Use of high-resolution metabolomics to assess the biological perturbations associated with maternal exposure to Bisphenol A and Bisphenol F among pregnant African American women

Abstract

Background: Human and animal exposure to bisphenol A (BPA) has been associated with adverse developmental and reproductive effects. The molecular mechanisms by which BPA exposure exerts its effects are not well-understood, even less known about its analogues bisphenol F (BPF). To address these knowledge gaps, we conducted an untargeted metabolome-wide association study (MWAS) to identify metabolic perturbations associated with BPA/BPF exposures in a pregnant African American cohort.

Methods: From a subset of study participants enrolled in the Atlanta African American Maternal-Child cohort, we collected both urine samples, for targeted exposure assessment of BPA (N = 230) and BPF (N = 48), and serum samples, for high-resolution metabolomics (HRM) profiling (N = 230), during early pregnancy (8-14 weeks' gestation). Using an established untargeted HRM workflow consisting of MWAS modeling, pathway enrichment analysis, and chemical annotation and confirmation, we investigated the potential metabolic pathways and features associated with BPA/BPF exposures.

Results: The geometric mean creatinine-adjusted concentrations of urinary BPA and BPF were 0.85 ± 2.58 and 0.70 ± 4.71 µg/g creatinine, respectively. After false positive discovery rate correction at 20 % level, 264 and 733 unique metabolic features were significantly associated with urinary BPA and BPF concentrations, representing 10 and 12 metabolic pathways, respectively. Three metabolic pathways, including steroid hormones biosynthesis, lysine and lipoate metabolism, were significantly associated with both BPA and BPF exposure. Using chemical standards, we have confirmed the chemical identity of 16 metabolites significantly associated with BPA or BPF exposure.

Conclusions: Our findings support that exposure to BPA and BPF in pregnant women is associated with the perturbation of aromatic amino acid metabolism, xenobiotics metabolism, steroid biosynthesis, and other amino acid metabolism closely linked to stress responses, inflammation, neural development, reproduction, and weight regulation.

Keywords: Bisphenol A; Bisphenol F; High-resolution metabolomics; Metabolic perturbations; Urinary bisphenol metabolites.

Fig. 1.

Significant metabolic features associated with bisphenol A (BPA) and bisphenol F (BPF). Red dots represent the features that were positively associated with BPA/BPF and blue dots represent the metabolic features that were negatively associated with BPA/BPF. Dashed line is the threshold −log₁₀ (FDR_B-H < 0.2). Note: Some metabolites identified in later chemical annotation and confirmation are labelled in the plots.

Fig. 2.

Significant metabolic pathways associated with bisphenol A (BPA) and/or bisphenol F (BPF).

Fig. 3.

Potential molecular mechanisms underlying the effects of bisphenol analogues toxicity on pregnant women. Molecules in red denoted the metabolites confirmed and positively associated with BPA/BPF. Molecules in blue denoted the metabolites confirmed and negatively associated with BPA/BPF. Acronym: ROS, reactive oxygen species; NMDA: N-methyl-D-aspartic acid; HPA axis: hypothalamic-pituitaryadrenal axis.