Interactive Effects of Prenatal Bisphenol Exposure and Postnatal Maternal Care on DNA Methylation in the Developing Brain

项目摘要/摘要 双酚(BPS)是一种常用的增塑剂，存在于许多塑料中，如食品储藏 容器和可重复使用的水瓶，以及食品罐头的衬里。通过口服摄入接触BP是 在人类人群中普遍存在，接触水平存在个体间的差异。产前暴露于 在人类中，BP与儿童的负面神经发育和行为结局有关 流行病学研究以及在出生前暴露于BP的啮齿动物模型中。 BPA和其他不含BPA的结构类似物，包括BPF和BPS，已经被证明起到了 主要影响雌激素受体信号的内分泌干扰物。以前的研究表明，BP 可以同时与雌激素受体α(ERα)和雌激素受体β结合，对基因产生影响 抄写。使用动物模型和人类胎盘组织的研究表明，BP可以交叉 胎盘和作用直接作用于胎儿。母亲的高血压也可能扰乱雌激素依赖 母体大脑的变化，这损害了产后的母体护理。 产前BP暴露和母婴护理的改变都与DNA甲基化水平的变化有关 这可以导致受影响基因转录丰度的稳定变化。然而， 产前BP暴露和特定基因座DNA甲基化修饰之间的潜在机制是 不是很出名。此外，改变产后护理对患有产前BP的后代的相对影响 暴露问题一直没有得到充分研究。 我提议的研究的主要目的是检查产前BP暴露对DNA的影响 特定基因座的甲基化修饰，特别是雌激素反应元件(ERE)，以及相应的 新生大鼠脑内基因转录的变化。此外，我将探索一种潜在有效的 干预，母体舔舔样触觉刺激，以减轻产前BP对DNA甲基化的影响 新生大鼠大脑中ERE的近端。我假设DNA甲基化改变是为了应对 出生前BP暴露增加将在新生大鼠大脑中ERE附近丰富，并相应地 雌激素反应基因转录丰度的差异。另外，我假设出生后 母体舔舔样刺激可部分逆转产前BP暴露对DNA的影响 新生大鼠脑内EREs附近的甲基化修饰通过增加EREs上的ERα结合。 培训潜力：在我提出的研究项目中，我将开展重要的研究 健康和疾病发展起源的能力概念框架，翻译 多组学数据集的研究和生物信息学分析。在这些培训经验之后，我的目标是成为 竞争独立的研究职位，并成功过渡到研究独立。

PROJECT SUMMARY / ABSTRACT Bisphenols (BPs) are commonly used plasticizers that are present in many plastics, such as food storage containers and reusable water bottles, as well as lining of food cans. BP exposure via oral consumption is ubiquitous in human populations with inter-individual variation in the levels of exposure. Prenatal exposure to BPs has been associated with negative neurodevelopmental and behavior outcomes for children in human epidemiological studies as well as in rodent models of prenatal BP exposure. BPs such as BPA and other “BPA-free” structural analogs, including BPF and BPS, have been shown to act as endocrine disruptors that primarily affect estrogen receptor signaling. Previous studies demonstrate that BPs can bind to both estrogen receptor alpha (ERα) and estrogen receptor beta to exert effects on gene transcription. Studies using animal models and human placental tissue have demonstrated that BPs can cross the placenta and exert effects directly on the fetus. Maternal BPs may also disrupt estrogen-dependent changes in the maternal brain which impairs postnatal maternal care. Both prenatal BP exposure and altered maternal care are associated with changes in DNA methylation levels across the genome which can lead to stable changes in transcript abundance of affected genes. However, the underlying mechanisms linking prenatal BP exposure and DNA methylation modifications at specific loci are not well-known. In addition, the relative effects of altered postnatal maternal care on offspring with prenatal BP exposure has been understudied. The primary objective of my proposed research is to examine the effects of prenatal BP exposure on DNA methylation modifications at specific loci, notably estrogen responsive elements (EREs), and corresponding changes in gene transcription in the neonatal rat brain. In addition, I will explore a potentially effective intervention, maternal licking-like tactile stimulation, to mitigate the effects of prenatal BP on DNA methylation proximal to EREs in the neonatal rat brain. I hypothesize that DNA methylation changes in response to increased prenatal BP exposure will be enriched in proximity to EREs in the neonatal rat brain and correspond to differences in transcript abundance of estrogen-responsive genes. In addition, I hypothesize that postnatal maternal licking-like stimulation would partially reverse the effects of prenatal BP exposure on DNA methylation modifications proximal to EREs in the neonatal rat brain via increased ERα binding at EREs. Training Potential: In tandem with my proposed research project, I will be developing important research competencies in the developmental origins of health and disease conceptual framework, translational research, and bioinformatic analyses of multi-omics datasets. Following these training experiences, I aim to be competitive for an independent research position and successfully transition to research independence.