Preconception exposure to bisphenol A and its alternatives: Effects on female fecundity mediated by oxidative stress and ovarian reserve.

Background: Various 'Bisphenol A (BPA)-free' alternatives have emerged in numerous personal products in recent years. However, it remains unclear whether BPA analogs affect female fecundity and possible biological mechanisms.

Objectives: We aimed to evaluate the relationships of bisphenol analogs with female fecundability and infertility and whether oxidative stress, inflammation, and ovarian reserve may play a mediation role in such associations.

Methods: This prospective preconception cohort study included 957 couples who attempted pregnancy. BPA and six alternatives were measured in women's urine samples. Bisphenol analogs-outcome associations were estimated using discrete-time Cox hazards and logistic regression models. A quantile g-computation (QGC) methodology was further applied to assess the joint effects of co-exposure to bisphenol analogs on fecundity. We also quantified three biomarkers, including malondialdehyde (MDA), C-reactive protein and Anti-Müllerian hormone (AMH), to explore possible biological pathways.

Results: Using an integrated analytical approach consisting of both single-pollutant and mixture models, we found that BPA and bisphenol AP (BPAP) were significantly associated with decreased fecundability (adjusted fecundability ratio (aFR) = 0.87, 95%CI: 0.81, 0.94 for BPA; aFR = 0.64, 95%CI: 0.48, 0.84 for BPAP) and increased risk of infertility (adjusted odd ratio (aOR) = 1.23, 95%CI: 1.06, 1.44 for BPA; aOR = 2.27, 95%CI: 1.29, 3.99 for BPAP) after controlling for other bisphenol analogs. The link between BPA and prolonged time to pregnancy was more prominent in overweight or obese women and those who had regular menstrual cycles. Bisphenol AF was associated with impaired fecundity in women aged 35 years or older. The mixed effects of bisphenol analogs on fecundity were statistically non-significant. Mediation analysis revealed a significant indirect effect of urinary MDA and serum AMH in bisphenol analogs-induced impaired fecundity, with all average causal mediation effects (ACME) showing statistical significance (P_ACME < 0.05).

Conclusions: Our prospective preconception cohort study suggests that BPA and BPAP may be associated with impaired female fecundity. Increased oxidative stress and decreased ovarian reserve may be the underlying pathways.