Association between metal mixture exposure and the risk of POI: a case control study

BACKGROUND: The adverse impacts of homeostasis disturbance of plasma trace elements on female reproduction, including premature ovarian insufficiency (POI), have received increasing attention recently, yet limited evidence has been reported so far. POI significantly affects women's quality of life and poses risks such as infertility and cardiovascular disease, necessitating the exploration of alternative risk factors. METHODS: The metals studied included Iron (Fe), Zinc (Zn), Selenium (Se), Cobalt (Co), Magnesium (Mg), Strontium (Sr), Lithium (Li), Copper (Cu), Aluminum (Al), Chromium (Cr), Manganese (Mn), Arsenium (As), Titanium (Ti), Vanadium (V), and Iodine (I) in POI patients (n = 30) and controls (n = 31). Using a case-control design, we employed logistic regression and Bayesian Kernel Machine Regression (BKMR) analyses to evaluate the relationship between individual and combined plasma metal exposures and the risk of developing POI. RESULTS: Mn levels were higher in the POI group (median [IQR]: 2.20 [1.58-2.81] µg/L) compared to controls (1.44 [1.04-2.57] µg/L; p = 0.050). Similarly, V levels were significantly elevated in the POI group (mean ± SD: 1.19 ± 0.32 µg/L) versus controls (1.00 ± 0.38 µg/L; p = 0.049). Logistic regression indicated that higher Co levels were associated with a 98% reduced risk of POI (OR: 0.02; 95% CI: 0.00-0.72; p = 0.032), while higher Cu and V levels were associated with increased POI risk (Cu: OR: 1.01; 95% CI: 1.00-1.01; p = 0.032; V: OR: 8.65; 95% CI: 1.09-68.98; p = 0.042). Meanwhile, the RCS analysis revealed that higher plasma Mn levels were associated with an increased risk of POI (P non-linear = 0.041). Using BKMR, we evaluated the joint and individual effects of four metals-Mn, Co, Cu, and V-on POI risk and observed a joint risk effect on POI when all four metals were at or above their 55th percentiles. In particular, Mn had a significant effect on POI risk, with its effect size increasing as the concentrations of the other three metals rose from their 25th to 75th percentiles, and remained significant when the other metals were fixed at their 75th percentiles. Notably, Co showed inverse associations with Mn-Cu-V exposure. Moreover, no significant interactions were observed between Mn and Co, Cu, or V in their association with POI risk. CONCLUSIONS: Key findings revealed positive associations between plasma metal levels with POI risk in both single-metal and mixture analyses, highlighting manganese as a potential correlative biomarker for POI.