Organophosphate flame retardant triphenyl phosphate (TPhP) induced colonic fibrosis by bringing about epithelial-mesenchymal transition

Abstract

Intestinal fibrosis is often observed in inflammatory bowel disease (IBD) and seriously affects intestinal health. Our previous study identified that triphenyl phosphate (TPhP), one kind of frequently used organophosphate flame retardants (OPFRs), induced IBD-like features in colon. Herein, we firstly observed extracellular matrix deposition in colon tissues, indicative of appearance of colonic fibrosis. Further studies showed that TPhP downregulated epithelial marker E-cadherin levels but upregulated alpha smooth muscle actin (α-SMA) in mouse colon tissues, and similar results were observed in cultured colon cells, indicating that fibrogenesis might be attributed to epithelial-mesenchymal transition (EMT). Further transcriptome and experimental data demonstrated that TPhP-induced EMT was closely associated with activated Wnt/β-catenin pathway. Moreover, FOXM1 facilitated the entrance of β-catenin into nucleus to regulate expression of Wnt target genes, promoting EMT initiation. Collectively, these findings demonstrated that TPhP induced colonic fibrosis in mice by activating EMT, and this work may provide new perspectives in exploring etiology of intestinal fibrosis and developing relevant treatment strategies.

Keywords: Colonic fibrosis; EMT; FOXM1; Triphenyl phosphate; Wnt/β-catenin signaling.