IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: Phthalates disrupt female reproductive health: a call for enhanced investigation into mixtures.

In brief: Exposure to phthalates, known endocrine-disrupting chemicals (EDCs), is ubiquitous, but the effects on women's reproductive health are largely unknown. This review summarizes the literature investigating associations between phthalate exposures and clinical reproductive outcomes and reproductive disease states in women, and it emphasizes the need to investigate the effects of phthalate mixtures on women's reproductive health. Abstract: Daily exposure to a mixture of phthalates is unavoidable in humans and poses a risk to reproductive health because they are known EDCs. Specific to female reproductive health, the literature has linked phthalate exposure to impairments in ovarian function, uterine function, pregnancy outcomes and endocrine signaling in the hypothalamic-pituitary-ovarian axis. However, limitations of these studies are that they primarily focus on single-phthalate exposures in animal models. Thus, the effects of real-life exposures to mixtures of phthalates and the clinical and translational impacts on reproductive function in women are largely unknown. This review summarizes the recent literature specifically investigating associations between phthalate mixture exposures and clinical reproductive outcomes and reproductive disease states in women. Because these studies are scarce, they are supplemented with the literature utilizing single-phthalate analyses in women and mechanistic basic science studies using phthalate mixture exposures. Main findings from the literature suggest that elevated phthalate exposure is associated with altered menstrual cyclicity, altered pubertal timing, disrupted ovarian folliculogenesis and steroidogenesis, ovarian disorders including primary ovarian insufficiency and polycystic ovary syndrome, uterine disorders including endometriosis and leiomyomas, poor in vitro fertilization outcomes and poor pregnancy outcomes. There is an urgent need to better incorporate phthalate mixtures in epidemiology (mixture analyses) and basic science (direct exposures) study designs. Furthermore, as exposure to multiple phthalates is ubiquitous, elucidating the mechanism of phthalate mixture toxicities is paramount for improving women's reproductive health.