Competitive Biotransformation Among Phenolic Xenobiotic Mixtures: Underestimated Risks for Toxicity Assessment

Humans are inevitably exposed to a complex mixture of organic contaminants (i.e., xenobiotics) through diet, environment, and behavior. Biotransformation makes key contributions to the elimination of xenobiotics and greatly mediates the toxicity. However, most biotransformation studies were conducted using individual chemical, and whether coexposure of multiple environmental chemicals will affect each other's fate in the human body is still in its infancy. In this study, bisphenol A (BPA) was selected as a model compound. Its biotransformation was investigated under single exposure/coexposure to other phenolic xenobiotics (triclosan, tetrabromobisphenol A, and bisphenol S) in liver microsome and cell models. The result shows that binary exposures exhibit significant inhibitory effects on the BPA metabolism, especially the sulfate conjugation. In combination of analysis on inhibition models and enzyme activity, the inhibition effect was suggested to be primarily driven by competition for metabolizing enzymes. A mixture with 22 phenolic chemicals was further examined to disrupt BPA at various human-relevant levels. Again, the result demonstrates significant inhibition on the BPA metabolism, indicating the possible natural existence of our finding. Overall, our results show that biotransformation of phenolic xenobiotics can be significantly altered by coexposure, which provides referential evidence on underestimated risks of simultaneous exposure to environmental toxicants.