Mercury (Hg) is known to be a hazardous toxin with a significant negative impact on female reproduction through mechanisms that remain unclear. The carotenoid fucoxanthin (FX) is an antioxidant with several positive effects on human health. This study aimed to examine the potential protective role of FX in reducing the Hg-induced bioenergetic disturbances in a human ovarian granulosa cell line model. (methods briefly) Hg was found to reduce the viability of granulosa cells in a concentration-dependent manner, with an estimated 72-hour EC50 of 10 µM. In contrast, FX (10 and 20 µM) improved cell viability. Hg (1 and 10 µM) significantly reduced cellular ATP levels, mitochondrial membrane potential, oxygen consumption rates, and lactate production. Additionally, Hg impaired the activities and kinetics of mitochondrial complexes I and III and reduced the expression of mitochondrial genes ND1, ND5, cytochrome B, cytochrome C oxidase, and ATP synthase subunits 6 and 8. According to tests on mitochondrial membranes, Hg increased membrane fluidity by reducing saturated fatty acid levels and increasing those of unsaturated fatty acids. Hg also promoted mitochondrial swelling and enhanced the inner mitochondrial membrane permeability to hydrogen and potassium ions. FX (10 µM) was shown to mitigate the negative effects of Hg on the viability of treated granulosa cells, bioenergetics parameters, and mitochondrial membrane integrity in a concentration-dependent manner. Based on these findings, bioenergetic disruption may be a key underlying cause of Hg-induced ovarian dysfunction. Furthermore, FX may have a potential therapeutic role in treating ovarian disorders caused by Hg-induced disruption of granulosa cell bioenergetics.

Cisplatin (cis-diamminedichloroplatinum II) (CDDP) is an FDA approved anticancer therapy that is commonly used in women’s cancer treatment protocols, such as breast, cervical, endometrial, and gestational trophoblastic cancers. Premature ovarian insufficiency/failure is a well-known long-term risk of chemotherapy including CDDP in women. Granulosa cells (GCs) are an essen-tial ovarian cell type that promotes oocyte growth and is crucial for ovarian reproductive function. Many types of chemotherapeutic agents, such as CDDP, could induce GCs apoptosis, which could result in ovarian failure. Hyperoside (HYP) is a flavonoid known for its beneficial phar-macological properties, including anti-inflammatory and antiapoptotic effects. Hence the current work aimed to evaluate the potential cytoprotective impact of HYP on CDDP-induced cytotoxicity in a human ovarian GCs cell line model. Forty-eight-hour exposure to 5-10µM CPPD resulted in reduction of GCs viability in a dose-dependent manner. HYP (40µM) was found to ameliorate this CPPD-induced effect on GCs viability. CPPD in a concentration-dependent way, dramatically reduced cellular ATP, mitochondrial activities, cellular progesterone, and estradiol secretion. It also increased oxidative stress markers, Akt kinase activity, cytochrome c levels, caspase -3.-8.-9, and Bax/Bcl2 ratio. These cytotoxic effects of CDDP on the treated GCs, were mitigated to varying degrees by HYP (40 µM). In conclusion, CDDP-induced cytotoxic effects on GCs seem to be the possible underlying cellular and molecular mechanisms of CDDP-induced ovarian insufficien-cy/failure. The study also demonstrated the therapeutic potential of HYP in mitigating CDDP-induced ovarian injury. Further studies are warranted to investigate the potential benefit of HYP as an adjuvant to CDDP treatment protocols to avoid adverse ovarian effects.