Ochratoxin A induces global DNA hypomethylation and oxidative stress in neuronal cells in vitro

摘要

Recently, it was reported that ochratoxin A (OTA) mycotoxin, produced by a number of Aspergillus and Penicillium fungal species, may cause neuropsychological impairment or mental and emotional disorders but the mechanism of neurotoxicity remains unknown. Adverse effects of OTA in human (SHSY5Y) and mouse (HT22) neuronal cell lines were studied in vitro. OTA was found to be non-cytotoxic in both cell lines at concentrations 2.5-30 umol/1, which are above the levels reported for human and animal plasma. OTA led to slightly elevated chromosomal instability in HT22 cells at concentrations of 15-30 umol/1 after 48 h, while in SHSY5Y cells, no evidence for genotoxic effects was observed at concentrations of 2.5-30 umol/1. OTA treatment at 10 umol/1 resulted in elevated levels of unmethylated cytosines in CpG dinucleotides (up to 1.4-fold), elevated levels of intracellular reactive oxygen species (up to 1.6-fold), and in elevated levels of oxidized DNA purines (up to 2.2-fold) in both cell lines. Detectedglobal DNA hypomethylation and oxidative stress were found to be reversible in 96 h and 24-72 h, respectively. In general, the observed partem of OTA-induced effects in both cell lines was similar, but HT22 cells exhibited higher sensitivity, as well asbetter repair capacity in response to OTA toxicity. In conclusion, the results suggest that oxidative stress and epigenetic changes are directly involved in OTA-induced neurotoxicity, while cytotoxicity and genotoxicity cannot be considered as primary cause of toxicity in neuronal cells in vitro.