SAT-227 Diet-Induced Obesity and Prenatal Androgen Exposure Reprogram the Fetus and Cause Transgenerational PCOS-Like Phenotypic Changes in Adult Female Offspring

Abstract

The fetal life is a critical window of developmental patterning affecting growth trajectories before birth and can influence the risk of reproductive and metabolic disease in adulthood. Maternal obesity and elevated prenatal androgens are two prominent potential exposures which may affect the development of the embryo and its postnatal life. If in utero androgen exposure with or without maternal obesity increase female offspring susceptibility for transgenerational inheritance of reproductive and metabolic disease has not been investigated. Therefore we fed female mice high-fat high sucrose (HFHS) or control diet (CD) diet for 6 weeks prior mating to induce obesity and exposed pregnant female mice to prenatal androgen exposure with dihydrotestosterone (DHT) or vehicle during the embryonic day (E) 16.5-E18.5. At weaning, first, second and third generation (F1, F2, and F3) female offspring from DHT exposed mothers with diet-induced obesity had longer anogenital distance (AGD), a marker of in utero androgen exposure, and disturbed estrous cycle compared with offspring from vehicle treated mothers fed CD. F1 and F3 female offspring from DHT exposed mothers and great-grand mothers with diet-induced obesity weighed more compared to offspring from vehicle-treated obese mothers, and F3 female offspring from great-grand DHT exposed mothers had more fat mass assessed by EchoMRI. Additionally, F1 and F3 female offspring from DHT exposed mothers and great-grand mothers with or without diet-induced obesity displayed a lower respiration exchange ratio and reduced energy expenditure than offspring from vehicle-treated mothers fed CD assessed by the metabolic cages. Finally, mice were superovulated to collect MII oocytes for single-cell RNA sequencing. Our preliminary analysis reveal that genes related to preimplantation embryonic imprinting are differentially expressed in F1, F2, and F3 female offspring from DHT exposed mothers, grandmothers, and great-grandmothers fed CD, and in mice from mothers with diet-induced obesity. These results demonstrate that in utero androgen exposure and diet-induced obesity contribute to transgenerational effects on reproductive and metabolic phenotypes in adult female offspring, involving altered expression of preimplantation imprinting genes in germ cells.