Investigation on metabolic perturbations and molecular mechanism of toxicity of triclosan in mice colon by using metabolomics-based omics integration

Triclosan, as man-made antimicrobial agent, has been widely used as additives in personal care and household products for decades. There is ample evidence that triclosan was frequently detected in human bodily fluids and tissues, causing adverse effects on human health, such as increasing risks of allergies and asthma, altering immune responses, and disrupting endocrine functions. Our recently studies demonstrated that triclosan could exacerbate colitis and colitis-associated colorectal tumorigenesis in mice colon with the presence of gut microbiota. However, the molecular mechanisms and metabolic perturbations involved in the process remain unclear. In this study, we propose to utilize our experience gained from metabolomics investigations on liver toxicity associated with triclosan exposure, and to develop approaches of metabolomics-based omics integration, particularly the novel spatial metabolomics and mass spectrometry imaging for studying complex molecular events involved in triclosan induced colon toxicity. Firstly, we will investigate of triclosan induced metabolic perturbations in mice colon. The perturbed metabolites and metabolic pathways between the control and exposed group will be determined using nontargeted metabolomics and targeted metabolomics. Secondly, MALDI-TOFMS imaging method will be developed and applied for in-situ detection of the perturbed metabolites in colon tissues from mice exposed with triclosan. Thirdly, 3D intestinal cell spheroids that are physiologically and functionally close to the organs in the living body will be used to examine the joint toxic effects of triclosan and its downstream metabolites based on their appearance in mice colon tissues. Finally, the perturbed metabolic pathways in both in vitro and in vivo samples upon triclosan exposure experiments will be verified using metabolomics-based proteomics. The obtained results are expected to provide a comprehensive view of metabolic perturbations and correlation between triclosan exposure and the development of colon diseases and promote the better understanding of the colon toxicity induced by triclosan exposure.