Bisphenol S fetal exposure in ewes exhibiting contrasted metabolic status impaired the ovarian follicular development of fetuses and lambs.

The size of the ovarian reserve, defined by the pool of primordial follicles, is established during fetal life in women and sheep. The prenatal period is a critical window of sensitivity, especially for ovarian development. Maternal metabolic status and nutrition during gestation can influence fetal programming, and affect the establishment of ovarian reserve. In addition, the developing fetus is particularly sensitive to endocrine disruptors. Bisphenol A (BPA), a plasticizer widely used in food packaging, has deleterious effects on fetal folliculogenesis. BPA has been banned from the food industry and has been replaced mainly by bisphenol S (BPS), whose effects on ovarian development remain poorly characterized.The objective of this study was to determine the effects of in utero exposure to BPS (50 µg/kg/day) on ovarian development in female fetuses, and lambs, using histology and/or magnetic resonance imaging (MRI). In addition, pregnant ewes exhibited contrasted metabolic status (lean versus fat), allowing assessment of the interaction between maternal nutrition and BPS exposure. This study was divided into two experiments. In the first, pregnant ewes received daily subcutaneous injection of BPS for 3 months, and fetal ovarian development was analyzed at 130 days of gestation. In the second, pregnant ewes were exposed daily to BPS through food for 3 months and female lambs were then monitored up to 4-month-old (pre-puberty). In offspring of fat mothers, the body weight of the fetuses increased but this increase was not observed anymore in lambs. Plasma anti-Mullerian hormone (AMH) concentrations decreased in 1-month-old lambs and the antral follicle number increased in both fetuses and 4-month-old lambs from well-fed mothers. In addition, a significant interaction between maternal metabolic status and gestational BPS exposure was reported for the numbers of primordial, intermediate and total follicles of fetuses, with a similar trend for pre-antral follicles. Such significant interaction was also reported for the number of intermediate follicles in 4-month-old lambs, with a similar tendency being reported for AMH concentration.In conclusion, maternal nutrition and gestational exposure to BPS had deleterious consequences on the body growth and ovarian follicular development in the offspring. In addition, BPS effects differ according to the maternal metabolic status. Thus, the maternal environment affected folliculogenesis in both fetuses and lambs. Further research is needed to determine whether these alterations have long-term deleterious effects on their reproductive function in adulthood.