Toxicity and Detoxification of Imidacloprid in the Murine Ovary

7.项目摘要 新烟碱类化合物是合成的尼古丁衍生物，可作为全身性神经毒物。它们用于 大规模农业系统，私人家庭花园，以及作为兽药。使用 烟碱类杀虫剂正在迅速增加，因为它们继续取代已知的危险有机磷酸酯 和氨基甲酸甲酯杀虫剂。它们的普遍存在和迅速增加的使用导致长期接触 非目标物种，包括人类、鱼类、鸟类和传粉者。尽管他们越来越受欢迎，文学是 缺乏在非靶种属中评价类烟碱毒性的研究，特别是关于生殖毒性的研究 功能给药后6小时，在大鼠卵巢中发现了吡虫啉和两种代谢物， 给药后12小时的峰浓度。目前尚不清楚这些代谢物是否通过 血管或卵巢是否具有代谢母体化合物的代谢机制。一些 已经在体内证实了吡虫啉对卵巢的负面影响， 卵泡异常、血浆激素浓度变化和氧化应激证据 在卵巢细胞中。除了这些病理学终点，关于IMI或IMI的机制知之甚少。 它的代谢物会引起卵巢毒性。拟议的工作将测试假设， 卵巢卵泡毒性通过乙酰胆碱途径和卵巢本身有助于这种卵毒性使用其 新陈代谢机制目标1将描述吡虫啉和相关吡虫啉的毒性终点 通过基因表达和体外卵泡中类固醇生成的变化来调节代谢物。目标2将 确定卵巢是否具有代谢吡虫啉的代谢机制。目标3将决定 乙酰胆碱途径在吡虫啉诱导的卵巢毒性中的作用。总的来说，这些实验将 提供了一个全面的概述，吡虫啉及其代谢物的影响， 卵巢，重点是卵巢代谢机制和乙酰胆碱的鉴定 途径。通过完成这些实验和研究培训计划中概述的其他活动， 申请人将学习最先进的研究技术，发展技术写作技能，并创建一个强大的 生殖生物学家、毒理学家和兽医临床医生网络。

7. PROJECT SUMMARY Neonicotinoids are synthetic nicotine derivatives that act as systemic neurotoxicants. They are used in large-scale agricultural systems, in private home gardens, and as veterinary pharmaceuticals. The use of neonicotinoid insecticides is rapidly increasing as they continue to replace known dangerous organophosphate and methylcarbamate insecticides. Their ubiquitous and rapidly increasing use results in chronic exposure of non-target species including humans, fish, birds, and pollinators. Despite their rising popularity, the literature is devoid of studies that evaluate neonicotinoid toxicity in non-target species, especially regarding reproductive function. Imidacloprid and two metabolites have been identified in the rat ovary 6 hours post dosing and reach peak concentrations at 12 hours post dosing. It is unknown whether these metabolites reach the ovary via the vasculature or whether the ovary has the metabolic machinery to metabolize the parent compound. Some negative effects of imidacloprid on the ovary have been demonstrated in vivo including morphological abnormalities of ovarian follicles, changes in plasma hormone concentrations, and evidence of oxidative stress in ovarian cells. Beyond these pathologic endpoints, little is known about the mechanisms through which IMI or its metabolites cause ovarian toxicity. The proposed work will test the hypothesis that imidacloprid causes ovarian follicle toxicity via acetylcholine pathways and the ovary itself contributes to this ovotoxicity using its metabolic machinery. Aim 1 will characterize the toxic endpoints of imidacloprid and relevant imidacloprid metabolites through changes in gene expression and steroidogenesis in ovarian follicles in vitro. Aim 2 will determine whether the ovary has the metabolic machinery to metabolize imidacloprid. Aim 3 will determine the role that acetylcholine pathways play in imidacloprid-induced ovarian toxicity. Collectively these experiments will provide a comprehensive overview of the effects of imidacloprid and its metabolites on both immature and mature ovaries, with a focus on mechanism and the identification of ovarian metabolic machinery and acetylcholine pathways. Through the completion of these experiments and other actives outlined in the research training plan, the applicant will learn state of the art research techniques, develop technical writing skills, and create a strong network of reproductive biologists, toxicologists, and veterinary clinicians.