47 Transcriptomic effects of increased maternal estradiol on fetal organs in late-gestation ewes

Abstract The World Health Organization estimates that 15 million babies are born preterm each year, with one newborn dying every 40 seconds. Understanding the mechanisms that initiate normal parturition is critical to identifying disruptions associated with preterm birth. In sheep, activation of the fetal hypothalamic-pituitary-adrenal axis, resulting in cortisol secretion, is believed to be the initial trigger for labor. We previously established a sheep model in which estradiol (E2) administration reliably induces parturition, enabling controlled investigation of labor mechanisms. In this study, we used this model to investigate the transcriptomic effects of E2 on fetal organ maturation. Pregnant ewes at late gestation (days 139–142) were randomly assigned to an E2-treated (n = 6; 4 Silastic® implants × 50 mg each) or a control (n = 6; 4 empty implants) group. Implants were inserted subcutaneously in the axillary region, and ewes were euthanized 26 h post-treatment for tissue and blood collection. Samples of the fetal hypothalamus, pituitary, adrenal gland, and lungs were collected for RNA sequencing. Estradiol concentration was assessed in maternal systemic blood, umbilical vein, and fetal vein samples. Maternal E2 levels increased five-fold in treated ewes (p ≤ 0.01), while umbilical and fetal E2 levels were not affected relative to controls. Differentially expressed genes (DEGs) (p ≤ 0.05; |log2FC| ≥ 1) were identified in all fetal tissues: 4 (hypothalamus), 240 (pituitary), 5 (adrenal), and 2 (lungs). These findings suggest that maternal E2 indirectly influences fetal organ gene expression, particularly in the pituitary, potentially contributing to fetal organ maturation and preparedness for birth. (Supported by USDA 2021-67015-34277)