Dieldrin-induced differential gene methylation and parkinsonian toxicity (R01ES031237)

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.

Grant Number: 3R01ES031237-05S1
NIH Institute/Center: NIH
Principal Investigator: Alison Bernstein