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

极端高温和共同暴露于气候变化引起的有害藻华毒素对卵巢的影响（R01ES032144 的管理补充）

• 批准号: 10838834
• 负责人: Shuo Xiao
• 金额: $ 31.84万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10838834
• 关键词: 3-Dimensional; Adverse effects; Affect; Age; Antral; Benchmarking; Birth; Birth Rate; Cells; Cellular Stress; Coitus; Competence; Conceptions; Cyanobacterium; Data; Development; Dose; Encapsulated; Environmental Risk Factor; Event; Exposure to; Female; Female infertility; Fertility; Food; Frequencies; Fresh Water; Genes; Global Warming; Goals; Gonadotropins; Growth; Health; Heat Stress Disorders; Heat-Shock Response; High temperature of physical object; Homeostasis; Hormone secretion; Human; In Vitro; Infertility; Livestock; Low Birth Weight Infant; Mammals; Meiosis; Methods; Modeling; Molecular; Mus; Oocytes; Oogenesis; Ovarian; Ovarian Diseases; Ovarian Follicle; Ovary; Ovulation; Parents; Pathway interactions; Physiologic Thermoregulation; Play; Pregnancy; Pregnancy Outcome; Prevention; Prospective, cohort study; Recreation; Reproduction; Reproductive Health; Research; Role; Somatic Cell; Speed; System; Temperature; Testing; Toxin; United States National Institutes of Health; Weather; Woman; adverse outcome; aged; biological adaptation to stress; climate change; contaminated drinking water; cyanoginosin LR; epidemiologic data; experience; exposed human population; extreme heat; extreme temperature; female fertility; folliculogenesis; global health; global temperature; harmful algal blooms; human data; in vitro Model; in vivo; marine; oocyte maturation; oocyte quality; ovotoxicity; prevent; remediation; reproductive; response; stressor; trend; urban area

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.

项目摘要 气候变化越来越被认为是对人类健康的全球威胁。气候变化的一个主要后果 变化是更频繁和强烈的极端高温事件。先前的研究表明， 妇女怀孕期间暴露于酷热或炎热天气，例如早产/死产和出生体重不足; 然而，关于酷热对女性生育能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， 性交前两周受孕率下降，8-10个月出生率大幅度下降 暴露于较高的环境温度和胃窦狭窄之间存在负相关， 育龄妇女的卵泡计数。这些人类数据强调，极端高温可能会影响卵巢功能。 卵泡发育和卵母细胞成熟。以前的研究使用大型农场动物 长期以来一直记录热应激对卵母细胞质量的有害影响。然而，不知道是否 热应激对卵母细胞的直接影响、热应激对卵母细胞的间接影响和热应激对卵母细胞的影响是导致卵母细胞质量下降的主要原因。 整个卵泡，或两者，以及所涉及的分子机制。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（HABs）是蓝藻的过度生长，通常被称为“蓝绿藻”。 人类通过受污染的饮用水、食物和娱乐场所接触有害藻华释放的毒素。 活动在我们的父R 01项目（ES 032144）中，我们已经证明，微囊藻毒素-LR（MC-LR），最 常见的HAB毒素，干扰促性腺激素依赖性卵泡成熟和相关激素分泌， 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压力源，但生殖影响 真实的世界中的多重危机，如共同暴露于极端高温和有害藻华毒素是未知的。我们 初步数据显示，体外极热暴露激活了小鼠的热休克反应基因， 抑制卵泡生长、激素分泌、排卵和卵母细胞 减数分裂以温度依赖的方式。有了这些发现，我们假设极热激活了 热休克和其他细胞应激反应以干扰卵泡发生和/或卵子发生，和 共同暴露于极端高温加剧了HAB毒素诱导的卵巢毒性，这将在两个实验中进行测试。 使用我们建立的3D封装体外卵泡生长（eIVFG）系统的特定目的。在目标1中，我们 确定极端高温破坏卵泡发生和/或卵子发生的机制。在目标2中，我们将 确定共同暴露于极端高温和HAB毒素对卵巢的影响。同时增加 极端高温和有害生物的趋势，预计在未来几十年内只会升级，阐明卵巢癌的发病率。 破坏极端高温及其与赤潮毒素共同接触的影响将使我们能够加快发展 预防、缓解和补救方法，以保护女性生殖健康和生育力。