Toxicity and Detoxification of Imidacloprid in the Murine Ovary

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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.