The association between prenatal bisphenol F exposure and infant neurodevelopment: The mediating role of placental estradiol

Abstract

Background: There are limited population studies on the neurodevelopmental effects of bisphenol F (BPF), a substitute for bisphenol A. Furthermore, the role of placental estradiol as a potential mediator linking these two factors remains unclear.

Objective: To examine the association between maternal prenatal BPF exposure and infant neurodevelopment in a prospective cohort study and to explore the mediating effects of placental estradiol between BPF exposure and neurodevelopment in a nested case-control study.

Methods: The prospective cohort study included 1077 mother-neonate pairs from the Wuhu city cohort study in China. Maternal BPF was determined using the liquid/liquid extraction and Ultra-performance liquid chromatography tandem mass spectrometry method. Children's neurodevelopment was assessed at ages 3, 6, and 12 months using Ages and Stages Questionnaires. The nested case-control study included 150 neurodevelopmental delay cases and 150 healthy controls. Placental estradiol levels were measured using enzyme-linked immunosorbent assay kits. Generalized estimating equation models and robust Poisson regression models were used to examine the associations between BPF exposure and children's neurodevelopment. In the nested case-control study, causal mediation analysis was conducted to assess the role of placental estradiol as a mediator in multivariate models.

Results: In the prospective cohort study, the pregnancy-average BPF concentration was positively associated with developmental delays in gross-motor, fine-motor, and problem-solving ( OR_{total ASQ}: 1.14(1.05, 1.25), OR_gross-motor: 1.22(1.10, 1.36), OR_fine-motor: 1.19(1.07, 1.31), OR_{problem-solving}: 1.11(1.01, 1.23)). After sex-stratified analyses, pregnancy-average BPF concentration was associated with an increased risk of neurodevelopmental delays in the gross-motor (OR_gross-motor:1.30(1.12, 1.51)) and fine-motor (OR_fine-motor: 1.22(1.06, 1.40)) domains in boys. In the nested case-control study, placental estradiol mediated 16.6% (95%CI: 4.4%, 35.0%) of the effects of prenatal BPF exposure on developmental delay.

Conclusions: Our study supports an inverse relationship between prenatal BPF exposure and child neurodevelopment in infancy, particularly in boys. Decreased placental estradiol may be an underlying biological pathway linking prenatal BPF exposure to neurodevelopmental delay in offspring.

Keywords: Bisphenol F; Child neurodevelopment; Estradiol; Placenta.