Continuous Dermal Exposure to Triclocarban Perturbs the Homeostasis of Liver-Gut Axis in Mice: Insights from Metabolic Interactions and Microbiome Shifts

Humans are constantly exposed to antimicrobial triclocarban (TCC) via direct skin contact with personal care and consumer products, but the safety of long-term dermal exposure to TCC remains largely unknown. Herein, we used a mouse model to evaluate the potential health risks from the continuous dermal application of TCC at human-relevant concentrations. After percutaneous absorption, TCC circulated in the bloodstream and largely entered the liver-gut axis for metabolic disposition. Nontargeted metabolomics approach revealed that TCC exposure perturbed mouse liver homeostasis, as evidenced by the increased oxidative stress and impaired methylation capacity, leading to oxidative damage and enhancement of upstream glycolysis and folate-dependent one-carbon metabolism. Meanwhile, TCC was transformed in the liver through hydroxylation, dechlorination, methylation, glucuronidation, sulfation, and glutathione conjugation. TCC-derived xenobiotics were subsequently excreted into the gut, and glucuronide and sulfate metabolites could be further deconjugated by the gut microbiota into their active free forms. In addition, microbial community analysis showed that the composition of gut microbiome was altered in response to TCC exposure, indicating the perturbation of gut homeostasis. Together, through tracking the xenobiotic-biological interactions in vivo, this study provides novel insights into the underlying impacts of dermally absorbed TCC on the liver and gut microenvironments.