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 Osteopathic Medicine, Michigan State University, East Lansing, MI, United States of America.
Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
Neurobiol Dis. 2020 Jul;141:104947. doi: 10.1016/j.nbd.2020.104947. Epub 2020 May 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 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.
人类和动物研究表明，接触有机氯杀虫剂狄氏剂会增加患帕金森病 (PD) 的风险。先前的研究表明，发育性狄氏剂暴露会增加雄性 C57BL/6 小鼠对 MPTP 毒性的神经元易感性，这可能是通过改变多巴胺 (DA) 的包装和周转。然而，MPTP 模型与 PD 病理生理学的相关性一直受到质疑。因此，我们研究了狄氏剂诱导的 α-突触核蛋白 (α-syn)-预形成纤维 (PFF) 模型中的神经毒性，该模型更好地反映了 PD 发病机制中观察到的 α-syn 病理学和毒性。具体来说，我们使用“双打击”模型来确定发育性狄氏剂暴露是否会增加对 α-syn PFF 诱导的神经毒性的易感性。从繁殖前 1 个月开始，母鼠每 3-4 天接受狄氏剂 (0.3mg/kg) 或载体玉米油处理，直至幼鼠 22 日龄断奶。在 12 周龄时，雄性和雌性后代接受纹状体 α-syn PFF 或对照生理盐水注射。与雄性对 MPTP 的易感性增加一致，我们的结果表明，发育性狄氏剂暴露仅使雄性小鼠对 PFF 诱导的毒性更为敏感。具体来说，在雄性后代中，狄氏剂加剧了 PFF 注射后 6 个月时在挑战性横梁上的运动缺陷，并增加了纹状体中的 DA 周转。然而，雄性后代在 PFF 注射后 1 或 2 个月时纹状体中磷酸化 α-syn 聚集 (pSyn) 既没有加剧，也没有在 PFF 注射后 6 个月时纹状体中 TH 和 NeuN 丧失加剧。总的来说，这些数据表明，发育性狄氏剂暴露会导致 α-syn 病诱导的行为和生化缺陷的雄性特异性加剧。这一性别特异性结果与之前在 MPTP 模型中的研究结果一致，也与该暴露范式先前报告的对雄性和雌性表观基因组的性别特异性影响以及男性中 PD 的更高患病率和更严重的病程一致。本项目中建立的新型双打击环境毒物/PFF 暴露范式可用于探索其他与 PD 相关的暴露如何改变散发性 PD 中神经元对 α-syn 病的易感性的机制。
