Critical review of the toxicity mechanisms of bisphenol F in zebrafish (Danio rerio): Knowledge gaps and future directions.

Replacement chemicals for bisphenol A, such as bisphenol F (BPF), are detected in aquatic environments worldwide and can potentially exert negative effects on aquatic organisms. We synthesized peer-reviewed literature reporting molecular and physiological responses in zebrafish following exposure to BPF, as BPF is closely related to BPA structure and is a dominant replacement chemical in the marketplace. Global concentrations of BPF in aquatic environments were compiled and compared to physiological and behavioral impacts reported in zebrafish (e.g., developmental abnormalities, oxidative stress, immunotoxicity, endocrine disruption, and neurotoxicity). Using computational approaches, we elucidate BPF-mediated molecular networks and reveal novel biomarkers associated with BPF exposure. Functional classes of proteins including inflammatory cytokines, ATPases, peroxidases, and aromatic l-amino decarboxylases represent novel, underexplored targets of toxicity. Most revealing of this critical review is that few studies report biological responses to BPF at levels present in aquatic environments. Recommendations for future investigations based on knowledge gaps include: (1) Mechanistic studies in the central nervous system of zebrafish to address neurotoxicity; (2) Behavioral assays in zebrafish that assess the effects of BPF on anxiolytic, social, and fear-related behaviors; (3) Studies that broaden understanding of potential endocrine disrupting effects of BPF, for example insulin signaling is predicted to be sensitive to BPF exposure; (4) Studies into metabolic disruption with a focus on glutathione and aromatic amino acids, based upon pathway analysis data; (5) Studies utilizing mixture exposures with other BPA analogs to reflect environmental conditions more accurately.