Investigating additive impact of heat stress on zearalenone-induced ovotoxicity

过去几十年来，全球环境温度稳步上升。气候温度升高会导致严重的极端事件，例如热量增加，导致哺乳动物物种出现热应激（HS）、热休克和热衰竭。欧洲研究表明存在性别差异，其中女性更容易因热浪而死亡。同样，在动物中，雌性生殖受到热应激引起的不孕症的损害，其表型表现为不排卵、受孕率降低和妊娠维持率低。与肥胖和多囊卵巢综合征 (PCOS) 等代谢性疾病类似，HS 期间的动物会出现高胰岛素血症，我们的研究小组发现 HS 会改变卵巢胰岛素信号传导和类固醇激素的产生。在哺乳动物中，多种化合物会改变内分泌信号，破坏内源性激素的产生。这种内分泌干扰物是一种饮食污染物玉米赤霉烯酮，它作为非甾体雌激素损害女性生殖。欧洲食品管理局已确定人体接触；然而，美国并没有这样做。在高胰岛素血症（肥胖）的不同生理模型中，卵巢对环境卵毒性暴露变得更加敏感。具体而言，Roach 女士将探讨以下假设：ZEA 暴露会改变卵巢信号传导，以及热应激会加重 ZEA 诱导的卵毒性。由于猪和人类对 ZEA 暴露具有相似的敏感性，因此将使用猪动物模型，并且将完成两个具体目标。目标 1 将确定 HS 期间暴露于 ZEA 的表型和内分泌影响。目标 2 将确定 HS 期间暴露于 ZEA 是否会改变卵巢组织形态以及参与卵泡发生、胰岛素信号传导、类固醇生成和细胞凋亡的途径。总的来说，这些实验将确定对单独和组合暴露于 ZEA 和 HS 的表型和分子效应的全面理解。此外，该奖学金还将通过为罗奇女士提供额外的科学和教学培训来扩展她的技术和智力能力，以在生殖生理学和毒理学专家的指导下促进她的职业发展。这是毒理学的一个新兴领域，将使罗奇女士处于气候变化和毒理学交叉领域的最前沿。总之，该提案将支持爱荷华州立大学动物科学系 Crystal Roach 女士在 Aileen Keating 博士的赞助下进行研究和职业发展培训。

Global ambient temperatures have steadily increased over the past decades. Increased climate temperatures cause severe extreme incidents, such as increased thermal heat, causing heat-stress (HS), heat shock, and heat exhaustion among mammalian species. European studies show gender differences, in which women are more susceptible to death by heatwaves. Likewise, in animals, female reproduction is compromised by heat- stress induced infertility, phenotypically noted as anovulation, reduced conception rate, and low pregnancy maintenance. Resembling metabolic disorders such as obesity and polycystic ovarian syndrome (PCOS), animals during HS are hyperinsulinemic, and our research group have discovered that HS alters ovarian insulin signaling and steroid hormone production. In mammalian species, various compounds alter endocrine signaling disrupting endogenous hormonal production. Such an endocrine disruptor is a dietary contaminant, zearalenone, which acts as a non-steroidal estrogen to impair female reproduction. Human exposure has been identified in the European Food Authority; however, such is not established in the United States. In a different physiological model of hyperinsulinemia, obesity, the ovary becomes more sensitive to environmental ovotoxic exposures. Specifically, Ms. Roach will explore the hypothesis that ZEA exposure alters ovarian signaling and that heat stress is additive to ZEA-induced ovotoxicity. A pig animal model will be used since both pigs and humans have similar sensitivities to ZEA exposure, and two specific aims will be completed. Aim 1 will determine the phenotypic and endocrine impacts of ZEA exposure during HS. Aim 2 will determine if exposure to ZEA during HS alters ovarian histomorphology and pathways involved in folliculogenesis, insulin signaling, steroidogenesis, and apoptosis. Collectively, these experiments will determine a comprehensive understanding of phenotypic and molecular effects of ZEA and HS exposures alone and in combination. In addition, this fellowship will expand Mrs. Roach's technical and intellectual competencies by providing her with additional scientific and didactic training to enhance her career development under the mentorship of an expert in reproductive physiology and toxicology. This is a niche and emerging area of toxicology that will position Ms. Roach to be at the forefront of the intersection between climate change and toxicology. In all, this proposal will support the research and career development training of Ms. Crystal Roach in the Department of Animal Science at Iowa State University under the sponsorship of Dr. Aileen Keating.