Investigating modes of action of glyphosate-induced ovotoxicity

7. 项目总结:

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.