MAMBO

Bisphenol A (BPA) has been used to produce plastic as tin can coating, polycarbonate and epoxy resins in the food industry. BPA was shown to exhibit deleterious effects on the reproductive function (hypothalamus and gonads) in both males and females. Because of all its side effects, BPA has been prohibited from food industry (French law n°2012-1442) and new formulations containing bisphenol S (BPS) as substitute have been proposed. It is, therefore, of importance to investigate BPS effects in human (before environmental exposure rises), as first data obtained in rodents and zebrafish suggest similar effects of both molecules. On the other hand, BPA has also been described as a risk factor for metabolic disorders such as diabetes and obesity. Lipid metabolism is crucial for ovarian functions and oocyte developmental competence and there is an increasing proportion of obese women with reproductive complications. This proposal aimed to assess whether BPS can affect female reproduction in human, and to decipher the potential interactions with metabolic status. BPA showed estrogenic effects affecting folliculogenesis (follicle activation, growth and steroidogenesis). We will thus study acute and chronic effects of BPS on metabolism and ovarian physiology, at several stages of development in both human and ovine model. We chose the ovine model as it is physiologically closer to the human species in terms of metabolism and reproduction, compared to rodent models. The kinetics of folliculogenesis, embryo development and fetal development are comparable between the ovine and human species. Moreover, during ovine and human fetal development, endocrine disruptors have been shown to impact the ovary, pancreas and brain (hypothalamus) in similar temporal windows of sensitivity. So far, BPS effects are mostly described in zebrafish or rodent models, and the metabolic components have not yet been investigated. We therefore plan to study the BPS effects on both the ovarian function and metabolism using human ovaries and ovine experimental models. Several physiological stages will be investigated. The ovary (and especially the fetal ovary) is a sensitive tissue affected even by low dose of BPA and thus a relevant tissue to investigate BPS effects. In human, ovarian studies will be developed in relation with metabolic clinical data from women (BMI, glycemia) and will concern 2 stages, fetal ovaries and granulosa cells in adults. The effects of BPS on meiosis initiation in human germ cells and follicle formation will be studied after xenografting human fetal ovaries in immunodeficient mice. We will also collect human granulosa cells and follicular fluid from women undergoing in vitro fertilization (IVF) procedure, and study both the level and the effects of BPS in these compartments. Using the ovine model, we will compare and complete the physiological stages studied in human. The ovine model enables to study 2 groups of ewes with metabolic differences (induced by high or low energy diets). Fetal metabolism, placental functions, ovarian and hypothalamic physiology will be studied after acute or chronic fetal exposure to bisphenol in sheep (maternal perfusion). Precise steps of folliculogenesis will be studied after BPS exposure, enabling to study primordial follicle activation, pre-antral to antral follicle growth, oocyte quality and granulosa steroidogenesis. The originality of MAMBO proposal is therefore to investigate the effects of BPS at various sensitive stages: follicle and oocyte development in adults, early embryo development, and the development of fetus and young females following in utero exposure.