Carbon tetrachloride exposure induces ovarian damage through oxidative stress and inflammatory mediated ovarian fibrosis.

Carbon tetrachloride (CCL4) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL4 is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL4 on ovarian function has not been reported. In this study, we found that the mice treated with CCL4 showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17β-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1β, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL4 group. In the CCL4 treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL4 could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL4 inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL4 exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis.