes related to transcriptional regulation (such as methyl CpG binding protein 2, MeCP2) and to affective and stress responses (such as cannabinoid receptor 1, CB1 and corticotrophin-releasing factor receptor 2, CRFR2, respectively…”

“, 1982; Abel, 1993, 2004) or genetic imprinting, with very limited analysis of epigenetic reprogramming of the sperm prior to conception (Franklin et al., 2010; Miller et al., 2010; Mychasiuk et al., 2012).”

“…stress or environmental insults, using a variety of paradigms across developmental stages, on offspring behavior, neurology, and sperm (Bale, 2014; Franklin et al., 2010; Yehuda & Lehrner, 2018), although not all stressors have been shown to affect offspring through sperm (Dietz et al., 2011).”

“A shorter, repeated version of the MS model commonly used in mice can be less reliable, sometimes eliciting changes but with no consistent effects (Millstein and Holmes 2007), possibly due to the dams ability to adapt and provide compensatory care to the pups (Franklin et al. 2010).”

“In the context of early-life adversity, Franklin et al. (2010) reported increased methylation of genes coding for methyl CpG-binding protein 2 (MeCP2) and the cannabinoid receptor-1 (CB1) and decreased methylation for the genes coding for corticotrophin-releasing factor receptor 2 (CRFR2) in the…”

“These alterations may be derived from genetic disruptions or environmental modulations that may lead to epigenetic alteration of the ECS, as revealed by early stress-induced alterations in methylation patterns of the cannabinoid CB1 gene (Franklin et al., 2010).”

“Furthermore, although raised in normal conditions, F1, F2 and F3 offspring of the F0 males display most of the behavioural alterations of the F0 adult males (Franklin et al., 2014).”

“…in rodent models of psychosis, among others (Steptoe et al., 2001; Welberg and Seckl, 2001; Koenig et al., 2002; Seo et al., 2006; Van den Hove et al., 2006; VanbesienMailliot et al., 2007; Murgatroyd et al., 2009; Franklin et al., 2010; Morgan and Bale, 2011; Matrisciano et al., 2012).”

“Furthermore, maltreatment of rat pups results in a life-long, and even a transgenerational, effect on behavior and DNA methylation (Roth et al., 2009; Franklin et al., 2010).”

“Maternal separation (8), social defeat (9), and chronic variable stress (10) are correlated with hypersensitivity to similar stresses in descendants in mice.”

“…highly plastic and therefore environmental factors are able to shape the forming networks within the brain and neuroendocrine system (Bock et al., 2014) through epigenetic modifications to a number of genes within the HPA axis (Weaver et al., 2004; Murgatroyd et al., 2009; Franklin et al., 2010).”

“Promoter DNA methylation is associated with altered MECP2 expression in autistic brains [30,31], and altered Mecp2 expression in the brains of stressed mice [32].”

“Male mice who experienced MS also had changes in sperm DNA methylation (Franklin et al., 2010), although it is still unclear on how much effect this method of epigenetic transmission has on offspring.”

“These observations have significant implications, especially considering the evidence that show stress early in life can cause epigenetic mechanisms that persist through adulthood and across generations (Gross and Hen, 2004; Franklin et al., 2010; Zhang et al., 2013).”

“Early life stress is a prominent risk factor for neuropsychiatric diseases, and in rodents it leads to increased anxiety and depressive-like behavior that can be observed even in the offspring, albeit this second generation was never exposed to such stress (Franklin et al , 2010).”

“epigenetic and cytoplasmically transmitted effects is a second major area of possible advance[6,19] for instance as heritable factors in cancers;[119,120] obesity, metabolic, and cardiovascular disease[121,122] and response to stress.[123,124] Including these inheritance processes may considerably enhance the limited…”

“ternal separation combined with unpredictable maternal stress” (MSUS), separating mice mothers from their pups at “any time during the dark cycle” daily, and then either placing the mothers in a restraint or in a forced-swim task [42, 43].”

“demonstrated that trait transmission in mice occurs through males, altering DNA methylation in the germline, and affects the offspring in a sex-dependent manner [284].”

“Based on a large body of work (Bale et al., 2010; Borrelli et al., 2008; Franklin et al., 2010; Haggarty et al., 2010; McGill et al., 2006; Mueller & Bale, 2008; Sweatt, 2009), epigenetic mechanisms are excellent candidates for this enduring, augmented expression of the Crh gene in hippocampus.”

