Investigating modes of action of glyphosate-induced ovotoxicity

7.项目概要： 大约11%的美国女性患有不孕症，通常没有任何明确的原因。在出生时，女性 生来就有一个不可替代的卵母细胞池，即雌性配子。以卵巢为目标的化学品暴露， 消耗和/或破坏卵母细胞池，这在生理上表现为不育和加速进入 进入更年期绝经后的岁月与许多有害健康的因素有关， 因此，在这种生理状态下花费更长的时间会增加女性发展这种健康的机会 并发症除了卵泡耗竭外，一些化学品暴露通过影响卵巢功能而导致不孕。 荷尔蒙分泌 草甘膦（GLY）是在农村和城市环境中广泛使用的除草剂，并且年使用量为155 百万磅在细胞系中，GLY可降低卵巢17β-受体中的关键酶星星和CYP 19 A的表达。 雌二醇合成在我们的初步实验中，我们发现体内GLY暴露减少了 星星和CYP 19 A，并增加AKT（pAKT）的磷酸化，这是一种关键的卵巢调节分子。这些 这些改变转化为GLY对雌性配子和性类固醇激素产生的潜在影响。在 目的1，我们将确定增加的pAKT对卵泡发生的贡献，使用离体和体内 approach.目的2将研究降低的星星和CYP 19 A对17β-雌二醇水平的表型效应， 雌性小鼠的卵巢周期和生育力结果。这两个目标的特征都是时间和剂量依赖性 对GLY暴露的反应。这些目标的完成将彻底质疑我们的中心假设， GLY改变卵巢PI 3 K信号传导，导致pAKT增加，但星星和CYP 19 a减少， 对雌性小鼠的卵泡发生、17β-雌二醇合成和生育力的伴随影响，以及时间 GLY暴露后发生的可能转化为受损女性的事件的机制图 生育能力将被构建。使用生成的知识，考虑GLY作为女性生殖 有毒物质是可能的。此外，鉴定卵巢内损害女性生殖系统的GLY靶点， 生育将完成。

7. Project summary: Approximately 11% of U.S. females suffer from infertility, often without any clear cause. At birth, females are born with an irreplaceable pool of oocytes, the female gamete. Chemical exposures that target the ovary can deplete and/or damage this oocyte pool, which is manifested physiologically as infertility and accelerated entry into the menopausal state. The post-menopausal years are associated with a number of deleterious health issues, thus, a longer time spent in this physiological state increases a woman’s chance to develop such health complications. In addition to follicle depletion, some chemical exposures cause infertility by impacting ovarian hormone production. Glyphosate (GLY) is a widely used herbicide in rural and urban environments and annual use comprises 155 million lbs. In cell lines, GLY reduces expression of STAR and CYP19A, critical enzymes in ovarian 17β- estradiol synthesis. In our preliminary experiments, we have discovered that GLY exposure in vivo reduces STAR and CYP19A, and increases phosphorylation of AKT (pAKT), a key ovarian regulatory molecule. These alterations translate into potential impacts of GLY on female gamete and sex steroid hormone production. In aim 1, we will determine the contribution of increased pAKT on folliculogenesis, using an ex vivo and in vivo approach. Aim 2 will investigate a phenotypic effect of reduced STAR and CYP19A on 17β-estradiol levels, ovarian cyclicity and fertility outcomes in female mice. Both aims will characterize a time- and dose-dependent response to GLY exposure. Completion of these aims will thoroughly interrogate our central hypothesis that GLY alters ovarian PI3K signaling leading to increased pAKT but reduced STAR and CYP19a, with concomitant impacts on folliculogenesis, 17β-estradiol synthesis and fertility in female mice and a temporal mechanistic map of events that occur upon GLY exposure which could translate into compromised female fertility will be constructed. Using the generated knowledge, consideration of GLY as a female reproductive toxicant will be possible. Additionally, identification of GLY targets within the ovary that compromise female fertility will be completed.