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Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-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.
Affiliation
  • Gezer AO; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Cell and Molecular Biology Graduate Program, College of Natural Sciences, Michigan State University, East Lansing, MI, United States of America; College of Oste
  • Kochmanski J; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • VanOeveren SE; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • Cole-Strauss A; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • Kemp CJ; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • Patterson JR; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • Miller KM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • Kuhn NC; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
  • Herman DE; Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, United States of America.
  • McIntire A; Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, United States of America.
  • Lipton JW; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Mercy Health St. Mary's, Grand Rapids, MI, United States of America.
  • Luk KC; Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, United States of America.
  • Fleming SM; Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, United States of America.
  • Sortwell CE; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Mercy Health St. Mary's, Grand Rapids, MI, United States of America.
  • Bernstein AI; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Mercy Health St. Mary's, Grand Rapids, MI, United States of America. Electronic address: bernst79@msu.edu.
Neurobiol Dis ; 141: 104947, 2020 07.
Article in En | MEDLINE | ID: mdl-32422283
ABSTRACT
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 α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to α-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 α-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 PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn aggregation (pSyn) in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific exacerbation of synucleinopathy-induced behavioral and biochemical deficits. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD.
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Full text: 1 Database: MEDLINE Main subject: Pesticides / Parkinsonian Disorders / Dieldrin / Alpha-Synuclein / Protein Aggregation, Pathological / Motor Activity Limits: Animals Language: En Journal: Neurobiol Dis Journal subject: NEUROLOGIA Year: 2020 Type: Article

Full text: 1 Database: MEDLINE Main subject: Pesticides / Parkinsonian Disorders / Dieldrin / Alpha-Synuclein / Protein Aggregation, Pathological / Motor Activity Limits: Animals Language: En Journal: Neurobiol Dis Journal subject: NEUROLOGIA Year: 2020 Type: Article