Investigating modes of action of glyphosate-induced ovotoxicity

研究草甘膦诱导的卵毒性的作用模式

• 批准号: 9182466
• 负责人: Aileen Frances Keating
• 金额: $ 22.5万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182466
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Aromatase; Birth; Cell Line; Chemical Exposure; Cholesterol; Classification; Cytochrome P450; Data; Dermal; Development; Dose; Endocrine Disruptors; Endocrine disruption; Environment; Environmental Exposure; Enzymes; Estradiol; Estrogen Receptor beta; Estrus; Event; Exposure to; Female; Fertility; Foundations; Gametogenesis; Genetic Transcription; Germ Cells; Glean; Goals; Gonadal Steroid Hormones; Growing Follicle; Health; Herbicides; In Vitro; Infertility; Ingestion; Knowledge; Maintenance; Maps; Measurement; Mediating; Menopause; Messenger RNA; Methods; Molecular Target; Monitor; Mus; Oocytes; Oral; Outcome; Ovarian; Ovarian hormone; Ovary; Partner in relationship; Pathway interactions; Pattern; Periodicity; Phosphorylation; Physiological; Post-Transcriptional Regulation; Postmenopause; Pregnancy Outcome; Primordial Follicle; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Proxy; Reproduction; Reproductive Health; Rural; Side; Signal Transduction; Signaling Molecule; Staining method; Stains; Steroid biosynthesis; Time; Translating; Woman; base; folliculogenesis; glyphosate; in vivo; male; meetings; novel; ovotoxicity; postnatal; reproductive; reproductive function; research study; response; steroidogenic acute regulatory protein; toxicant

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.

7.项目总结： 大约11%的美国女性患有不孕不育，通常没有任何明确的原因。在出生时，雌性是 生下来就有不可替代的卵母细胞池，即雌配子。以卵巢为靶点的化学暴露可能 耗尽和/或破坏这个卵母细胞池，这在生理上表现为不孕和加速进入 进入更年期状态。绝经后的岁月与许多有害健康有关。 因此，处于这种生理状态的时间越长，女性发展这种健康的机会就越大 并发症。除了卵泡衰竭外，一些化学物质暴露还会影响卵巢，从而导致不孕不育。 荷尔蒙的产生。 草甘膦是一种在农村和城市环境中广泛使用的除草剂，年使用量为155 百万磅。在细胞系中，甘氨酸降低卵巢17β-1的关键酶STAR和CYP19A的表达 雌二醇的合成。在我们的初步实验中，我们发现体内接触Gly可以减少 STAR和CYP19A，并增加卵巢关键调节分子AKT(PACT)的磷酸化。这些 这些变化转化为GLY对雌性配子和性类固醇激素产生的潜在影响。在……里面 目的1、我们将通过体外和体内实验来确定增加的pakt在卵泡发生中的作用。 接近。目的2将研究还原的STAR和CyP19A对17个β-雌二醇水平的表型影响。 雌性小鼠的卵巢周期和生育结果。这两个目标都将表征一种时间和剂量依赖的 对GLY暴露的反应。这些目标的实现将彻底质疑我们的核心假设 甘氨酸改变卵巢PI3K信号导致PAKT增加，但STAR和CYP19a减少， 对雌性小鼠卵泡发生、17β-雌二醇合成和生育力的影响 GLY暴露时发生的事件的机械地图，可能会转化为受危害的雌性 生育能力将被构建。利用生成的知识，将GLY视为雌性生殖器 毒药将成为可能。此外，识别卵巢内危害雌性的GLY靶标 生育将会完成。