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

产前双酚暴露和产后母亲护理对发育中大脑 DNA 甲基化的相互作用

• 批准号: 10678118
• 负责人: Samantha Lauby
• 金额: $ 7.17万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678118
• 关键词: Affect; Animal Model; Binding; Bioinformatics; Biological; Birth; Brain; Caring; Child; Competence; Consumption; DNA; DNA Methylation; DNA analysis; Data Set; Development; Disease; Dose; Elements; Endocrine Disruptors; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Exposure to; Female; Fetus; Food; Gene Expression; Genes; Genetic Transcription; Genome; Grooming; Health; Household Products; Human; Hypothalamic structure; Impairment; Life; Link; Location; Long-Term Effects; Medial; Methylation; Modeling; Modification; Mothers; Multiomic Data; Neonatal; Oral; Outcome; Placenta; Plasticizers; Plastics; Population; Positioning Attribute; Preoptic Areas; Promoter Regions; RNA Polymerase II; Rattus; Receptor Signaling; Research; Research Project Grants; Risk Reduction; Rodent Model; Site; Tissues; Training; Transcript; Translational Research; Water; analog; behavioral outcome; bisulfite sequencing; chromatin immunoprecipitation; differential expression; disorder risk; effective intervention; epidemiology study; estrogen disruption; experience; inter-individual variation; male; neurodevelopment; offspring; postnatal; pregnant; prenatal; prenatal exposure; receptor binding; response; tactile stimulation; transcriptome

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.

项目总结/摘要 双酚（BPs）是一种常用的增塑剂，存在于许多塑料中，例如食品储存。 容器和可重复使用的水瓶，以及食品罐的衬里。通过口服摄入的BP暴露是 在人群中普遍存在，暴露水平存在个体间差异。产前暴露于 在人类中，BPs与儿童的神经发育和行为结果有关 流行病学研究以及产前BP暴露的啮齿动物模型。 BP如BPA和其他“不含BPA”的结构类似物，包括BPF和BPS，已被证明可作为 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 可与雌激素受体α（ERα）和雌激素受体β结合，对基因表达产生影响， 转录。使用动物模型和人类胎盘组织的研究表明，BP可以通过 胎盘直接对胎儿产生影响。母体BP也可能破坏雌激素依赖性 产妇大脑的变化，损害了产后产妇护理。 产前BP暴露和母亲护理的改变都与DNA甲基化水平的变化有关 这可以导致受影响基因的转录丰度的稳定变化。但 产前BP暴露与特定基因座DNA甲基化修饰之间的潜在机制是 不知名。此外，产后母亲护理的改变对患有产前BP的后代的相对影响 暴露程度还未得到充分研究。 我提出的研究的主要目标是检查产前BP暴露对DNA的影响。 在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 新生大鼠大脑中基因转录的变化。此外，我将探索一种潜在的有效方法， 干预，母亲舔样触觉刺激，以减轻产前BP对DNA甲基化的影响 在新生大鼠脑中靠近ERE的位置。我假设DNA甲基化的变化是对 增加的产前BP暴露将在新生大鼠脑中的ERE附近富集， 雌激素反应基因转录丰度的差异。另外，我假设产后 母体舔样刺激可部分逆转产前BP暴露对DNA的影响， 通过增加ERα与ERE的结合，在新生大鼠脑中靠近ERE的甲基化修饰。 培训潜力：在我提出的研究项目的同时，我将开展重要的研究 健康和疾病概念框架的发展起源的能力，翻译 研究和多组学数据集的生物信息学分析。通过这些培训经验，我的目标是 有竞争力的独立研究职位，并成功过渡到研究独立。