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.
Highlights
The transgenerational effect of environmental toxicants was first demonstrated in rodent models in 2005 [1]
We assessed the induction of heritable epigenetic Pomc-related variants by fetal alcohol exposure in isogenic Fischer 344 (F344) rats maintained in standardized conditions in order to control both genetic and environmental sources of variations
We found the Pomc gene expression level was significantly lower in male offspring derived from the fetal alcohol-fed male germline (AFM) in the F2 and F3 generations (Fig 1C and 1E)
Summary
The transgenerational effect of environmental toxicants was first demonstrated in rodent models in 2005 [1]. Our recent study using a human cohort of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) identified higher DNA methylation of the proopiomelanocortin (POMC) gene, which regulates stress axis functions, in mothers (and in their children) who gave birth to children with fetal alcohol spectrum disorder [22]. These data support the notion that epigenetic mechanisms might be involved in transgenerational effects of alcohol. The data of this study indicate a significant increase in methylation levels in the proximal part of Pomc promoter with the concomitant reduction in Pomc mRNA levels, in association with enhancement of stress hormone response to a stress challenge and increased anxiety-like behaviors in F1, F2, or F3 male progeny of the alcohol-fed mother’s male lineage
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