Exposure to extrinsic stressors, social defeat or bisphenol A, eliminates sex differences in DNA methyltransferase expression in the amygdala

Abstract

Chemical and psychological stressors can exert long lasting changes in brain function and behavior. Changes in DNA methylation have been shown to be an important mechanism mediating long lasting changes in neural function and behavior, especially for anxiety-like or stress responses. Here we examined the effects of either a social or chemical stressor on DNA methyltransferase (DNMT) gene expression in the amygdala, an important brain region modulating stress responses and anxiety. In adult California mice (Peromyscus californicus) that were naïve to social defeat, females had higher levels of Dnmt1 expression in punch samples of the central amygdala (CeA) than males. In addition, social defeat stress reduced Dnmt1 and Dnmt3a expression in the CeA of females but not males. A second study using more anatomically specific punch samples replicated these effects for Dnmt1. Perinatal exposure, spanning from periconception through lactation, to bisphenol A or ethinyl estradiol (estrogens in birth control pills) also abolished sex differences in Dnmt1 expression in the CeA but not basolateral amygdala. These findings identify a robust sex difference in Dnmt1 expression in the CeA that is sensitive to both psychological and chemical stressors. Our results suggest that future studies should examine the impact of psychological and chemical stressors on DNA methylation in the CeA and that Dnmt1 may have an underappreciated role in plasticity in behavior.

Sex Differences in Autism Spectrum Disorder: a Review

“…In addition, dendritic spines are mediated by sex hormones in many areas of the brain and are abnormal in several mouse models of ASD and individuals with ASD [42–50]. Finally, animal studies have indicated that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) have sex-specific effects on behavior and can be influenced by sex hormones [51,52]. These epigenetic mechanisms, along with chromatin modifications, and microRNA expression, are new areas of interest in the ASD field and may be influenced by sex hormones to contribute to susceptibility [53].…”

Sex differences: Transcriptional signatures of stress exposure in male and female brains

“…Apart from the classic stress‐related genes presented so far, other genes have been reported to modulate their expression in a sex‐specific way. For example clock genes, genes involved in the sex steroid system, and genes encoding for epigenetic mediators …”

“…Given the fact that MR and GR are both two important transcription factors and that epigenetic players such as DNA methyltransferases seem to be modulated by sex in the context of stress, it would not be surprising to find altered transcription levels on a more general scale. Unfortunately, large‐scale approaches taking into consideration sex as a variable are still poorly represented in stress research .…”

“…For example clock genes, 115 genes involved in the sex steroid system, 101,103 and genes encoding for epigenetic mediators. 104,116,117 The gene expression changes described so far have been specifically observed in the context of physical stressors. In contrast, psychological stressors, such as footshock witnessing, have unfortunately received less attention.…”

Epigenetic Advances in Behavioral and Brain Sciences Have Relevance for Public Policy

“…One factor that has profound implications for physical and mental health is psychosocial stress, and experimental approaches in both animal models (Hunter, McCarthy, Milne, Pfaff & McEwen, 2009; Makhathini, Abboussi, Stein, Mabandla & Daniels, 2017; Roth, Zoladz, Sweatt & Diamond, 2011; Tsankova et al, 2006; Wright et al, 2017) and humans (Edelman et al, 2012; Mehta et al, 2013; Rusiecki et al, 2013; Uddin et al, 2010; Unternaehrer et al, 2012; Ursini et al, 2011; Yehuda et al, 2013) reliably link stress with epigenetic alterations. For example, subjecting a rodent to psychosocial stress in the form of predatory and/or restraint stress (Makhathini et al, 2017; Roth et al, 2011) or social defeat stress (LaPlant et al, 2010; Wright et al, 2017) evokes robust changes in DNMTs and DNA methylation. Mildly stressful experiences evoke rapid changes in DNA methylation in adult participants of a Trier Social Stress Test, a lab-based stress paradigm useful for studying stress responses in humans (Edelman et al, 2012; Unternaehrer et al, 2012).…”