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Dieldrin-induced differential gene methylation and parkinsonian toxicity

狄氏剂诱导的差异基因甲基化和帕金森毒性

基本信息

批准号：
10115257
负责人：
Alison Bernstein
金额：
$ 59.23万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-21 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10115257
关键词：
3-Dimensional Adult Affect Biological Biological Assay Brain Candidate Disease Gene Cell Culture Techniques Corpus striatum structure DNA Modification Process DNMT3a Data Development Dieldrin Disease Disease susceptibility Dopamine Elderly Environment Environmental Risk Factor Epidemiology Epigenetic Process Etiology Exposure to Functional disorder Funding Gene Expression Gene Expression Profile Genes Genetic Goals HDAC9 gene High Pressure Liquid Chromatography Immunohistochemistry In Situ In Vitro Individual Inherited Injections Knowledge Link Luciferases Mass Spectrum Analysis Mediating Mediator of activation protein Methods Methylation Mission Modeling Modification Mus Mutation NR4A2 gene National Institute of Environmental Health Sciences Neurites Neurons Parkinson Disease Parkinsonian Disorders Pathogenesis Pathologic Pathway Analysis Pathway interactions Periodicity Phenotype Play Predisposition Presynaptic Terminals Radioactive Risk Risk Factors Role Scanning Sequencing By Hybridizations Site-Directed Mutagenesis Specificity System Testing Toxic Environmental Substances Toxic effect Western Blotting alpha synuclein base cell type cytotoxicity dopaminergic neuron epidemiology study epigenome experimental study genome-wide genomic locus in vivo in vivo Model laser capture microdissection male methylation pattern motor behavior mouse model neurotransmission nigrostriatal pathway novel offspring organochlorine pesticide pesticide exposure response sex synaptic function synucleinopathy tool toxicant transcriptome sequencing uptake

项目摘要

Project Summary The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation and disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases risk of sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in new data from our NIEHS-funded R21, α-synuclein (α-syn) preformed fibrils (PFFs). The epigenome is a potential mediator of this relationship between developmental exposures, increased neuronal vulnerability, and adult disease. In line with this idea, we recently identified sex-specific differential methylation patterns in response to developmental dieldrin exposure. We hypothesize that dieldrin-induced epigenetic modifications during development cause changes in gene expression and phenotype that persist into adulthood, altering the sensitivity to parkinsonian insults and contributing to the development of PD. To test this hypothesis, we will determine cell-type specific DNA modifications and expression profiles of previously identified candidate genes in the dieldrin model (Aim 1); analyze the function of synaptic terminals in our novel dieldrin/PFF two-hit model (Aim 2); and determine if dieldrin or altered expression of candidate genes affects susceptibility to α-syn PFFs in a dopaminergic neuron cell culture model (Aim 3). The long-term goal of these experiments is to determine whether dieldrin-associated differentially methylated genes play a functional role in the biological response to parkinsonian toxicity. Completion of these aims will further the mission of NIEHS to increase our understanding of how the environment affects people in order to promote healthier lives, with a specific project goal of connecting exposures with functional changes in gene expression, neuronal phenotype, and PD susceptibility. The experiments proposed here will help to establish a biological mechanism linking developmental exposure to late life disease. This project will also expand our repertoire of tools for interrogating the function of epigenetic changes by establishing an in vitro experimental paradigm to connect specific epigenetic mechanisms with parkinsonian toxicity. With our in vivo model that combines developmental exposure with adult PFF injections, we will have a set of experimental systems in place that will allow us to test a wide variety of exposures, as well as combinations of exposures, both in vivo and in vitro. Together, this suite of tools will enable us to explore the mechanisms by which PD- related exposures alter neuronal vulnerability in PD, furthering the goal of NIEHS to understand how combined exposures affect disease pathogenesis and individual susceptibility.

项目总结