Ovarian impacts of extreme heat and co-exposure to climate change-induced harmful algal bloom toxins (Admin Supplement to R01ES032144)

项目总结 气候变化日益被认为是对人类健康的全球性威胁。气候的一个主要后果 变化是极端高温事件发生频率更高、强度更大的事件。先前的研究表明， 妇女怀孕期间暴露在酷热或炎热天气中，如早产/死产和低出生体重； 然而，极热对女性生育力的影响却知之甚少，这种影响高达10-15%。 包括美国在内的世界各地的女性。人口统计学研究显示，经历高温的女性 性交前两周受孕减少，出生率大幅下降8-10个月 后来，暴露在更高的环境温度和更少的陈词滥调之间存在负相关 育龄妇女卵泡计数。这些人类数据突出表明，酷热可能会影响卵巢 受孕前卵泡发育和卵母细胞成熟。之前使用大型农场动物进行的研究 早就证明了热应激对卵母细胞质量的有害影响。然而，目前还不清楚 热应激对卵母细胞的直接影响是导致卵母细胞质量下降的原因，热应激对卵母细胞质量的间接影响 整个卵泡，或两者兼而有之，以及涉及的分子机制。全球气温上升也是一个 其他气候变化和环境危机的主要驱动因素，如与气候变化有关的有害藻类 水华(HAB)是蓝藻的过度生长，通常被称为蓝藻。 人类通过受污染的饮用水、食物和娱乐活动接触到赤潮释放的毒素。 活动。在我们的父R01项目(ES032144)中，我们已经证明了微囊藻毒素-LR(MC-LR)，最 常见的赤潮毒素，干扰促性腺激素依赖性卵泡成熟和相关激素的分泌， 和排卵。到目前为止，大多数研究都集中在单一类型的气候变化应激源上，但对生殖的影响 现实世界中的多重危机，如共同暴露在极端高温和赤潮毒素中，是未知的。我们的 初步数据显示，体外极端高温暴露激活了小鼠的热休克反应基因 它还抑制卵泡生长、激素分泌、排卵和卵母细胞 以依赖温度的方式进行减数分裂。根据这些发现，我们假设极端高温会激活 热休克和其他细胞应激反应干扰卵泡发生和/或卵子发生，以及 联合暴露在高温下会加剧HAB毒素引起的卵巢毒性，这将分两个阶段进行测试 使用我们建立的3D包裹式体外卵泡生长(EIVFG)系统进行特定的靶点。在目标1中，我们将 确定极端高温扰乱卵泡发生和/或卵子发生的机制。在目标2中，我们将 确定共同暴露在极端高温和赤潮毒素下对卵巢的影响。给出同时增加的 极端高温和赤潮的趋势，预计只会在未来几十年内升级，阐明卵巢 极端高温的破坏作用及其与HAB毒素的共同暴露将使我们能够加快发育 制定预防、缓解和补救措施，以保护女性生殖健康和生育能力。

PROJECT SUMMARY Climate change is increasingly recognized as a global threat to human health. One major consequence of climate change is the more frequent and intense extreme heat events. Previous research reveals adverse effects of exposure to extreme heat or hot weathers on women’s pregnancy, such as preterm/still birth and low birth weight; however, little is known regarding the impacts of extreme heat on female fertility which affects up to 10-15% women worldwide including the US. Demographic studies revealed that women experiencing high temperatures two weeks before the sexual intercourse had reduced conceptions and a large decline in birth rates 8-10 months later, and there were negative associations between exposure to higher ambient temperatures and less antral follicle counts in reproductive aged women. These human data highlight that extreme heat likely affects ovarian follicle development and oocyte maturation before the conception. Previous research using large farm animals has long documented the deleterious effects of heat stress on oocyte quality. However, it is unknown whether the compromised oocyte quality is caused by the direct impact of heat stress on oocytes, the indirect effect on the entire follicles, or both, as well as the molecular mechanisms involved. The global temperature rise is also a major driver of other climate change and environmental crises, such as climate change-related harmful algal blooms (HABs) which are the excessive growth of cyanobacteria, often refers to as the ‘blue-green algae’. Humans are exposed to toxins released from HABs via contaminated drinking water, food, and recreational activities. In our parent R01 project (ES032144), we have demonstrated that microcystin-LR (MC-LR), the most common HAB toxin, interfered with gonadotropin-dependent follicle maturation and related hormone secretion, and ovulation. So far, most studies focus on a single type of climate change stressor, but the reproductive impact of multiple crises in the real world such as co-exposure to extreme heat and HAB toxins is unknown. Our preliminary data revealed that exposure to extreme heat in vitro activated heat shock response genes in mouse follicular cells and/or oocytes, and it also inhibited follicle growth, hormone secretion, ovulation, and oocyte meiosis in a temperature-dependent manner. With these findings, we hypothesize that extreme heat activates heat shock and other cellular stress responses to interfere with folliculogenesis and/or oogenesis, and co-exposure to extreme heat exacerbates HAB toxin-induced ovarian toxicities, which will be tested in two Specific Aims using our established 3D encapsulated in vitro follicle growth (eIVFG) system. In Aim 1, we will identify the mechanisms by which extreme heat disrupts folliculogenesis and/or oogenesis. In Aim 2, we will determine the ovarian impacts of co-exposure to extreme heat and HAB toxins. Giving the concurrently increasing trends of extreme heat and HABs, which is only projected to escalate in the coming decades, elucidating ovarian disrupting effects of extreme heat and its co-exposure to HAB toxins will enable us to speed up the development of prevention, mitigation, and remediation methods to protect female reproductive health and fertility.