Transcriptomic and proteomic profiling reveals the intestinal immunotoxicity induced by aflatoxin M1 and ochratoxin A

Abstract

Mycotoxins-contaminated milk could threaten human health; therefore, it is necessary to demonstrate the toxicological effect of mycotoxins in milk. Most recently, researchers have paid more attention to the immunotoxic effects of the individual cereal-contaminating mycotoxins, namely, zearalenone and deoxynivalenol. However, there is scant information about the intestinal immunotoxicity of aflatoxin M1 (AFM1), let alone that of a combination of AFM1 and ochratoxin A (OTA), which often co-occur in milk. To reveal the inflammatory response caused by these mycotoxins, expression of inflammation-related genes in differentiated Caco-2 cells was analyzed, demonstrating a synergistic effect of the mixture of AFM1 (4 μg/mL) and OTA (4 μg/mL). Integrative transcriptomic and proteomic analyses were also performed. A cross-omics analysis identified several mechanisms underlying this synergy: (i) compared with stimulation with either compound alone, combined use resulted in stronger induction of proteins involved in immunity-related pathways; (ii) combination of the two agents targeted different points in the same pathways; and (iii) combination of the two agents activated specific inflammation-related pathways. These results suggested that combined use of AFM1 and OTA might exacerbate intestinal inflammation, indicating that regulatory authorities should pay more attention to food contamination by multiple mycotoxins when performing risk assessments.