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

BACKGROUND: Trichothecenes are a family of structurally related mycotoxins typically found in cereal crops, thus threatening the health of human digestive tract. In colonic epithelial cells (CECs), trichothecenes inhibit protein synthesis and cell proliferation, induce oxidative stress, DNA damage, ribotoxic stress response (RSR), endoplasmic reticulum stress (ERS), unfolded protein response (UPR), inflammation, and apoptosis, destruct cell junctions, and alter mucus composition. Although recent studies have enhanced the understanding on the molecular mechanisms of these toxic effects, interconnections between these toxic effects were poorly established.

AIM OF REVIEW: This review comprehensively summarizes the influence of trichothecenes on CECs. This review emphasizes the elucidation of molecular mechanisms and signaling pathways underlying trichothecene toxicity, in an attempt to integrate diverse toxic effects into a unified mechanistic framework.

KEY SCIENTIFIC CONCEPTS OF REVIEW: 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.