Transgenerational inheritance of fetal alcohol effects on proopiomelanocortin gene expression and methylation, cortisol response to stress, and anxiety-like behaviors in offspring for three generations in rats: Evidence for male germline transmission

Abstract

Previously it has been shown that fetal alcohol exposure increases the stress response partly due to lowering stress regulatory proopiomelanocortin (Pomc) gene expression in the hypothalamus via epigenetic mechanisms for multiple generations in mixed-breed rats. In this study we assess the induction of heritable epigenetic changes of Pomc-related variants by fetal alcohol exposure in isogenic Fischer 344 rats. Using transgenerational breeding models and fetal alcohol exposure procedures, we determined changes in hypothalamic Pomc gene expression and its methylation levels, plasma corticosterone hormone response to restraint stress, and anxiety-like behaviors using elevated plus maze tests in fetal alcohol-exposed offspring for multiple generations in isogenic Fischer rats. Fetal alcohol-exposed male and female rat offspring showed significant deficits in POMC neuronal functions with increased Pomc gene methylation and reduced expression. These changes in POMC neuronal functions were associated with increased plasma corticosterone response to restraint stress and increased anxiety-like behavior. These effects of fetal alcohol exposure persisted in the F1, F2, and F3 progeny of the male germline but not of the female germline. These data suggest that fetal alcohol exposure induces heritable changes in Pomc-related variants involving stress hyperresponsiveness and anxiety-like behaviors which perpetuate into subsequent generations through the male germline via epigenetic modifications.

Epigenetic insight into effects of prenatal alcohol exposure on stress axis development: Systematic review with meta‐analytic approaches

“…Findings in animal models are largely consistent with the human literature: PAE animals show higher basal corticosterone levels, increased HPA responsiveness to stressors (increased ACTH, CRH, vasopressin responses; Gangisetty et al, 2014Gangisetty et al, , 2022Govorko et al, 2012;Lu et al, 2018); reduced POMC gene expression in the arcuate nucleus (Bekdash et al, 2013;Gangisetty et al, 2014;Govorko et al, 2012); reduced GR expression in the amygdala and PVN (Lam et al, 2018;Raineki et al, 2019); altered GR and mineralocorticoid (MR) expression in the hippocampus (Raineki et al, 2018), most of which, varied by the sex, nature of the stressor, time course, and endocrine endpoint measures (Lam et al, 2018;Raineki et al, 2019). POMC gene expression reduction in PAE rats may be an important component of stress hyperresponsivity, since POMC-derived peptides β-endorphin and their receptors suppress CRH secretion into the pituitary portal blood (Plotsky et al, 1991), and POMC neuronal transplants into the PVN suppress stress hyperresponse in PAE offspring rats (Logan et al, 2015).…”

Epigenetic Effects in HPA Axis Genes Associated with Cortical Thickness, ERP Components and SUD Outcome

“…Our findings indicating hypermethylation of the promoter region within the POMC gene are especially interesting in view of previous reports that prenatal use of alcohol increases the stress response of exposed offspring in part due to the lowering of POMC expression through an epigenetic mechanism [ 94 ]. In the most recent work by these investigators [ 95 ] fetal alcohol-exposed rat offspring showed increased POMC methylation and reduced gene expression that was associated with increased plasma corticosterone response to restraint stress and increased anxiety-like behavior.…”

Fetal alcohol spectrum disorders

“…Alcohol can disrupt development by inducing DNA methylation and histone acetylation in gene clusters and altering gene expression 121 . Epigenetic alterations resulting from PAE have been observed in animal models and humans, and these changes may be lifelong and inherited by future generations 118,[122][123][124] . A pattern of DNA methylation in buccal epithelial cells was reasonably accurate (positive predictive value 90%; negative predictive value 78.6%) in discriminating children with FASD from typically developing controls or children with autism spectrum disorders 125 .…”