Sexually dimorphic epigenetic regulation of fetal brain development by environmental stressors

项目摘要 行为和认知神经发育障碍的患病率，如自闭症谱系障碍 （ASD）是增加产前暴露于致病性环境应激源，如抗癫痫药， 稳定情绪的药物，丙戊酸（VPA）和有机磷杀虫剂，如毒死蜱。下- 说谎的细胞和分子机制尚不清楚。许多精神障碍是性二态性的。一些 (e.g., ASD和ADHD）在男性中更常见，而其他（例如，抑郁症和焦虑症） 在女性中更为常见。这项研究计划的目标是调查这些性别的生物学基础 胚胎小鼠大脑在妊娠早期暴露于环境应激源的差异，在出现之前， 性激素水平。PI发表的工作已经确定了VPA诱导的激活中的性别差异。 表观遗传标记，H3 K4 me 3，导致Bdnf的性二态表达，Bdnf是编码脑源性 神经营养因子这些关于BDNF的研究建立了一个实验范例，用于识别其他性- 调节大脑发育的双态蛋白质，可能介导环境的致病作用， 精神压力对大脑发育的影响一个重要的线索，潜在的机制是，酶 调节H3 K4 me 3的H3 K4-脱甲基酶JARID 1C和JARID 1D由X上的基因编码， Y染色体，因此被假定为在两种性别中差异表达。的 这项研究计划的具体目标是：1）确定与早期大脑发育有关的基因（此外， Bdnf），由于性二态性，在男性和女性中对VPA的反应不同， H3 K4三甲基化和2）测试JARID 1基因表达和酶活性在H3 K4三甲基化中更高的假设。 男性比女性，从而提供了一个合理的机制，性二态基因表达在 胎儿大脑鉴定这些基因，特别是如果发现与一个或多个发育相关的基因， 相关的信号通路，将导致更清楚地了解神经发育障碍的病因， 并为未来的假设驱动的举措提供基础，以确定致病性 其他环境应激因素在妊娠早期的作用机制。

PROJECT SUMMARY The prevalence of neurodevelopmental disorders of behavior and cognition such as autism spectrum disorders (ASDs) is increased by prenatal exposure to pathogenic environmental stressors such as the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) and organophosphate insecticides such as chlorpyrifos. The under- lying cellular and molecular mechanisms are not known. Many mental disorders are sexually dimorphic. Some (e.g., ASD and ADHD) are more common in males whereas others (e.g., major depression and anxiety) are more common in females. A goal of this research program is to investigate the biological basis for these sex differences in fetal mouse brain exposed to environmental stressors during early gestation, prior to the appear- ance of sex hormones. Published work by the PI has identified VPA-induced sex differences in the activating epigenetic mark, H3K4me3, leading to sexually-dimorphic expression of Bdnf, the gene encoding brain-derived neurotrophic factor. These studies with Bdnf establish an experimental paradigm for identifying other sexually- dimorphic proteins that regulate brain development and that may mediate the pathogenic effects of environ- mental stressors on brain development. An important clue to the underlying mechanism is that the enzymes that regulate H3K4me3, the H3K4-demethylases, JARID1C and JARID1D, are encoded by genes on the X and Y-chromosomes, respectively, and are therefore postulated to be differentially expressed in the two sexes. The specific aims of this research program are to 1) identify genes involved in early brain development (in addition to Bdnf) that are expressed differently in males and females in response to VPA due to sexually dimorphic H3K4 trimethylation and 2) test the hypothesis that JARID1 gene expression and enzyme activity are greater in males than in females, thereby providing a plausible mechanism for sexually dimorphic gene expression in the fetal brain. Identification of such genes, particularly if found to be associated with one or more developmentally relevant signaling pathways, will lead to a clearer understanding of the etiology of neurodevelopmental disor- ders such as ASDs and provide the basis for future, hypothesis driven initiatives to determine the pathogenic mechanisms of action of other environmental stressors acting during early gestation.