Developmental Dieldrin Exposure Alters DNA Methylation at Genes Related to Dopaminergic Neuron Development and Parkinson’s Disease in Mouse Midbrain

Abstract

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 midbrains were dissected. 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 (FDR<0.05), including DMCs at the Nr4a2 and Lmx1b genes, which are involved in dopaminergic neuron development and maintenance. Developmental dieldrin exposure had distinct effects on the male and female epigenome. Furthermore, a separate set of changes in DNA methylation was identified after adult exposure to dieldrin, suggesting that adult and developmental dieldrin toxicity may not act through a shared epigenetic mechanism. Together, our data suggest that developmental dieldrin exposure establishes sex-specific poised epigenetic states early in life. These poised epigenomes may mediate sensitivity to additional environmental stimuli and contribute to the development of late-life neurodegenerative disease, including PD.

Parkinson’s Disease-Associated, Sex-specific Changes in DNA Methylation at PARK7 (DJ-1), ATXN1, SLC17A6, NR4A2, and PTPRN2 in Cortical Neurons

“…[61][62][63] In a previous animal model study, we showed that developmental exposure to the organochlorine pesticide dieldrin, which is known to be associated with increased PD risk, led to sex-specific hypermethylation in the Nr4a2 gene body in female mice. 64 These previous results, along with our present data, suggest that sexspecific epigenetic regulation at the NR4A2 gene may play a role in idiopathic PD risk.…”

“…One previous study found decreased expression of PTPRN2 in the SN of PD patients, while another found increased expression in DA neurons from PD patients with LRRK2 G2019S mutations. 73,74 Interestingly, given the known role of environmental exposures in PD and work in our lab investigating pesticide exposures and PD, 64,75 another study found an association between pesticide exposure and hypomethylation at a CpG in PTPRN2 in blood. 76 Taken together, our data adds to a growing collection of evidence supporting a role for epigenetic regulation of PTRPN2 in PD.…”

The Pathology of Parkinson’s Disease and Potential Benefit of Dietary Polyphenols

“…Pesticides can also target the SN. Dieldrin, an organochlorine pesticide, causes neurotoxic damage to the dopaminergic system [ 73 ]. Rotenone, an organophosphate, increases α-synuclein aggregation and inhibits mitochondrial complex I [ 74 ].…”

Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease

“…Beyond changes to DNA sequences, pesticides could affect gene expression epigenetically [ 131 , 132 ]. There is evidence that pesticide exposure is linked to alterations in DNA methylation [ 133 , 134 , 135 ]. Of particular relevance in this regard would be genes that encode proteins affecting AD etiology, such as that encoding Paraoxonase-1 (PON1) [ 136 , 137 ].…”