Toxicological interactions between mycotoxins from ubiquitous fungi: Impact on hepatic and intestinal human epithelial cells

Chemosphere. 2018 Jul;202:538-548. doi: 10.1016/j.chemosphere.2018.03.122. Epub 2018 Mar 20.


Aflatoxin B1 (AFB1), deoxynivalenol (DON), fumonisin B1 (FB1) and ochratoxin A (OTA) are toxic fungal metabolites co-occurring naturally in the environment. This study aimed to evaluate the toxicological interactions of these mycotoxins concerning additive, antagonistic and synergistic toxicity towards human cells. The theoretical biology-based Combination index-isobologram method was used to evaluate the individual and binary effect of these toxins and determine the type of the interaction using as models Caco-2 (intestinal) and HepG2 (hepatic) cells. Cytotoxicity was assessed using the MTT test at the concentrations of 0.625-20 μM for all the compounds. DON exerted the highest toxicity toward both cells, OTA and AFB1 also showed a dose-effect response, whereas no toxicity was verified for FB1. Synergism or antagonism effects occurred when exposing AFB1-DON and AFB1-OTA on Caco-2 cells at higher or lower concentrations, respectively; while DON-OTA showed synergism throughout all inhibition levels. Concerning HepG2, AFB1-DON exerted a strong synergism, regardless of the level; whereas AFB1-OTA had slight synergism/nearly additive effect; and, OTA-DON had a moderate antagonism/nearly additive effect. Synergistic strengths as high as a dose reduction index of 10 for AFB1-DON were observed in hepatic cells. Taken together our findings indicate that the toxicological effects differ regarding the type of mycotoxins used for combinations and the stronger synergistic effect was observed for mixtures containing DON in both cells. Therefore, even though DON has not been classified as to its carcinogenicity to humans, this mycotoxin may present a serious threat to health, mainly when co-occurring in the environment.

Keywords: Antagonism; Caco-2 cells; Combination index; HepG2 cells; Mycotoxins; Synergism.

MeSH terms

  • Cell Proliferation / drug effects*
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Fungi / metabolism*
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Mycotoxins / adverse effects*
  • Tumor Cells, Cultured


  • Mycotoxins