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Human and animal studies have shown that exposure to the organochlorine
pesticide dieldrin is associated with increased risk of Parkinson’s
disease (PD). Despite previous work showing a link between developmental
dieldrin exposure and increased neuronal susceptibility to MPTP toxicity
in male C57BL/6 mice, the mechanism mediating this effect has not been
identified. Here, we tested the hypothesis that developmental exposure to
dieldrin increases neuronal susceptibility via genome-wide changes in DNA
methylation. Starting at 8 weeks of age and prior to mating, female
C57BL/6 mice were exposed to 0.3 mg/kg dieldrin by feeding (every 3 days)
throughout breeding, gestation, and lactation. At 12 weeks of age, pups
were sacrificed and ventral mesencephalon, containing primarily substantia
nigra, were microdissected. DNA was isolated and dieldrin-related changes
in DNA methylation were assessed via reduced representation bisulfite
sequencing (RRBS). We identified significant, sex-specific differentially
methylated CpGs (DMCs) and regions (DMRs) by developmental dieldrin
exposure (FDRNr4a2 and Lmx1b genes, which are involved in dopaminergic
neuron development and maintenance. Developmental dieldrin exposure had
distinct effects on the male and female epigenome. Together, our data
suggest that developmental dieldrin exposure establishes sex-specific
poised epigenetic states early in life. These poised epigenomes may
mediate sensitivity to subsequent toxic stimuli and contribute to the
development of late-life neurodegenerative disease, including PD.
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