Associations of urinary bisphenol A and its emerging substitutes with subfecundity in preconception couples: a prospective nested case-control study

Global infertility rates have noticeably increased in recent decades. The effects of environmental exposures on human fertility have been well-noted. However, Evidence on couple-based preconception exposure to bisphenols (BPs), particularly emerging substitutes, and fecundity remains limited. This study aimed to investigate the exposure profiles of 14 classic and emerging BPs in the preconception period as well as their impacts on couple fecundity, to assess both the individual effects of specific compounds and the combined effects of mixtures in males and females, and to evaluate the health risks induced by BPs exposure after tolerable daily intake (TDI) value was tightened in 2023. This nested case-control study involved 1934 preconception individuals in two research sites of China, from October 2016 to May 2025. The case and control groups were comprised of 318 and 649 couples with time to pregnancy (TTP) > 12 and ≤ 12 menstrual cycles, respectively. BPs were quantified in preconception urine samples using ultra-performance liquid chromatography-tandem mass spectrometry, including novel substitutes that had not been measured and reported in human beings, such as 2,2’-diallyl bisphenol A (DBA) and 4-hydroxy-4’-isopropoxydiphenylsulfone (D8). Generalized linear, weighted quantile sum and Bayesian kernel machine regression models were employed to assess individual and mixture effects of BPs on subfecundity. The positive associations of BPs and subfecundity risks were observed in both females and males. Mixed BPs were positively correlated with subfecundity in females (OR = 2.84, 95% CI: 2.23–3.61), males (OR = 4.21, 95% CI: 3.24–5.47), and couples (OR = 6.73, 95% CI: 4.81–9.41), with DBA and bisphenol AF (BPAF) identified as major contributors. Health risk assessment indicated that although few participants had an estimated daily intake (EDI) exceeding the 2015 TDI (4000 ng/kg bw/day), most (81.8%-100%) surpassed the 2023 TDI (0.2 ng/kg bw/day). This study provides the first evidence linking novel bisphenols, BPAF and DBA, to increased subfecundity risk and highlights significant health risks in a population with an intention to conceive, underscoring the urgency to regulate a broader range of bisphenols to protect reproductive health.