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

NEUROBIOLOGY OF DISEASE

卷:141

Article

Gezer, Aysegul O.^1,2,3  Kochmanski, Joseph¹  VanOeveren, Sarah E.¹  Cole-Strauss, Allyson¹  Kemp, Christopher J.¹  Patterson, Joseph R.¹  Miller, Kathryn M.¹  Kuhn, Nathan C.¹  Herman, Danielle E.⁵  McIntire, Alyssa⁵  Lipton, Jack W.^1,4  Luk, Kelvin C.⁶  Fleming, Sheila M.⁵  Sortwell, Caryl E.^1,4  Bernstein, Alison, I^1,4 

[1] Michigan State Univ, Coll Human Med, Dept Translat Neurosci, Grand Rapids, MI USA

[2] Michigan State Univ, Cell & Mol Biol Grad Program, Coll Nat Sci, E Lansing, MI 48824 USA

[3] Michigan State Univ, Coll Osteopath Med, E Lansing, MI 48824 USA

[4] Mercy Hlth St Marys, Grand Rapids, MI USA

[5] Northeast Ohio Med Univ, Coll Pharm, Dept Pharmaceut Sci, Rootstown, OH USA

[6] Univ Penn, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA USA

关键词: Parkinson's;    Pesticide;    Synuclein;    Neurotoxicity;    Neuroinflammation;    Sex differences;   

DOI  :  10.1016/j.nbd.2020.104947

来源: Elsevier

【 摘 要 】

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 malespecific 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 alpha-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.