The Impact of Metal Exposure, Vaginal Microbiota, and Their Interactions on Fertility: A Prospective Cohort Study.

To explore the effects of metal exposure, vaginal microbiota, and their interactions on time to pregnancy (TTP). A total of 200 couples were recruited in Nanjing. Ultimately, 150 women from whom prepregnancy blood samples and vaginal swabs were collected by trained clinicians were included. After one year of follow-up, the participants were categorized into a pregnant group (n=100) and a non-pregnant group (n=50). Vaginal microbiota were analyzed using 16S rRNA sequencing to examine the microbiota structure, while blood samples were analyzed for concentrations of 22 metal elements using inductively coupled plasma-Mass Spectrometry. The associations between metal exposure, vaginal microbiota, and TTP were analyzed using Cox regression, random forest, and Bayesian kernel machine regression (BKMR). A significant difference in β-diversity of prepregnancy vaginal microbiota was observed between the pregnant and non-pregnant groups (PERMANOVA test P<0.001). In the pregnant group, the relative abundance of Lactobacillus was significantly higher, while Gardnerella (P=0.005) and Atopobium (P=0.007) abundances were significantly lower. Random forest modeling confirmed these three genera as key predictors of fertility. Cr, Na, Co, Ni, and Cu were the main metals associated with fertility. Elevated Cr, Cu, and Ni concentrations were linked to reduced fertility in cubic spline analysis. BKMR analysis identified Cu (PIP: 1.0000) as the key factor influencing fertility. Notably, Cu and Cr exhibited the strongest interactions with key bacterial genera, particularly Atopobium, Gardnerella, and Lactobacillus. This study systematically reveal the interaction between metal exposure and vaginal microbiota in relation to female fertility, offering new insights into reproductive health risks.