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Your Environment. Your Health.

DEVELOPMENTAL PESTICIDE EXPOSURE AND EPIGENETIC AGING IN THE BRAIN

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/F32ES031426/format/word)
Principal Investigator: Kochmanski, Joseph John
Institute Receiving Award Michigan State University
Location East Lansing, MI
Grant Number F32ES031426
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jan 2020 to 31 Dec 2021
DESCRIPTION (provided by applicant): Project Summary The majority (~90%) of Parkinson's disease (PD) cases are not caused by an inherited monogenic mutation, but are rather likely due to a complex interaction between genes and environmental factors. Supporting this idea, epidemiological and mechanistic studies have identified an association between pesticide exposure, particularly to organochlorine pesticides such as dieldrin, and increased risk of sporadic PD. In animal models, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to a dopaminergic toxicant and, in new preliminary data from our lab, to synucleinopathy induced by α-synuclein preformed fibrils. Furthermore, in a recently published study, we found that developmental dieldrin exposure induces sex-specific changes in DNA methylation and transcription, including at genes related to dopaminergic neuron development and Parkinson's disease. However, our previous work only examined a single, 12-week- old time point, and did not consider that environmental factors can also modify longitudinal rates of epigenetic aging. By modifying transcriptional regulation over time, epigenetic aging could alter biological function, gene- environment interactions, and disease risk in the aged human. Since age is the primary risk factor for PD and other neurodegenerative diseases, it is critical to define how environmental exposures affect the long-term epigenetic mechanisms involved in disease susceptibility and etiology. The central hypothesis of this proposal is that developmental exposure to the organochlorine pesticide dieldrin will alter the trajectory of epigenetic aging in brain tissue at specific genes related to Parkinson's disease (PD). To test this hypothesis, we will utilize a developmental mouse exposure paradigm to determine whether developmental exposure to the organochlorine pesticide dieldrin alters rates of epigenetic aging. Epigenetic aging will be measured by aging out dieldrin-exposed animals and collecting substantia nigra tissue from matched littermates throughout the life-course. In Aim 1, we will determine whether developmental dieldrin exposure alters DNA methylation patterns from birth to 12 weeks of age at dieldrin-associated differentially methylated genes in substantia nigra of male and female mice. In Aim 2, we will further characterize long-term epigenetic aging at the same candidate genes in substantia nigra samples from developmentally exposed mice at 6 months, 9 months, and 12 months of age. At the completion of this study, we expect to produce a list of candidate loci where developmental dieldrin exposure alters rates of epigenetic aging. Furthermore, we expect to show that age- and dieldrin-associated changes in DNA methylation are associated with altered gene transcription. In this way, we aim to provide support for the idea that developmental toxicant exposures can modify disease risk into adulthood via gene-specific changes in epigenetic aging.
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Frederick Tyson
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