Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of alpha-synuclein-preformed fibril-induced toxicity and motor deficits.

Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of alpha-synuclein-preformed fibril-induced toxicity and motor deficits.

Gezer Aysegul O; Kochmanski Joseph; VanOeveren Sarah E; Cole-Strauss Allyson; Kemp Christopher J; Patterson Joseph R; Miller Kathryn M; Kuhn Nathan C; Herman Danielle E; McIntire Alyssa; Lipton Jack W; Luk Kelvin C; Fleming Sheila M; Sortwell Caryl E; Bernstein Alison I

Neurobiology of disease

2020

2020-05-15

Human and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the alpha-synuclein (alpha-syn)-preformed fibril (PFF) model, which better reflects the alpha-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to alpha-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal alpha-syn PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated

Neuroinflammation; Neurotoxicity; Parkinson's; Pesticide; Sex differences; Synuclein

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journalArticle

104947

141

1095-953X 0969-9961

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Department of Pharmaceutical Sciences

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