Exposure to 6PPD-Q induces dysfunctions of ovarian granulosa cells: Its potential role in PCOS

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q), an environmental pollutant derived from the ozonolysis of the widely used tire rubber antioxidant 6PPD, has been found to accumulate in air, dust, and water, posing significant health risks. While its reproductive toxicity in male organisms has been established, its effects on female reproductive health remain unclear. Polycystic ovary syndrome (PCOS), a common endocrine disorder in premenopausal women, is known to be influenced by environmental pollutants. In this study, we exposed BALB/c mice intraperitoneally to 6PPD-Q, and they exhibited PCOS-like changes after 40 days, including alterations in hormone levels, estrous cycle arrest, and polycystic ovarian morphology. Then we identified significantly elevated levels of 6PPD-Q in the follicular fluid of PCOS patients compared to those with tubal infertility, and these levels were associated with clinical parameters. In the human ovarian granulosa cell line (KGN) studies, we demonstrated that 6PPD-Q induced granulosa cell apoptosis by inhibiting the PI3K/AKT/FOXO1 pathway, leading to ovarian damage and fertility decline. To our knowledge, this is the first study to report 6PPD-Q levels in human follicular fluid and its detrimental effects on female reproductive health, underscoring the need for further research on environmental impacts on PCOS.