Retinoic acid rescues heat stress-induced estrous cycle disruption by enhancing Cyp19a1 expression through the Ca2+-pSTAT3-H3K27me3 axis†.

Global warming poses a public health risk, and heat-induced reproductive defects are a growing concern for both humans and animals. Disrupted estrous cycle and reduced estrogen synthesis are notable changes in females exposed to heat stress (HS); however, the underlying mechanism remains largely unknown, thus effective preventive or interventional strategies are still lacking. Here, by focusing on Cyp19a1, the gene encoding the rate-limiting enzyme for estrogen synthesis in ovarian granulosa cells, we identify HS as a trigger for Ca2+ release from the endoplasmic reticulum (ER). The increased intracellular Ca2+ flux functions as a high-temperature sensor and activates STAT3 phosphorylation. The activated Ca2+-pSTAT3 cascade disrupts the expression of H3K27me3-modifying enzymes, thus elevating H3K27me3 levels and finally repressing Cyp19a1. Moreover, we demonstrate that retinoic acid (RA), the primary active metabolite of vitamin A, rescues CYP19A1 expression by antagonizing HS on multiple layers of the cascade. In vivo, RA administration rescues estrogen synthesis and corrects the estrous cycle in female mice under HS. Together, our study establishes a mechanistic link between HS and impaired estrogen synthesis and identifies the antagonistic function of RA. Finally, we propose a nutritional strategy to prevent or alleviate high temperature-induced estrus disorders in females.