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.

自闭症谱系障碍是由社会行为和沟通缺陷以及 重复定型行为。这种疾病的发生率正在增加，男性的发生率较高 表明环境中的内分泌破坏者可能是主要贡献者。值得注意的是，年轻男性与 自闭症通常具有肿大的皮质，尤其是在神经元数量更多的前额叶皮层中 Glia（Courchesne等，2010； Edmonson等，2014）。有趣的是，我们还发现 产后暴露于BPA导致大鼠内侧前额叶皮层中神经元的数量增加 （MPFC）（Sadowlski等，2014）。在此提案中，广泛的内分泌破坏者Bisphenol的影响 A（BPA）将在大鼠MPFC的开发过程中进行检查。中心假设是BPA改变了 MPFC发育早期的凋亡和/或神经发生，通过改变基因表达及其作用 持续通过表观遗传甲基化。因为这些时机和数量存在性别差异 早期的细胞过程，性别在差异上很脆弱。 AIM 1将在男性和雌性大鼠MPFC中发生凋亡时首先描述。接下来，那天 围绕凋亡的最高率和/或性别差异时，幼崽会口服摄取 BPA。暴露后，凋亡标记以及神经元和神经胶质的数量将在立体学上是 在青春期和成年之前进行评估。接下来，胎儿幼崽将在妊娠上暴露于BPA。 皮质神经发生峰值。 BRDU是分隔单元的标记，也将被施用以测试BPA是否 改变神经发生率。将对所有组的动物子集进行测试 断奶年龄之前的行为是社会行为早期缺陷的指标。总体而言，这个目标将确定 BPA在发育过程中的细胞机制可以使皮质偏向多余的神经元 以及神经胶质和自闭症特征。 与BPA暴露后的细胞变化相关的基因表达的变化 MPFC将在AIM 2中进行表征。 以及与激素受体和凋亡相关的那些。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脆弱性的特定时间和机制 内分泌破坏者，因此可以避免或改善暴露。