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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要双酚 (BP) 是常用的增塑剂，存在于许多塑料中，例如食品储存塑料容器和可重复使用的水瓶，以及通过口服摄入的食品罐内衬。在人群中普遍存在，但产前接触水平存在个体差异。 BP 与人类儿童的负面神经发育和行为结果有关流行病学研究以及产前血压暴露的啮齿动物模型。 BPA 等 BP 和其他“不含 BPA”的结构类似物（包括 BPF 和 BPS）已被证明可以起到先前的研究表明，内分泌干扰物主要影响雌激素受体信号传导。可以与雌激素受体α（ERα）和雌激素受体β结合，对基因产生影响使用动物模型和人类胎盘组织的研究表明 BP 可以交叉。胎盘并直接对胎儿产生影响，母体血压也可能破坏雌激素依赖性。母亲大脑的变化会损害产后母亲护理。产前血压暴露和孕产妇护理的改变都与 DNA 甲基化水平的变化有关整个基因组，这可能导致受影响基因的转录本丰度发生稳定变化。将产前 BP 暴露与特定位点 DNA 甲基化修饰联系起来的潜在机制是此外，改变产后母亲护理对患有产前血压的后代的相对影响尚不清楚。曝光度尚未得到充分研究。我提出的研究的主要目的是检查产前血压暴露对 DNA 的影响特定位点的甲基化修饰，特别是雌激素反应元件（ERE），以及相应的此外，我将探索一种潜在有效的方法。干预，母体舔舐式触觉刺激，以减轻产前血压对 DNA 甲基化的影响我推测新生大鼠大脑中 ERE 附近的 DNA 甲基化会发生变化。增加的产前 BP 暴露将在新生大鼠大脑中的 ERE 附近富集，并相应此外，我渴望产后的雌激素反应基因转录丰度的差异。母体舔舐刺激会部分逆转产前血压暴露对 DNA 的影响通过增加 ERE 上的 ERα 结合，新生大鼠大脑中 ERE 附近的甲基化修饰。培训潜力：为了配合我提出的研究项目，我将开展重要的研究健康和疾病概念框架发展起源的能力，转化根据这些培训经验，我的目标是进行多组学数据集的研究和生物信息分析。竞争独立研究职位并成功过渡到研究独立。