IL-17A介导的免疫应答在氟中毒动物睾丸炎症反应过程中的作用研究

Fluorosis is a kind of zoonotic disease which widely exists in the world. Due to its active chemical property and narrow safety range, mild higher fluoride exposure can exhibit toxic effects. Epidemiological and experimental investigations have confirmed the reproductive effects of fluoride. Based on the findings already known and our previous studies, as well as the clues inferred by sequencing analysis, it is suggested that IL-17 signaling pathway may be the key link of the immunoresponse in testis of the fluorosed animals. Therefore, in this project, the experimental models of animal fluorosis, experimental autoimmune orchitis, IL-17A knockout, and IL-17A function improvement will be established to evaluate the effects of fluoride on immunoresponse during the inflammatory reaction in testis, alteration in IL-17A and the related signaling pathway, and the influence of changed IL-17A function on the testis immunoresponse in the fluorosed animals. By deeply analyzing whether IL-17A and its related signaling pathway were involves in the inflammatory reaction in testis of animals with fluorosis, the mechanism of fluoride reproductive toxicity will be further understood, and it will also be helpful to provide valuable animal models and the experimental theory for studying on the human health.

氟中毒是全世界广泛存在的一种人畜共患性地方病，由于其化学性质活泼，安全范围极窄，稍有过量就会引起毒性作用，流行病学调查和实验室研究均证实了氟的雄性生殖毒性。本课题组依照已有报道，结合前期实验结果和测序分析，提出IL-17信号通路可能是氟中毒动物睾丸免疫应答反应的中心环节。因此，本项目选取动物睾丸为研究对象，通过构建氟中毒动物模型、实验性自身免疫性睾丸炎模型、IL-17A基因敲除和IL-17A功能加强模型，检测氟对睾丸炎症反应过程中免疫应答的影响、IL-17A及其信号通路的变化、以及睾丸IL-17A功能改变对氟中毒动物睾丸炎症的影响，深入分析IL-17A及其信号通路是否参与调控了氟中毒动物睾丸的炎症反应过程，从而进一步揭示氟的生殖毒性机理，也为人类相关健康问题提供动物模型与实验依据。

氟中毒是全世界广泛存在的一种人畜共患性地方病，严重危害人畜健康。流行病学调查和实验室研究均证实了氟的雄性生殖毒性。本课题组依照已有报道，结合前期实验结果和测序分析，提出IL-17信号通路是氟中毒动物睾丸免疫应答反应的中心环节。因此，本项目选取动物睾丸为研究对象，构建了氟中毒动物模型、实验性自身免疫性睾丸炎模型、IL-17A基因敲除和IL-17A功能加强模型，结果显示，氟暴露导致小鼠自身免疫性睾丸炎，睾丸结构功能损伤，IL-17A含量升高，IL-17A信号通路活化。IL-17A重组蛋白睾丸注射进一步加重了氟诱导的小鼠自身免疫性睾丸炎，睾丸损伤加剧。然而，小鼠IL-17A敲除抑制了IL-17A信号通路，并有效地缓解氟暴露引起的睾丸损伤。上述结果表明，氟通过IL-17A及其信号通路诱导小鼠自身免疫性睾丸炎，最终造成睾丸结构和功能的损伤。同时，运用上述模型我们还发现氟通过IL-17A及其信号通路诱导肝脏损伤。本项目揭示了氟的生殖毒性机理，为进一步实施科学诊断和靶标药物设计提供了依据与思路。