Leveraging identification of endocrine disruptors using new approach methodologies based on human adult ovarian follicle cells

Reproduction is regulated by the endocrine system and its disturbances by endocrine disruptive chemicals (EDCs) may lead to infertility. As humans are constantly exposed to EDCs through the use of common household items and personal care products, it is important to test chemicals for their potential activity as endocrine disruptors affecting reproductive function. Project MERLON aims to study the effects of EDCs on sexual development and function in order to deliver new approach methodologies (NAMs) for EDC identification. While MERLON targets the vulnerable stages of development from fetal to puberty, MERLON2, with additional partner TalTech, will add one more sensitive window of susceptibility in female reproduction to the project: the adult preovulatory ovarian follicle, where the oocyte maturation takes place. In collaboration with TalTech, it was recently demonstrated that follicular somatic cells (FSCs) lose sensitivity to follicle stimulating hormone (FSH) in the presence of a mixture of 13 EDCs. FSH is crucial for both, the oocyte maturation and for the synthesis of steroid hormones by the FSCs. We have also demonstrated the intricate heterogeneity of somatic cells in the ovarian follicle. The roles that FSC subpopulations play in the adverse effects of EDCs is unknown and unaddressed by the initial MERLON project. MERLON2 will complement the aims of the consortium by developing NAMs based on single cell transcriptomics, automated image analysis and machine learning to understand the effect of EDCs on FSC subpopulations and their sensitivity to FSH. This will increase the research output for MERLON in the number of proposed NAMs and quantitative adverse outcome pathways. As a result of MERLON2 the range of stakeholders will enlarge, increasing the public awareness related to the harmful health effects of EDCs, and proposing new approaches to resolve the complicates issue of testing substances in everyday products for their adverse effects on human fertility.