Parkinson’s disease (PD) is the fastest-growing neurological disease worldwide, with increases outpacing aging and occurring most rapidly in recently industrialized areas, suggesting a role of environmental factors. Exposure to the organochlorine pesticide dieldrin is a risk factor for sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show a male-specific increased susceptibility to MPTP (a dopaminergic (DAergic) toxicant) as adults, and adult male mice exposed to dieldrin during development show increased susceptibility to synucleinopathy induced by α- synuclein (α-syn) preformed fibrils (PFFs), with dieldrin-induced exacerbation of PFF-induced deficits in motor behavior and dopamine (DA) turnover. We hypothesize that dieldrin-induced epigenetic modification during development causes changes in gene expression and phenotype that persist into adulthood,altering the sensitivity to Parkinsonian insults and contributing to the development of PD. Specifically, we hypothesized that alterations in DA handling contribute to the observed changes and assessed vesicular monoamine transporter 2 (VMAT2) function and DA release in this dieldrin/PFF two-hit model. Using a developmental dieldrin/PFF two-hit model, vesicular 3H-DA uptake assays and fast-scan cyclic voltammetry (FSCV) were performed 4 months post-PFF injection. Dieldrin induced an increase in DA release in striatal slices in PFF-injected animals, but no change in VMAT2 activity. These results suggest that developmental dieldrin exposure increases a compensatory response to synucleinopathy-triggered striatal DA loss. These findings are consistent with silent neurotoxicity, where developmental exposure to dieldrin primes the nigrostriatal striatal system to have an exacerbated response to synucleinopathy in the absence of observable changes in typical markers of nigrostriatal dysfunction and degeneration. The epigenome is a potential mediator of this relationship between developmental exposures, increased neuronal vulnerability, and adult disease. In support of this, we recently identified sex-specific differential methylation patterns in response to developmental dieldrin exposure, suggesting exposure establishes a sex-specific poised epigenetic state early in life that modulates adult susceptibility to neurotoxicity. Candidate genes with developmental dieldrin-induced differential modification include Nr4a2, a transcription involved in DAergic development, and Ephb2, a receptor tyrosine kinase that regulates axonal guidance during neuronal development. Using a 3D human neurosphere model, we have shown that modification of these candidate genes during proliferation alters the DAergic trajectory of these neurospheres later in differentiation and modifies a key marker of DAergic vulnerability to toxicity. Suggesting that these observed epigenetic modifications to candidate genes, NR4A2 and EPHB2 during development alter the DAergic differentiation in developing neurons which may modify susceptibility to toxicity later in life. Overall, data from this project investigates mechanisms in which developmental exposure to dieldrin may induce functional changes in phenotype that alter Parkinson’s disease susceptibility.
Read
