Associations of serum metal/metalloids with ovarian reserve and inflammation mediation: A repeated-measures longitudinal study

BACKGROUND: Little is known about associations of metal/metalloids (the widespread environmental pollutants) with ovarian reserve, and the underlying mechanisms. METHODS: We conducted a longitudinal study of 897 women (20-49 years) with 1958 repeated observations from two infertility centers in Hubei, China, and measured 22 serum metal/metalloids, C-reactive protein, cell-based inflammatory biomarkers, and anti-müllerian hormone (AMH) at baseline and follow-up surveys. We examined associations of metal/metalloid exposures with AMH levels and diminished ovarian reserve (DOR, defined as AMH < 1.1 ng/mL) risk using single- and multiple-metal/metalloid models, and explored the mediating role of inflammatory biomarkers. RESULTS: Of all observations, the median (P25, P75) of AMH levels was 2.81 (1.56, 4.90) ng/mL. Each 1-unit increment in log-transformed cobalt was cross-sectionally associated with 23.68% (13.57%, 32.60%) decreased AMH levels and 118% (33%, 255%) higher risk of DOR. Joint exposure to 22 metal/metalloids reduced AMH levels, with cobalt contributing the largest weight (0.3150) and posterior inclusion probability (0.9990). In longitudinal analyses, we observed decreased AMH levels in association with cobalt (13.61% [5.84%, 20.98%]), molybdenum (12.10% [2.60%, 20.76%]), and antimony (7.28% [0.26%, 13.79%]), and increased risks of DOR in association with nickel (1.23 [1.04, 1.46]), antimony (2.62 [1.62, 4.23]), and lead (1.32 [1.04, 1.66]). Additionally, white blood cell count, lymphocyte count, and percentage of monocyte mediated 7.15%-15.79% of the associations of cobalt with AMH levels and DOR risk. CONCLUSIONS: Our findings revealed the potential hazards of metal/metalloids on ovarian reserve, identified the key metal/metalloid specie (cobalt), and provided novel insights on inflammatory mechanisms for metal/metalloid-associated DOR.