Institute of Molecular Biology, National Academy of Sciences of Armenia, Hasratyan 7, 0014, Yerevan, Armenia.
Yerevan State University, A. Manoogian 1, 0025, Yerevan, Armenia.
Mycotoxin Res. 2020 Feb;36(1):73-81. doi: 10.1007/s12550-019-00370-y. Epub 2019 Aug 22.
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.
最近有报道称，一种由多种曲霉属和青霉属真菌产生的真菌毒素——赭曲霉毒素 A（OTA），可能会导致神经心理损伤或精神和情绪障碍，但神经毒性的机制尚不清楚。本研究在体外研究了 OTA 对人（SHSY5Y）和鼠（HT22）神经细胞系的不良影响。结果发现，在浓度为 2.5-30 μmol/l 的范围内，OTA 对两种细胞系均无细胞毒性，而这一浓度高于已报道的人类和动物血浆中的浓度。48 小时后，在浓度为 15-30 μmol/l 的情况下，OTA 会导致 HT22 细胞的染色体稳定性略有升高，而在 SHSY5Y 细胞中，在浓度为 2.5-30 μmol/l 的情况下，没有观察到遗传毒性作用的证据。在 10 μmol/l 的 OTA 处理下，两种细胞系中的未甲基化胞嘧啶在 CpG 二核苷酸中的水平升高（高达 1.4 倍），细胞内活性氧水平升高（高达 1.6 倍），氧化的 DNA 嘌呤水平升高（高达 2.2 倍）。在 96 小时和 24-72 小时内，检测到的全基因组 DNA 低甲基化和氧化应激均可逆转。总的来说，两种细胞系中观察到的 OTA 诱导效应模式相似，但 HT22 细胞对 OTA 毒性的敏感性更高，修复能力也更强。结论表明，氧化应激和表观遗传变化直接参与了 OTA 诱导的神经毒性，而细胞毒性和遗传毒性不能被认为是体外神经元细胞毒性的主要原因。
