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

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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.