Investigation of the immunotoxic effects of ochratoxin A on natural killer cell activity

Ochratoxin A (OTA) is a mycotoxin produced as a secondary metabolite by Aspergillus and Penicillium fungi species and detected in various food and animal feeds. It exhibits complex toxicity, involving alterations in different signaling pathways, including PI3K/Akt, MAPK/ERK, and NF-κB signaling pathways. It is thought that OTA exerts its immunotoxicity through reducing viability and proliferation, stimulation of inflammation, and interference with immune cell activity. Its detrimental effects on cell survival, cytotoxic activity, and cytokine release were reported in primary natural killer (NK) cells of mice and rats, whereas the molecular mechanisms underlying this toxicity remained elusive. This study aims to provide insight into mycotoxin-induced immune system impairments by unfolding the molecular mechanisms underlying OTA-induced innate immunotoxicity in NK cell activation. The findings demonstrate that OTA exposure leads to alterations in NK cell metabolism via PI3K/Akt, MAPK/ERK, and NF-κB pathways, alongside elevated degranulation levels and granzyme B expression. In addition, NK cell phenotyping revealed the upregulation of an activating receptor NKp46 levels, whose elevated expression was associated with the tumor microenvironment. Considering the potential of OTA as a human carcinogen and the elevated tumorigenesis risks associated with aberrant NK activity, this study provides valuable insights into the OTA-mediated toxicity of NK cell activation at molecular levels.