Endocrine-disrupting chemicals and ovarian somatic cells: knowledge gaps in non-follicular cell toxicology

Abstract Objective Infertility affects approximately 186 million individuals worldwide, with growing evidence implicating environmental factors, particularly endocrine-disrupting chemicals (EDCs). Ovaries, complex endocrine organs, are central to female fertility. We hypothesise that non-follicular cells have been especially overlooked, as the effects of EDCs on ovarian function remain underexplored. This study reviews the impact of 4 major EDC classes (bisphenols, phthalates, parabens, and per- and polyfluoroalkyl substances [PFAS]) across ovarian cell types to identify knowledge gaps and guide future research. Design Scoping review. Methods Peer-reviewed original research articles were searched in PubMed using predefined terms. Two reviewers screened studies and extracted data on EDC effects by cell type and molecular endpoints. Results Altogether 35 studies fulfilled the search criteria. Only 5 studies (5/35; 14.3%) investigated non-follicular cells. Endocrine-disrupting chemical exposure was consistently associated with impaired steroidogenesis, mitochondrial dysfunction, oxidative stress, and altered transcriptional regulation. Notably, bisphenols, PFAS, and phthalates downregulated steroidogenic enzymes (eg, STAR, CYP11A1, CYP19A1) and reduced oestradiol (E2) and progesterone (P4) synthesis. Mitochondrial and oxidative disruptions were often linked to hormone and viability changes. Transcriptomic analyses revealed activation of peroxisome proliferator-activated receptor gamma, reprogramming of lipid metabolism, and intra-/intercellular signalling pathways between somatic cells and oocytes. Conclusions Critical knowledge gaps persist regarding the effects of EDCs on non-follicular cells in mammalian ovaries. EDCs commonly impair steroidogenic cell function and oocyte competence, at non-cytotoxic and environmentally relevant concentrations. This review highlights the need to expand ovarian research beyond follicles and develop integrative models to improve EDC risk assessment for female fertility.