Postnatal maternal care impacts hypothalamic Esrrg gene expression, co-expression profiles, and the DNA methylome in prenatal bisphenol-exposed rats [BiSulfite-seq]

Background: Environmental exposures co-occurring during early life have a profound influence on neurodevelopment. Our previous work in rats suggests that postnatal maternal care modulates the effects of prenatal exposure to bisphenols, an estrogenic endocrine disrupting chemical, on offspring neurodevelopment. Elevated postnatal maternal licking/grooming and prenatal bisphenol exposure have known opposing effects on estrogen receptor alpha (Esr1) expression in the medial preoptic area (MPOA) of the hypothalamus, which could impact expression of estrogen-responsive genes. Based on this previous work, we hypothesized that postnatal maternal licking/grooming would mitigate the effects of prenatal bisphenol exposure on Esr1 expression and estrogen-responsive genes in the developing MPOA. In addition, we hypothesized that there would be interactive effects of prenatal bisphenol exposure and postnatal maternal licking/grooming on DNA methylation, particularly nearby estrogen responsive elements. Results: Our results indicated a significant interaction between prenatal bisphenol exposure and maternal postnatal licking/grooming on estrogen-related receptor gamma (Esrrg) expression in female pups. These interactions were also evident in co-expression gene profiles in female pups; the majority of which were enriched for estrogen-responsive genes. Finally, DNA methylation analyses indicated that adding postnatal maternal licking/grooming as a covariate influenced the number of differentially methylated regions for prenatal bisphenol-exposed male and female pups. These differentially methylated regions were enriched for binding sites for transcription factors that are known to interact with estrogen receptors, suggesting some secondary effects on postnatal gene regulation. Conclusions: These results suggest a novel biological mechanism in which postnatal maternal care can mitigate the negative neurodevelopmental impacts of prenatal bisphenol exposure.研究背景：早期生命阶段共存的环境暴露对神经发育具有深远影响。我们此前基于大鼠模型开展的研究表明，产后母鼠照料可调节产前暴露于双酚类物质（bisphenols）——一类雌激素内分泌干扰化学物（estrogenic endocrine disrupting chemical）——对子代神经发育的效应。已有研究证实，产后增加的舔舐/理毛行为与产前双酚暴露，对下丘脑内侧视前区（medial preoptic area, MPOA）内的雌激素受体α（estrogen receptor alpha, Esr1）表达具有相反的调控作用，这可能影响雌激素应答基因的表达水平。基于上述前期研究，我们提出两项假设：其一，产后母鼠舔舐/理毛行为可缓解产前双酚暴露对发育中MPOA内Esr1表达及雌激素应答基因的影响；其二，产前双酚暴露与产后母鼠舔舐/理毛行为会对DNA甲基化产生交互效应，尤其是在雌激素应答元件邻近区域。 研究结果：我们的研究结果显示，产前双酚暴露与产后母鼠舔舐/理毛行为之间存在显著交互作用，该作用可影响雌性幼崽的雌激素相关受体γ（estrogen-related receptor gamma, Esrrg）表达。这类交互效应在雌性幼崽的共表达基因谱中同样显著，其中多数基因富集于雌激素应答基因集合。最后，DNA甲基化分析表明，将产后母鼠舔舐/理毛行为作为协变量纳入分析，会改变产前双酚暴露的雄性和雌性幼崽的差异甲基化区域数量。上述差异甲基化区域富集有已知可与雌激素受体相互作用的转录因子结合位点，提示其对产后基因调控存在一定次级效应。 研究结论：上述结果揭示了一种全新的生物学机制，即产后母鼠照料可缓解产前双酚暴露对神经发育的负面影响。