Grant: Project Grant

Reproductive health relies on specialized brain circuits that control hormone release, fertility, and sexual development. Key neurons in the hypothalamus, called KNDy neurons, regulate the hormone GnRH, which is critical to maintain fertility in all mammals, including humans. Disruption of these circuits can lead to fertility disorders such as polycystic ovary syndrome (PCOS), a common condition affecting 10-15% of women worldwide. Factors that interfere with brain development before birth, including excess androgens (e.g., high testosterone levels) or environmental chemicals like TBECH (a widely used flame retardant substance present in households, water, and food), may alter these circuits and increase the risk of reproductive problems. This project will use advanced lab-grown human brain models, called hypothalamic organoids, to study how these neurons develop and regulate reproductive hormones. We will investigate how prenatal androgen exposure or TBECH affects these neural circuits and the timing of hormone release, which is crucial for fertility. By integrating hormone-producing neurons into these organoids, we can model sex-specific responses and identify how disruptions occur at the cellular and molecular level. We will also test how exposure to TBECH during pregnancy affects brain development and reproductive outcomes in mice, providing complementary in vivo insights. Our research will reveal fundamental mechanisms that control reproductive health, identify how prenatal hormones or environmental disruptions may cause fertility disorders, and guide the discovery of new biomarkers or treatments to improve reproductive outcomes.