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 μmol/l, 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 μmol/l after 48 h, while in SHSY5Y cells, no evidence for genotoxic effects was observed at concentrations of 2.5–30 μmol/l. OTA treatment at 10 μmol/l 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. Detected global DNA hypomethylation and oxidative stress were found to be reversible in 96 h and 24–72 h, respectively. In general, the observed pattern of OTA-induced effects in both cell lines was similar, but HT22 cells exhibited higher sensitivity, as well as better 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.

中文翻译：

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ch曲霉毒素A在体外诱导神经元细胞中的整体DNA低甲基化和氧化应激。

最近，据报道，许多曲霉和青霉产生的produced曲霉毒素A（OTA）霉菌毒素真菌物种可能会引起神经心理学障碍或精神和情感障碍，但神经毒性的机制尚不清楚。体外研究了OTA对人（SHSY5Y）和小鼠（HT22）神经元细胞系的不良影响。发现OTA在两种细胞系中均无细胞毒性，浓度为2.5–30μmol/ l，高于人类和动物血浆中报道的水平。在48 h后，OTA导致HT22细胞中15–30μmol/ l浓度的染色体不稳定性稍微升高，而SHSY5Y细胞中2.5–30μmol/ l的浓度没有遗传毒性的证据。以10μmol/ l的OTA处理导致CpG二核苷酸中未甲基化的胞嘧啶水平升高（最高1.4倍），细胞内活性氧水平升高（最高1.6倍），两种细胞系中氧化的DNA嘌呤水平升高（最高2.2倍）。检测到的总体DNA低甲基化和氧化应激分别在96 h和24–72 h可逆。通常，在两种细胞系中观察到的OTA诱导作用模式相似，但是HT22细胞显示出更高的敏感性以及对OTA毒性的更好修复能力。总之，结果表明氧化应激和表观遗传变化直接参与OTA诱导的神经毒性，而细胞毒性和基因毒性不能被认为是体外神经元细胞毒性的主要原因。两种细胞系中OTA诱导作用的观察模式相似，但HT22细胞显示出更高的敏感性以及对OTA毒性的更好修复能力。总之，结果表明氧化应激和表观遗传变化直接参与OTA诱导的神经毒性，而细胞毒性和基因毒性不能被认为是体外神经元细胞毒性的主要原因。两种细胞系中OTA诱导作用的观察模式相似，但HT22细胞显示出更高的敏感性以及对OTA毒性的更好修复能力。总之，结果表明氧化应激和表观遗传变化直接参与OTA诱导的神经毒性，而细胞毒性和基因毒性不能被认为是体外神经元细胞毒性的主要原因。