In vivo toxicity evaluations of halophenolic disinfection byproducts in drinking water: A multi-omics analysis of toxic mechanisms

Halophenolic disinfection byproducts (DBPs) in drinking water have attracted considerable concerns in recent years due to their wide occurrence and high toxicity. The liver has been demonstrated as a major target organ for several halophenolic DBPs. However, little is known about the underlying mechanisms of liver damage caused by halophenolic DBPs. In this study, 2,4,6-trichlorophenol (TCP), 2,4,6-tribromophenol (TBP) and 2,4,6-triiodiophenol (TIP) were selected as representative halophenolic DBPs and exposed to C57BL/6 mice at an environmentally-relevant concentration (0.5 μg/L) and two toxicological concentrations (10 and 200 μg/L) for 12 weeks. Then, a combination of histopathologic and biochemical examination, liver transcriptome, serum metabolome, and gut microbiome was adopted. It was found that trihalophenol exposure significantly elevated the serum levels of alkaline phosphatase and albumin. Liver inflammation was observed at toxicological concentrations in the histopathological examination. Transcriptome results showed that the three trihalophenols could impact immune-related pathways at 0.5 μg/L, which further contributed to the disturbance of pathways in infectious diseases and cancers. Notably, TBP and TIP had higher immunosuppressive effects than TCP, which might lead to uncontrolled infection and cancer. In terms of serum metabolic profiles, energy metabolism pathway of citrate cycle and amino acid metabolism pathways of valine, leucine, and isoleucine were also significantly affected. Integration of the metabolomic and transcriptomic data suggested that a 12-week trihalophenol exposure could prominently disturb the glutathione metabolism pathway, indicating the impaired antioxidation and detoxification abilities in liver. Moreover, the disorder of the intestinal flora could interfere with immune regulation and host metabolism. This study reveals the toxic effects of halophenolic DBPs on mammalian liver and provides novel insights into the underlying mechanisms of hepatotoxicity.