Mechanisms of Phthalate-Induced Accelerated Ovarian Aging in Experimental Models

Accelerated ovarian aging is associated with early infertility as well as other adverse health outcomes. Little is known about the factors that accelerate ovarian aging, but several studies indicate that exposure to phthalates accelerates ovarian aging. This is a significant human health concern because humans are ubiquitously and unavoidably exposed to phthalates. Thus, it is imperative to study the mechanisms of phthalate-induced accelerated ovarian aging so that strategies can be developed to prevent phthalate-induced ovarian aging. This review focuses on the mechanisms by which phthalates cause ovarian aging in non-human experimental models and highlights gaps in the literature. Phthalate exposure may accelerate ovarian aging and in turn, accelerate female reproductive aging through several mechanisms. Specifically, phthalates can alter steroidogenesis and folliculogenesis, ultimately dysregulating estrous cyclicity and decreasing fertility. Phthalate-induced disruptions in the brain and gut contribute to these changes. Additionally, phthalate exposures increase ovarian inflammation and oxidative stress, which contribute to accelerated ovarian aging. Phthalate exposure also increases ovarian autophagy, mitochondrial dysfunction, and apoptosis, which ultimately increase follicular atresia and accelerate depletion of the follicle reserve. Phthalates accelerate ovarian aging through numerous interlinked mechanisms that may be used as targets for prevention, inhibition, or reversal of phthalate-induced ovarian aging in patients experiencing infertility. Further studies should investigate the effects of environmentally relevant phthalate exposures on these mechanisms and explore therapies that target these mechanisms.