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Our previous study demonstrated that ovarian wild-type P53-induced phosphatase 1 (WIP1) expression decreased with age. We hypothesized that WIP1 activity was related to ovarian aging. The role of WIP1 in regulating ovarian aging and its mechanisms remain to be elucidated. Adult female mice with or without WIP1 inhibitor (GSK2830371) treatment were divided into three groups (Veh, GSK-7.5, GSK-15) to evaluate the effect of WIP1 on ovarian endocrine and reproductive function and the ovarian reserve. In vitro follicle culture and primary granulosa cell culture were applied to explore the mechanisms of WIP1 in regulating follicular development. This study revealed that WIP1 expression in atretic follicle granulosa cells is significantly lower than that in healthy follicles. Inhibiting WIP1 phosphatase activity in mice induced irregular estrous cycles, caused fertility declines, and decreased the ovarian reserve through triggering excessive follicular atresia and primordial follicle activation. Primordial follicle depletion was accelerated via PI3K-AKT-rpS6 signaling pathway activation. In vitro follicle culture experiments revealed that inhibiting WIP1 activity impaired follicular development and oocyte quality. In vitro granulosa cell experiments further indicated that downregulating WIP1 expression promoted granulosa cell death via WIP1-p53-BAX signaling pathway-mediated apoptosis. These findings suggest that appropriate WIP1 expression is essential for healthy follicular development, and decreased WIP1 expression accelerates ovarian aging by promoting follicular atresia and primordial follicle activation. [ABSTRACT FROM AUTHOR]

Parabens, a type of endocrine-disrupting chemicals, are widely used as antibacterial preservatives in food and cosmetics in daily life. Paraben exposure has gained particular attention in the past decades, owing to its harmful effects on reproductive function. Whether low-dose paraben exposure may cause ovarian damage has been ignored recently. Here, we investigated the effects of chronic low-dose propylparaben (PrPB) exposure on ovarian function. Female C57BL/6J mice were exposed to PrPB at a humanly relevant dose for 8 months. Our results showed that chronic exposure to PrPB at a humanly relevant dose significantly altered the estrus cycle, hormone levels, and ovarian reserve, accelerating ovarian aging in adult mice. These effects are accompanied by oxidative stress enrichment, leading to steroidogenesis dysfunction and acceleration of primordial follicle recruitment. Notably, melatonin supplementation has been shown to protect against PrPB-induced steroidogenesis dysfunction in granulosa cells. Here, we report that daily chronic PrPB exposure may contribute to ovarian aging by altering oxidative stress-mediated JNK and PI3K-AKT signaling regulation, and that melatonin may serve as a pharmaceutical candidate for PrPB-associated ovarian dysfunction. [Display omitted] • Chronic exposure to PrPB at a humanly relevant dose accelerated ovarian aging. • Low-dose PrPB exposure decreased steroidogenesis and ovarian reserve of adult mice. • The oxidative stress-mediated JNK and PI3K-AKT pathways promoted ovarian aging. • Melatonin was a potential intervention to improve PrPB-induced ovarian function. [ABSTRACT FROM AUTHOR]

Embryonic exposure to environmental chemicals may result in specific chronic diseases in adulthood. Parabens, a type of environmental endocrine disruptors widely used in pharmaceuticals and cosmetics, have been shown to cause a decline in women's reproductive function. However, whether exposure to parabens during pregnancy also negatively affect the ovarian function of the female offspring in adulthood remains unclear. This study aims to investigate the effects of prenatal propylparaben (PrP) exposure on the ovarian function of adult mice aged 46 weeks, which is equivalent to the age of 40 years in women. Pregnant ICR mice were intraperitoneally injected with human-relevant doses of PrP (i.e., 0, 7.5, 90, and 450 mg/kg/day) during the fetal sex determination period—from embryonic day E7.5 to E13.5. Our results revealed that ovarian aging was accelerated in PrP-exposed mice at 46 weeks, with altered regularity of the estrous cycle, decreased serum estrogen (E2) and progesterone (P4) levels, reduced size of the primordial follicle pool, and increased number of atretic follicles. It was found that prenatal exposure to human-relevant doses of PrP exacerbated ovarian oxidative stress, inflammation, and fibrosis, which promoted follicular atresia by activating the mitochondrial apoptosis pathway. To compensate, the depletion of primordial follicles was also accelerated by activating the PI3K/AKT/mTOR signaling pathway in PrP-exposed mice. Moreover, PrP induced hypermethylation of CpG sites in the promoter region of Cyp11a1 (a 17.16–64.28% increase) partly led to the disrupted steroidogenesis, and the altered methylation levels of imprinted genes H19 and Peg3 may also contribute to the phenotypes observed. These remarkable findings highlight the embryonic origin of ovarian aging and suggest that a reduced use of PrP during pregnancy should be advocated. [Display omitted] •Prenatal PrP exposure decreased steroidogenesis and the ovarian reserve of adult mice. •Oxidative stress-induced inflammation and fibrosis promoted follicle atresia. •The hypermethylation of Cyp11a1 decreased its expression level in PrP-exposed mice. •Changed methylation level of H19 and Peg3 contributed to PrP-induced ovarian aging. [ABSTRACT FROM AUTHOR]