Association between novel per- and poly-fluoroalkyl substances and premature ovarian insufficiency: a case-control study

Abstract

Study question: Do novel per- and poly-fluoroalkyl substances (Novel PFAS) have associations with premature ovarian insufficiency (POI)?

Summary answer: Hexafluoropropylene oxide dimer acid (HFPO-DA), perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), and perfluoropentanesulfonic acid (PFPeS) are associated with an increased risk of POI, and the effect is worse with exposure to mixtures.

What is known already: As public health concerns following Novel PFAS exposure are rising globally, there is a need to understand the exact association between Novel PFAS and various diseases. Epidemiologic studies suggest traditional PFAS exposures adversely affect women's reproductive health, but the association between exposure to Novel PFAS and POI remains unclear.

Study design size duration: A retrospective research study, including 371 women, with (case group, n = 151) and without POI (control group, n = 220), was conducted between June 2023 and May 2024.

Participants/materials setting methods: Thirteen types of Novel PFAS and basal concentrations of FSH, LH, estradiol (E2), and anti-Müllerian hormone (AMH) in plasma samples were measured in plasma samples collected during the early follicular phase (Days 2-5) of a natural menstrual cycle. In addition, characteristics of participants were collected. Both adjusted logistic regression and Bayesian kernel machine regression (BKMR) were used to evaluate associations between Novel PFAS (alone or as a mixture) and POI. Effect modification by age was also investigated.

Main results and the role of chance: The concentrations of HFPO-DA, PFBA, PFPeA, and PFPeS in the case group were significantly higher than in the reference group. The adjusted logistic regression models demonstrated positive associations between plasma concentrations of HFPO-DA, PFBA, PFPeA, and PFPeS with the risk of POI [OR_adj = 2.89 (95% CI: 1.84-4.53), 1.54 (95% CI: 1.17-2.02), 3.12 (95% CI: 2.20-4.43), and 2.07 (95% CI: 1.31-3.27), respectively, per 2.7-fold increase in Novel PFAS concentrations]. High concentrations of Novel PFAS showed a negative correlation with AMH and antral follicle count (AFC), but a positive correlation with FSH. After controlling for other covariates, HFPO-DA, PFBA, PFBS, PFPeA, and PFPeS were the major contributors based on the BKMR models.

Limitations reasons for caution: False positives cannot be ruled out. Therefore, experiments on PFBA, PFPeA, PFPeS, and HFPO-DA in vivo also need to be conducted in animal models.

Wider implications of the findings: Our study is the first to discover the impact of Novel PFAS on the incidence of POI, with an investigation of indicators such as AMH, FSH, and AFC. Considering increasingly severe environmental pollution, our research results provide a broader understanding of the impact of environmental endocrine disruptors on ovarian function, and suggest that women of reproductive age should reduce their exposure to Novel PFAS.

Study funding/competing interests: This work was supported by the National Key Research and Development Project of China (2022YFC2703002), National Natural Science Foundation of China (U24A20658, 82371726), Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212200), Shanghai Hospital Development Center Foundation (SHDC22022303, SHDC22022201), and Key project of Medical and Industrial intersection of Shanghai Jiao Tong University (YG2023ZD27), as well as Reproductive Medicine Research Project of the Chinese Red Cross Foundation (HSZH2024GFYZQ) and Open Fund Project of Shanghai Key Laboratory of Embryogenic Diseases (shelab2023ZD02). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no competing interests.

Trial registration number: N/A.

Keywords: mixture models; novel per- and poly-fluoroalkyl substances (Novel PFAS); premature ovarian insufficiency; reproductive health; sex hormones.

Figure 1.

Overall joint associations of the Novel PFAS mixture in infertile women diagnosed with POI. Overall joint associations of the Novel PFAS mixture (estimates and 95% CIs) in infertile women diagnosed with POI estimated by Bayesian kernel machine regression (BKMR) (n=371). All estimates were adjusted for age, BMI, education, infertility type, and living address. This figure plots the estimated difference in the probit of POI when exposures are at a particular percentile (x-axis) in comparison with when exposures are all at the 50th percentile. POI, premature ovarian insufficiency; PFAS, per- and poly-fluoroalkyl substances.

Figure 2.

Univariate exposure–response relationship of individual plasma Novel PFAS concentrations in infertile women diagnosed with POI. Univariate exposure–response relationship of individual plasma Novel PFAS concentrations (estimates and 95% CIs) in Chinese women diagnosed with POI estimated by Bayesian kernel machine regression (BKMR) for each Novel PFAS, with the other pollutants fixed at the median (n=371). All estimates were adjusted for age, BMI, education, infertility type, and living address. The boundaries of the gray areas represent the 95% CIs of the exposure–response relationship. For full chemical names, see Table 1. POI, premature ovarian insufficiency; PFAS, per- and poly-fluoroalkyl substance.