Elevated plasma molybdenum level increases the risk of premature ovarian insufficiency through vascular endothelial injury

STUDY QUESTION: Is elevated plasma molybdenum level associated with increased risk for idiopathic premature ovarian insufficiency (POI)? SUMMARY ANSWER: Elevated plasma molybdenum level is associated with an increased risk of idiopathic POI through vascular endothelial injury and inhibition of granulosa cell proliferation. WHAT IS KNOWN ALREADY: Excessive molybdenum exposure has been associated with ovarian oxidative stress in animals but its role in the development of POI remains unknown. STUDY DESIGN, SIZE, DURATION: Case-control study of 30 women with idiopathic POI and 31 controls enrolled from August 2018 to May 2019. In vitro experimentation. Animal studies using distilled water containing sodium molybdate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Logistic regression analysis of the association between plasma concentrations of molybdenum and calcium and POI odds ratio. Plasma samples were from 30 patients with idiopathic POI and 31 controls. Both groups were comparable in terms of age and body mass index. Proliferation assay, flow cytometry analyses for cell cycle, nitric oxide and calcium, gene expression, and protein analysis using human umbilical vein endothelial cells and KGN (human ovarian granulosa-like tumor cell line) cells. Sexual hormones, ovarian function, vascular injury, and platelet activation were evaluated in mice exposed to excessive molybdenum. MAIN RESULTS AND THE ROLE OF CHANCE: Case-control study showed that the elevation of plasma concentrations of molybdenum and calcium was positively associated with the POI odds ratio. In vitro study showed that molybdenum treatment increased the permeability of human umbilical vein endothelial cells through enhancing nitric oxide generation and cytosolic calcium influx. In vivo study showed that increased vascular permeability induced by molybdenum resulted in platelet activation and serotonin release within mouse ovaries. Serotonin decreased granulosa cell proliferation by inducing cellular quiescence. Molybdenum also directly inhibited granulosa cell proliferation by downregulating isocitrate dehydrogenase (IDH1). Inhibition of granulosa cell proliferation ultimately led to ovarian dysfunction in mice, including altered estrus cycles, serum sex hormone concentrations, ovarian morphology, and ovarian reserve. LIMITATIONS, REASONS FOR CAUTION: There are two limitations in the current study. First, it remains unclear whether the elevation of plasma molybdenum content is due to environmental exposure or altered metabolism. Second, rigorous and multicenter studies, with a larger sample size, should be carried out to confirm the elevation of plasma molybdenum and calcium concentrations in patients with idiopathic POI. WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight an association between elevated plasma concentrations of molybdenum and calcium and increased risk of idiopathic POI. This discovery offers crucial insights into the pathogenesis of idiopathic POI and the search for effective preventive measures. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (82271664), the interdisciplinary program of Shanghai Jiao Tong University (YG2022ZD028), the Research Projects of Shanghai Municipal Health Committee (202240343), and Shanghai Clinical Research Center for Cell Therapy (23J41900100). None of the authors has any conflict of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.