The associations of the concentrations of toxic metals (including metalloid) in blood and follicular fluid with the risk of diminished ovarian reserve

Abstract

Background: Diminished ovarian reserve (DOR), a triggering factor for female infertility, affects 10% ∼ 35% of women of reproductive age. It is still unclear whether exposure to toxic metals (including metalloid) is associated with DOR risk, especially with respect to their relationships with the clinical phenotypes of DOR. Methods: A case–control study including 439 patients was conducted, and Ba, Ni, As, Tl, Cd, Pb, Hg, Al and Cr levels in BL and FF were measured. Subsequent analyses were focused on Ba, Ni, As and Tl, which had the highest weights in the associations of the nine toxic metals (including metalloid) with DOR risk, by integrating weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR) models. Conditional logistic regression models and BKMR models were used to assess the individual and combined effects of Ba, Ni, As and Tl exposures on DOR risk. Multiple linear regression models were used to investigate the relationships between toxic metal (including metalloid) levels in BL and FF and the clinical characteristics of DOR. Results: The levels of Ba [second vs. lowest tertile: adjusted odds ratio (aOR) and 95 % confidence interval (CI) = 1.97 (1.13, 3.44); highest vs. lowest tertile: aOR (95 % CI) = 2.38 (1.32, 4.26)], Ni [highest vs. lowest tertile: aOR (95 % CI) = 2.59 (1.45, 4.65)] and As [highest vs. lowest tertile: aOR (95 % CI) = 1.96 (1.18, 3.25)] in BL, and Ba [highest vs. lowest tertile: aOR (95 % CI) = 4.60 (1.68, 12.61)] in FF were significantly associated with a higher risk of DOR, respectively. The significantly positive combined effect of the four toxic metals (including metalloid) on DOR risk was exhibited when their BL levels exceeded the 25th percentile compared with their median levels. Among these, As (0.9822) and Ba (0.9704) were the primary contributors to this relationship. Similarly, this finding was confirmed by the statistical results from FF samples, with a linear positive correlation between combined exposure and DOR risk, where Ba (0.9440) was the primary contributor. Finally, elevated levels of Ba, Ni, and As in BL and Ba in FF were significantly linked to the higher follicle–stimulating hormone (FSH) levels. The levels of Ba in BL and FF, as well as As in BL, were significantly associated with the lower luteinizing hormone (LH)/FSH ratio values. Conclusion: Overall, the results of this study indicate that elevated levels of Ba, Ni, As and Tl are associated with a higher risk of DOR, whether individually or in combination, and that Ba levels in BL and FF are stable contributors. In addition, exposure to Ba, Ni, As and Tl is linked to various clinical phenotype parameters of DOR. Further research is needed to confirm these associations and to identify potential mechanisms involved.

Keywords

• Diminished ovarian reserve
• Toxic metals (including metalloid)
• Single element model
• BKMR model
• WQS regression