Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-related Stress

Prenatal adversity or stress can have long-term consequences on developmental trajec-tories and health outcomes. Although the biological mechanisms underlying these effects are poorly understood, epigenetic modifications, such as DNA methylation, have the potential to link early-life environments to alterations in physiological systems, with long-term functional impli-cations. We investigated the consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early devel-opment. As these insults can have sex-specific effects on biological outcomes, we analyzed epige-nome-wide DNA methylation patterns in prefrontal cortex, a key brain region involved in cogni-tion, executive function, and behavior, of both males and females. We found sex-dependent and sex-concordant influences of these insults on epigenetic patterns. These alterations occurred in genes and pathways related to brain development and immune function, suggesting that PAE and food-related stress may reprogram neurobiological/physiological systems partly through central epigenetic changes, and may do so in a sex-dependent manner. Such epigenetic changes may re-flect the sex-specific effects of prenatal insults on long-term functional and health outcomes and may have important implications for understanding possible mechanisms underlying fetal alco-hol spectrum disorder and other neurodevelopmental disorders.产前逆境或应激可对个体发育轨迹与健康结局产生长期影响。尽管此类效应背后的生物学机制尚不完全明晰，但表观遗传修饰（epigenetic modifications）有望将早期生命环境与生理系统改变相关联，并带来长期功能层面的影响。本研究探讨了两种产前损伤——产前酒精暴露（PAE）与食物相关应激——对发育早期大鼠大脑DNA甲基化（DNA methylation）谱的影响。鉴于此类损伤可对生物学结局产生性别特异性影响，本研究对雌雄大鼠前额叶皮层（prefrontal cortex）这一参与认知、执行功能与行为调控的关键脑区的全基因组DNA甲基化模式进行了分析。研究发现，这两种产前损伤对表观遗传模式的影响兼具性别依赖性与性别一致性。此类改变发生于与脑发育及免疫功能相关的基因与通路中，提示产前酒精暴露与食物相关应激或可通过中枢表观遗传改变部分重塑神经生物学/生理系统，且该过程呈现性别依赖性特征。此类表观遗传改变或可反映产前损伤对长期功能结局与健康结局的性别特异性影响，同时对解析胎儿酒精谱系障碍及其他神经发育障碍的潜在致病机制具有重要价值。