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

This dataset contains all data for published figures and supplementary figures in the manuscript "Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits". GraphPad Prism files can be viewed in the free Viewer mode or data can be extracted by viewing files in a text editor. R and RStudio are freely available for running Rmd files. file_list.txt includes a list of all files included in this dataset 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 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 (pSyn) aggregation 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 increase in neuronal vulnerability to synucleinopathy. 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.本数据集包含论文《发育暴露于有机氯杀虫剂狄氏剂可导致雄性特异性加重α-突触核蛋白（α-synuclein, α-syn）预制纤维（preformed fibril, PFF）诱导的毒性与运动障碍》中已发表图表及补充图表的全部数据。 GraphPad Prism文件可通过免费Viewer模式打开查看，或通过文本编辑器提取其中数据。运行Rmd文件可使用免费开源的R与RStudio软件。file_list.txt文件收录了本数据集包含的全部文件清单。 摘要：已有人体及动物研究表明，暴露于有机氯杀虫剂狄氏剂与帕金森病（Parkinson’s disease, PD）发病风险升高相关。既往研究显示，发育阶段暴露于狄氏剂可增加雄性C57BL/6小鼠神经元对MPTP毒性的易感性，其机制可能与多巴胺（dopamine, DA）的包装及代谢转换有关。然而，MPTP模型与PD病理生理学的相关性曾受到质疑。因此，本研究采用更能反映PD发病过程中α-突触核蛋白病理改变与毒性的α-突触核蛋白预制纤维模型，探究狄氏剂诱导的神经毒性。具体而言，我们采用“二次打击”模型，旨在明确发育阶段暴露于狄氏剂是否会增加机体对α-突触核蛋白预制纤维诱导的突触核蛋白病的易感性。 实验中，母鼠在配种前1个月开始喂食狄氏剂（0.3 mg/kg，每3~4天一次）或对照玉米油，并持续至幼鼠出生后第22天断奶。幼鼠长至12周龄时，分别向雄性与雌性子代小鼠纹状体内注射α-突触核蛋白预制纤维或对照生理盐水。与既往观察到的雄性小鼠对MPTP易感性升高的结果一致，本研究结果证实，发育阶段暴露于狄氏剂仅会加重雄性小鼠体内α-突触核蛋白预制纤维诱导的毒性。具体表现为：在幼鼠注射α-突触核蛋白预制纤维6个月后，雄性子代小鼠在挑战性平衡杆实验中出现的运动障碍症状被狄氏剂进一步加重，且纹状体多巴胺代谢转换率升高。但无论在注射后1个月或2个月，雄性子代小鼠黑质（substantia nigra, SN）内磷酸化α-突触核蛋白（pSyn）聚集均未出现加重；注射后6个月时，黑质内酪氨酸羟化酶（tyrosine hydroxylase, TH）与NeuN阳性神经元丢失也未因狄氏剂暴露出现加剧。综上，上述数据表明，发育阶段暴露于狄氏剂可使雄性小鼠神经元对突触核蛋白病的易感性出现雄性特异性升高。这一性别特异性结果与既往MPTP模型中的研究发现、本团队此前报道的该暴露范式对雌雄子代表观基因组的性别特异性影响，以及男性PD患病率更高、病程更严重的临床现象均相符。本研究建立的新型环境毒物/α-突触核蛋白预制纤维二次打击暴露模型，可用于探究其他PD相关暴露因素如何改变散发性PD中神经元对突触核蛋白病的易感性机制。