Impacts of trichothecene mycotoxins on human colonic epithelial cells: molecular mechanisms and signaling pathways

Trichothecenes inhibit protein synthesis by binding to the ribosomal A-site, thus triggering RSR to activate MAPKs via PKR or ZAKα. Trichothecenes induce ERS and UPR, mediated by PERK/eIF2/ATF4 and Ire1α/XBP1 signaling, which potentially activate CHOP, MAPKs, p53, and NF-κB. Trichothecenes disturb the mitochondrial electron transport chain to overproduce ROS, further activating NF-κB. Trichothecenes induce nitric oxide overproduction via inducible nitric oxide synthase, which is transcriptionally activated by NF-κB. Trichothecenes may cause DNA damage by direct interaction or by oxidative stress, thereby activating ATM/p53 signaling. Trichothecenes modulate inflammation via MAPK, NF-κB, JAK/STAT, and UPR pathways. The cytotoxicity of trichothecenes depends on molecular structure, exposure dose, and cell differentiation status. Trichothecenes suppress cell proliferation via Wnt and/or JAK/STAT pathways, and induce apoptosis via mitochondrial and Fas pathways by regulating p53, CHOP, and BCL-2 family proteins. Trichothecenes impair epithelial integrity by reducing cell junction proteins through MAPK, Wnt and JAK/STAT pathways, and by inhibiting tight junction assembly through inactivating PKA. Trichothecenes reduce mucin production through MAPKs and IRE1β signaling.