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。项目摘要： 大约11％的美国女性患有不孕症，通常没有任何明显的原因。出生时，女性是 雌配子的卵母细胞有不可替代的卵母细胞。靶向卵巢的化学暴露可以 耗尽和/或损坏了这个卵母细胞，在物理上表现为不育症和加速进入 进入更年期。绝经后年与许多有害健康有关 问题，因此在这种身体状态上花费的时间更长，增加了女性发展这种健康的机会 并发症。除了叶分部的部署外，某些化学暴露通过影响卵巢而导致不育 马龙生产。 草甘膦（Gly）是在粗糙和城市环境中的广泛使用的除草剂，每年使用155 百万磅。在细胞系中，Gly降低了恒星和CYP19A的表达，卵巢17β-中的关键酶 雌二醇合成。在我们的初步实验中，我们发现体内的Gly暴露会减少 星和CYP19A，并增加Akt（PAKT）的磷酸化，这是一种关键的卵巢调节分子。这些 变化转化为Gly对女配子和性类固醇马酮产生的潜在影响。在 AIM 1，我们将使用离体和体内确定PAKT对卵泡发生的贡献 方法。 AIM 2将研究降低星和CYP19A对17β-雌二醇水平的表型效应， 雌性小鼠的卵巢循环和生育结果。两种目标都将表征时间和剂量依赖性 对Gly暴露的反应。这些目标的完成将彻底询问我们的中心假设 Gly会改变卵巢PI3K信号，导致PAKT增加，但降低了恒星和CYP19A，并具有 对雌性小鼠的卵泡发生，17β-雌二醇合成和生育能力的影响以及暂时的影响 在gly暴露时发生的事件的机械图，可能转化为受损的女性 生育能力将被建造。使用生成的知识，将Gly视为女性生殖 有毒物质是可能的。另外，鉴定卵巢中的gly靶标会损害女性 生育能力将完成。