Objective: To determine whether developmental exposure to dieldrin exacerbates susceptibility to α-synuclein (α-syn) preformed fibril (PFF)-induced synucleinopathy in adulthood.

Background: Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the nigrostriatal pathway and the formation of α-synuclein-containing Lewy bodies. About 90% of PD cases are sporadic and likely arise due to a complex interaction between genes and environmental factors. Epidemiological and mechanistic studies show an association between exposure to persistent organic pollutants, including pesticides and industrial toxicants, and increased PD risk. However, the mechanisms linking exposures and increased PD risk remain unclear.

Method: Mice were developmentally exposed to dieldrin during gestation and lactation. At 12 weeks of age, male and female F1 mice received unilateral intrastriatal injections of α-syn PFFs or saline. Motor behavior was assessed prior to injection and at 4- and 6-months post-injection. Mice were sacrificed at 1-, 2-, or 6- months post-injection and the following outcomes were assessed: p-syn aggregation by IHC and stereology, levels of dopamine and its metabolites by HPLC, and nigral degeneration by TH and NeuN IHC and stereology.

Results: Six months after PFF injections, we observed a dieldrin-induced, male-specific exacerbation of PFF-induced deficits in dopamine packaging and motor behavior. In contrast, female mice did not show a dieldrin-induced exacerbation of PFF-induced toxicity and did not show any PFF-induced motor deficits on the challenging beam test despite similar PFF-induced neuropathological and neurochemical changes. The dieldrin-induced, male-specific increase in neuronal vulnerability is consistent with previous results in the MPTP model and reflects the increased prevalence of PD and increased severity of disease course in males.

Conclusion: Our results show that developmental dieldrin exposure causes a male-specific exacerbation of susceptibility to parkinsonian toxicity. Our two-hit model is an experimental paradigm that can be used to explore the mechanisms by which PD-related exposures increase risk of sporadic PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/male-specific-exacerbation-of-susceptibility-to-%ce%b1-synuclein-pre-formed-fibrils-by-developmental-dieldrin-exposure-in-mice/