Environmental exposure to endocrine-disrupting chemicals (EDCs) is one of the causes of premature ovarian failure (POF). Hexavalent chromium (CrVI) is a heavy metal EDC widely used in more than 50 industries, including chrome plating, welding, wood processing, and tanneries. The US is one of the world's leading producers of chromium compounds. Recent data from USEPA indicate increased levels of Cr in drinking water from several American cities, which potentially predispose residents to various health problems. Women working in dichromate manufacturing industries and tanneries and living around Cr-contaminated areas experience several gynecological illnesses such as premature abortion, postnatal hemorrhage, birth complications, sub-fertility, and infertility. CrVI can pass through the placental barrier and cause adverse effects on the developing embryos and impair the reproductive functions in F1 offspring. Although epidemiological studies indicate that CrVI causes adverse reproductive health effects including infertility in women, the association between CrVI exposure and POF in unknown. The current study was performed to identify the molecular mechanism behind CrVI-induced POF. Results showed that prenatal exposure to CrVI in rats increased the risk of POF by increasing germ cell/oocyte apoptosis, accelerated germ cell nest (GCN) breakdown, advanced primordial follicle assembly and primary follicle transition in F1 offspring. CrVI increased germ cell apoptosis by upregulating the expression of p53, PUMA, p27, BAX, caspase-3 proteins and downregulating the expression of key cell survival proteins p-AKT, p-ERK, BCL2, BCL-XL, and XIAP. Though CrVI increased the expression of antioxidant enzyme SOD2, its antioxidant activity was diminished by Cr by increasing the translocation of p53 to mitochondria to co-localize with SOD-2. CrVI increased germ cell apoptosis by mediating p53-SIRT1-miR34a signaling network exhibited by iii increased expression of acetyl-p53 and miR34a, and decreased expression of SIRT1. Inhibition of SIRT1 attenuated CrVI-induced germ cell death by upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins through p53 acetylation. While ex vivo treatment of ovaries with CrVI and miR34a mimetics increased germ cell apoptosis, miR34a inhibitor treatment mitigated the effect of CrVI on germ cell apoptosis. CrVI advanced GCN breakdown and increased follicle atresia in F1 female progeny by targeting X-prolyl aminopeptidase (Xpnpep) 2, a POF marker in humans. CrVI increased Xpnpep2 expression during GCN breakdown, and decreased Xpnpep2 expression during postnatal follicle development. In all the developmental stages studied, Xpnpep2 inversely regulated the expression of Collagens 1, 3, and 4. As a result of the above events, CrVI induced early reproductive senescence or POF in CrVI exposed F1 offspring.