“, 2011); however, recent evidence suggests that environmental manipulation in fathers such as chronic stress (Bohacek et al., 2015; Franklin et al., 2010; Short et al., 2016), social instability (Saavedra-Rodrı́guez and Feig, 2013), diet (Carone et al.”

“This manipulation severely affects behavior across multiple generations (Franklin et al., 2011; Franklin et al., 2010; Weiss et al., 2011).”

“In this context, it was recently reported that chronic stress induces epigenetic changes, which impact DNA methylation patterns and consequent effects on gene expression in both germline and somatic tissues [30].”

“Furthermore, the role of CRF1 expression in oocytes of stressed rats as a potential mechanism for the transmission of stress effects to offspring has not been considered, although CRF1 messenger RNA (mRNA) is expressed in mature oocytes and is altered by stress (23), and other studies suggest that gene expression chan…”

“The impact of infant (male and female) separation on depressive-like behaviors and Crh and GR gene expression in the hypothalamus have been linked to DNA methylation profiles (Chen, Evans, et al., 2012; Franklin et al., 2010).”

“Low LG-ABN offspring also show decreased inhibitory GABAA eceptors in the locus coeruleus, medial PFC, and amygdala [48,49]. n addition, low LG-ABN offspring had increased DNA methylation n the promoter region of the GAD1 gene (the rate-limiting enzyme Please cite this article in press as: S.B. Burns, et al., Plastici…”

“Further, very recent studies have clearly demonstrated transgenerational transmission of programmed changes in depressive-like behaviors followingmaternal stress during lactation in mice (Franklin et al., 2010).”

“Toxic stress caused by family separation or similar adverse experiences in childhood can impact health through mechanisms of systemic inflammation, immune dysregulation, changes in neurocognitive development, heightened psychological reactivity, cellular aging, and DNA methylation (Drury et al., 2014; Fagundes et al.,…”

“Postnatal stress has also been shown to induce stress dysregulation in subsequent generations, including observations of behavioral deficits on the forced swim task and decreased blood glucose in response to acute restraint in first and second generation offspring of male mice exposed postnatally to unpredictable mate…”

“Two groups studying mice reported that epigenetic alterations induced by social stress could be transmitted to the next generation [121,122].”

“, 2010), and the impact of chronic and unpredictable infant separation on depressive-like behaviors in mice that experienced the stress and in their subsequent offspring has been linked to the DNA methylation profile of several stress-related and behaviorally relevant genes (Franklin et al., 2010).”

“Stress produces DNAmethylation changes at particular genes in the sperm of stressed mice [25], yet it is far from certain whether such modifications contribute to the differences seen in stress vulnerability (see below).”

“The basic concepts of this study were repeated in several other animal models of early-life adversity and found similar epigenetic alterations in genes such as the Bdnf (Roth et al., 2009), Avp (Murgatroyd et al., 2009), Crh (Elliott et al., 2010), Crhr2 (Franklin et al., 2010), Gad1 (Zhang et al., 2010b) and Olfr151…”

“Interestingly, though paternal stress does not impact behavioural phenotypes in male offspring, males are capable of transmitting the phenotype to their offspring suggesting that males act as ‘carriers’ of the epigenetic mark [61,62].”

“Animal studies also suggest that these epigenetic modifications can be passed to offspring (e.g., Franklin et al., 2010).”

“It has been hypothesized that these apparently heritable effects may be underpinned by an epigenetic mechanism transmitted via sperm.(43) However, these studies remain highly controversial in light of currently accepted models that epigenetic modifications are erased during meiosis.”

“The influence of father’s experience on offspring can be observed even under conditions when there is no direct paternal–offspring contact during the postnatal period (Anway & Skinner, 2006; Franklin et al., 2010; Gapp et al., 2014; Rodgers et al., 2015).”

“Mice exposed to chronic and unpredictable aversive events, for example, not only show characteristic methylation in the promoter of several genes in the germline, their offspring continue to show comparable patterns of methylation and resulting changes in gene expression (Franklin et al., 2010).”

“101 neurochemical and behavioural changes in the pups that persist into their adulthood (Franklin et al., 2010; Meaney et al., 1988; Moffett et al., 2007; Pryce et al., 2001; Weaver et al., 2004).”