BPA, Cortical Development and Gene Expression: Implications for Autism

自闭症谱系障碍的定义是社交行为和沟通方面的缺陷以及 重复的刻板印象行为。这种疾病的发病率正在增加，而且男性的发病率更高。 表明环境中的内分泌干扰物可能是主要贡献者。值得注意的是，年轻的男性 自闭症患者的大脑皮质通常增大，特别是在前额叶皮质，有更多的神经元和 Glia(Courchesne等人，2010年；Edmonson等人，2014)。有趣的是，我们还发现前和 出生后暴露于双酚A可导致大鼠内侧前额叶皮质神经元数量增加 (Mpfc)(Sadowlski等人，2014年)。在这项提案中，广泛存在的内分泌干扰物双酚的影响 A(BPA)，将在大鼠mPFC的发育过程中进行检测。中心假设是双酚A会改变 基因表达改变对mPFC发育早期细胞凋亡和/或神经发生的影响 坚持通过表观遗传的甲基化。因为在时间和数量上都有性别差异 在早期的细胞过程中，两性之间存在着不同的脆弱性。 目的1首先描述雄性和雌性大鼠mPFC发生凋亡的时间。接下来，在这几天 围绕着最高的凋亡率和/或当性别差异显著时，幼崽将口服 双酚A。暴露后，细胞凋亡标记物以及神经元和神经胶质细胞的数量将是立体的。 在青春期前和成年后进行评估。下一步，胚胎幼崽将在怀孕期间接触双酚A 皮质神经发生高峰期。细胞分裂的标志物BrdU也将被用来测试BPA 改变神经发生的速度。来自所有组的动物的子集将被测试其同种从属关系 断奶年龄前的行为作为早期社会行为缺陷的指标。总体而言，这个目标将确定 双酚A在发育过程中使大脑皮层偏向过量神经元的细胞机制 以及神经胶质和自闭症的特征。 双酚A暴露后伴随细胞变化的基因表达变化 MPFC将在AIM 2中描述。与自闭症有关的基因，如FOXG1和Pten， 以及与激素受体和细胞凋亡相关的基因将被包括在内。表观遗传变化 表明暴露于双酚A的长期影响也将被检查。 长期目标是了解这种无处不在的脆弱性的具体时间和机制 内分泌干扰物，从而可以避免或改善暴露。

Autism spectrum disorder is defined by deficits in social behavior and communication as well as repetitive stereotyped behaviors. The incidence of this disorder is increasing, and higher rates in males indicate that endocrine disruptors in the environment may be major contributors. Of note, young males with autism often have an enlarged cortex, particularly in the prefrontal cortex with greater numbers of neurons and glia (Courchesne et al., 2010; Edmonson et al., 2014). Interestingly, we have also found that pre- and postnatal exposure to BPA results in an increased number of neurons in the rat medial prefrontal cortex (mPFC) (Sadowlski et al., 2014). In this proposal, the effects of the widespread endocrine disruptor, bisphenol A (BPA), will be examined during the development of the rat mPFC. The central hypothesis is that BPA alters apoptosis and/or neurogenesis early in mPFC development by changing gene expression and its effects persist through epigenetic methylation. Because there are sex differences in the timing and amount of these early cellular processes, the sexes are differentially vulnerable. Aim 1 will first delineate when apoptosis occurs in the male and female rat mPFC. Next, on the days surrounding the highest rates of apoptosis and/or when the sexes diverge significantly, pups will orally ingest BPA. Following exposure, apoptotic markers and the number of neurons and glia will be stereologically assessed before puberty and in adulthood. Next, fetal pups will be gestationally exposed to BPA on days of peak cortical neurogenesis. BrdU, a marker of dividing cells, will also be administered to test whether BPA alters the rate of neurogenesis. A subset of animals from all groups will be tested for their conspecific affiliative behavior before weaning age as an indicator of early deficits in social behavior. Overall, this aim will identify the cellular mechanism during development by which BPA can bias the cortex toward an excess of neurons and glia and autistic characteristics. Changes in gene expression that are concomitant with cellular changes following BPA exposure in the mPFC will be characterized in Aim 2. Genes that have been implicated in autism, such as FOXG1 and Pten, as well as those associated with hormone receptors and apoptosis will be included. Epigenetic changes which indicate long-term effects of BPA exposure will also be examined. The long-term goal is to know the specific timing and mechanisms of vulnerability to this ubiquitous endocrine disruptor so that exposure can be avoided or ameliorated.