BPA, Cortical Development and Gene Expression: Implications for Autism

BPA、皮质发育和基因表达：对自闭症的影响

• 批准号: 9360123
• 负责人: JANICE M JURASKA
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360123
• 关键词: Adult; Affect; Age; Agreement; American Psychiatric Association; Animals; Apoptosis; Apoptotic; Area; Aromatase; Autistic Disorder; Awareness; Behavioral; Birth; Birth Intervals; Bromodeoxyuridine; CASP3 gene; Cell Death; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cerebral cortex; Characteristics; Chemicals; Child; Communication; Complex; Data; Development; Disease; Endocrine Disruptors; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; FOXG1B gene; Female; Gene Expression; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Hormone Receptor; Hormones; In Situ Nick-End Labeling; Incidence; Investigation; Label; Long-Term Effects; Medial; Methylation; Modification; Mutation; Neuroglia; Neurons; Oral; Perinatal; Play; Population; Prefrontal Cortex; Pregnancy; Puberty; Rattus; Receptor Protein-Tyrosine Kinases; Risk; Role; Sex Characteristics; Social Behavior; Stereotyped Behavior; Testing; Time; Variant; Visual Cortex; Weaning; affiliative behavior; autism spectrum disorder; base; bisphenol A; brain size; fetal; gene environment interaction; male; neurogenesis; postnatal; preference; prenatal; pup; sex; social communication

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.

自闭症谱系障碍的定义是社会行为和沟通的缺陷以及 重复的刻板行为。这种疾病的发病率正在增加，男性发病率更高 表明环境中的内分泌干扰物可能是主要因素。值得注意的是，年轻男性 自闭症患者的皮层通常增大，尤其是前额叶皮层，神经元数量较多， 神经胶质细胞（Courchesne 等人，2010；Edmonson 等人，2014）。有趣的是，我们还发现，预 出生后接触 BPA 会导致大鼠内侧前额皮质神经元数量增加 （mPFC）（Sadowlski 等人，2014）。在该提案中，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查。中心假设是 BPA 会改变 通过改变基因表达及其影响，促进 mPFC 发育早期的细胞凋亡和/或神经发生 通过表观遗传甲基化持续存在。因为这些行为的时间和数量存在性别差异 在早期的细胞过程中，两性都具有不同的脆弱性。 目标 1 首先描述雄性和雌性大鼠 mPFC 何时发生细胞凋亡。接下来的日子里 周围细胞凋亡率最高和/或当性别明显不同时，幼崽会口服摄入 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被立体化 在青春期前和成年期进行评估。接下来，胎儿幼崽将在妊娠期接触 BPA。 皮质神经发生高峰。分裂细胞标记物 BrdU 也将被施用以测试 BPA 是否 改变神经发生的速率。来自所有群体的一部分动物将接受同种亲缘关系测试 断奶前的行为作为早期社会行为缺陷的指标。总体而言，该目标将确定 发育过程中的细胞机制，BPA 可以通过该机制使皮质偏向过多的神经元 以及神经胶质细胞和自闭症特征。 暴露于 BPA 后伴随细胞变化的基因表达变化 mPFC 将在目标 2 中进行表征。与自闭症有关的基因，例如 FOXG1 和 Pten， 以及与激素受体和细胞凋亡相关的那些也将包括在内。表观遗传变化 表明还将检查 BPA 暴露的长期影响。 长期目标是了解这种无处不在的漏洞的具体时间和机制 内分泌干​​扰物，从而可以避免或改善接触。