Mechanisms by which "Everywhere" and "Forever" Environmental Chemicals Impact Ovarian Function and Female Fertility

Phthalates and per- and polyfluoroalkyl substances (PFAS) are widespread environmental contaminants that are consistently detected in follicular fluid, serum, and reproductive tissues. This review synthesizes current experimental and epidemiological evidence on the molecular and cellular mechanisms by which phthalates and PFAS impair ovarian function and female fertility. Human studies primarily identify exposure-outcome associations, whereas animal, ex vivo, and in vitro models provide most of the causal and mechanistic evidence. Phthalates and PFAS disrupt interconnected pathways involved in folliculogenesis, steroidogenesis, mitochondrial homeostasis, inflammatory signaling, and cell survival. These chemicals dysregulate pathways governing primordial follicle activation and ovarian reserve maintenance, and impair estradiol and progesterone synthesis. A central mechanistic theme by which phthalates and PFAS impair ovarian function and fertility involves mitochondrial dysfunction, which promotes oxidative stress and contributes to apoptosis. However, evidence for phthalate- and PFAS-induced ovarian necroptosis, pyroptosis, immune-cell infiltration, and inflammation-driven fibrosis remains limited and is often based on a small number of studies conducted at doses above typical human exposures. Although mixture studies are relatively scarce, available data indicate that mixtures can perturb mitochondrial activity, steroid secretion, follicle dynamics, inflammatory signaling, and Hippo-pathway endpoints. Overall, altered folliculogenesis and steroidogenesis, mitochondrial dysfunction, oxidative stress, and apoptosis emerge as the best-supported mechanisms linking phthalate and PFAS exposure to ovarian toxicity. This review also highlights the need for exposure-relevant studies, quantitative pathology, and stronger integration of experimental mechanisms with human biomonitoring data.