Isocyanates Induces DNA Damage, Apoptosis, Oxidative Stress, and Inflammation in Cultured Human Lymphocytes
Isocyanates Induces DNA Damage, Apoptosis, Oxidative Stress, and Inflammation in Cultured Human Lymphocytes
复制标题
DOI：
10.1002/jbt.20260
复制
发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
Maudar, Kewal Krishan
中科院分区：
文献类型：
--
作者：
Mishra, Pradyumna Kumar;Panwar, Hariom;Maudar, Kewal Krishan
异氰酸酯是一类含有异氰酸酯基团（-NCO）的低分子量芳香和脂肪族化合物，是具有多种工业用途的重要原料；然而，职业和意外接触这些化合物的病理生理影响迄今尚不清楚。虽然文献中现有的初步证据表明，异氰酸酯及其衍生物可能对健康产生有害影响，包括免疫毒性，但这种影响背后的分子机制从未得到解决。本研究旨在评估异氰酸甲酯（MIC）对健康人体志愿者体外培养淋巴细胞的免疫毒性反应。研究评估了剂量依赖性和时间过程反应（n = 3），使用n -琥珀酰氨基基n -甲基氨基甲酸酯（MIC的替代化学替代品）。共济失调毛细血管扩张突变（ATM）和γ - H2AX蛋白磷酸化状态对DNA损伤的评价annexin-V/PI法、凋亡DNA阶梯法、线粒体去极化法测定细胞凋亡指数；CM-H2DCFDA诱导氧化应激，生成8-羟基-2'脱氧鸟苷；抗氧化防御系统酶谷胱甘肽还原酶水平；并进行多重细胞仪头阵列分析，量化炎症因子、白细胞介素-8、白细胞介素-1 β、白细胞介素-6、白细胞介素-10、肿瘤坏死因子、白细胞介素-12p70等参数的分泌水平。研究结果显示了剂量和时间依赖性反应，在基因组水平上为迄今未知的异氰酸酯暴露免疫毒性后果的分子机制提供了证据。我们预计这些数据以及文献中报道的其他研究将有助于设计更好的方法来评估职业和意外暴露于异氰酸酯的风险。(C) 2008 Wiley期刊有限公司中华生物医学杂志，2008；在线发表于Wiley InterScience （www.interscience.wiley.com）。DOI 10:1002 / jbt.20260
Isocyanates, a group of low molecular weight aromatic and aliphatic compounds containing the isocyanate group (-NCO), are important raw materials with diverse industrial applications; however, pathophysiological implications resulting from occupational and accidental exposures of these compounds are hitherto unknown. Although preliminary evidence available in the literature suggests that isocyanates and their derivatives may have deleterious health effects including immunotoxicity, but molecular mechanisms underlying such an effect have never been addressed. The present study was carried out to assess the immunotoxic response of methyl isocyanate (MIC) on cultured human lymphocytes isolated from healthy human volunteers. Studies were conducted to evaluate both dose-dependent and time-course response (n = 3), using N-succinimidyl N-methylcarbamate, a surrogate chemical substitute to MIC. Evaluation of DNA damage by ataxia telangiectasia mutated (ATM) and gamma H2AX protein phosphorylation states; measure of apoptotic index through annexin-V/PI assay, apoptotic DNA ladder assay, and mitochondrial depolarization; induction of oxidative stress by CM-H2DCFDA and formation of 8-hydroxy-2'deoxy guanosine; levels of antioxidant defense system enzyme glutathione reductase; and multiplex cytometric bead array analysis to quantify the secreted levels of inflammatory cytokines, interleukin-8, interleukin-1 beta, interleukin-6, interleukin-10, tumor necrosis factor, and interleukin-12p70 parameters were carried out. The results of the study showed a dose- and time-dependent response, providing evidence to hitherto unknown molecular mechanisms of immunotoxic consequences of isocyanate exposure at a genomic level. We anticipate these data along with other studies reported in the literature would help to design better approaches in risk assessment of occupational and accidental exposure to isocyanates. (C) 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:429-440, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10:1002/jbt.20260