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首页> 外文期刊>Chemico-biological interactions >Gene expression in benzene-exposed workers by microarray analysis of peripheral mononuclear blood cells: induction and silencing of CYP4F3A and regulation of DNA-dependent protein kinase catalytic subunit in DNA double strand break repair.
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Gene expression in benzene-exposed workers by microarray analysis of peripheral mononuclear blood cells: induction and silencing of CYP4F3A and regulation of DNA-dependent protein kinase catalytic subunit in DNA double strand break repair.

机译：通过微阵列分析对外周单核血细胞的微阵列分析的基因表达：CYP4F3A的诱导和沉默和DNA双链断裂修复中的DNA依赖性蛋白激酶催化亚基的调节。

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Benzene causes hematotoxicity and leukemia in humans. To analyze benzene-caused aberrant gene expression, we examined differential gene expression by microarray analysis of peripheral mononuclear blood cells from seven workers diagnosed with benzene poisoning and seven matched controls. Twenty-two genes were found up-regulated and 18 down-regulated in benzene patients compared with controls. Here we report the characterization of two benzene-regulated genes. CYP4F3A, which encodes the leukotriene B(4) (LTB(4)) omega-hydroxylase, is important for inactivation of LTB(4) in neutrophils. CYP4F3A mRNA was found elevated in all patients; moreover, CYP4F3A mRNA and protein were induced by benzene metabolite phenol in HL-60 and K562 cells as well as ex vivo in human peripheral neutrophils. Silencing of CYP4F3A in HL-60 cells by lentiviral delivery of CYP4F3A-specific siRNA reduced cell survival to 56%, 44%, 22%, 14%, and 3% at 3, 4, 5, 6, and 7 days, respectively; the results suggest that CYP4F3A is a critical positive regulator of HL-60 proliferation. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) regulates non-homologous end joining (NHEJ) in DNA double strand break (DSB) repair. DNA-PKcs mRNA was found consistently increased in the patients and DNA-PKcs mRNA and protein were induced by hydroquinone in HL-60 cells. In a DSB model, hydroquinone induced the formation of gamma-H2AX foci, a marker of DSBs, in HL-60 cells. The findings indicate that hydroquinone induces DSBs and induction correlates with elevated levels of DNA-PKcs and NHEJ. Similar results were obtained in K562 cells treated with phenol. Since NHEJ is error-prone, induction of DNA-PKcs and NHEJ may contribute to mutagenesis and leukemia by benzene. To our knowledge, the study demonstrated for the first time that benzene and metabolites induce CYP4F3A and DNA-PKcs both in vivo and in vitro. Induction of the genes may play a role in the pathogenesis of benzene hematotoxicity and serve as biomarkers of benzene exposure.
机译：苯导致人类的血管毒性和白血病。为了分析苯引起的异常基因表达，我们通过七个患有苯中毒和七种匹配对照的七名工人进行了微阵列分析的微阵列分析差异基因表达。发现二十两种基因上调，与对照相比，在苯患者中下调18个。在这里，我们报告了两个苯调节基因的表征。 CYP4F3A编码白三烯B（4）（LTB（4））ω-羟化酶，对于在中性粒细胞的LTB（4）中失活是重要的。 CYP4F3A mRNA在所有患者中发现升高;此外，通过HL-60和K562细胞中的苯代谢物酚以及人外周性中性粒细胞的离体诱导CYP4F3A mRNA和蛋白质。通过慢病毒递送CYP4F3A特异性siRNA的CYP4F3A在HL-60细胞中沉默细胞存活率降低至56％，44％，22％，14％和3％，3,4,5,6和7天;结果表明，CYP4F3A是HL-60增殖的关键阳性调节剂。 DNA依赖性蛋白激酶催化亚基（DNA-PKCS）调节DNA双链突破（DSB）修复中的非同源终端连接（NHEJ）。发现DNA-PKCS mRNA在患者中始终如一地增加，并且通过HL-60细胞中的氢醌诱导DNA-PKCS mRNA和蛋白质。在DSB模型中，氢醌诱导在HL-60细胞中形成γ-H2AX焦点，DSB的标志物。结果表明，氢醌诱导DSB和诱导与DNA-PKCS和NHEJ的升高相相关。用苯酚处理的K562细胞中获得了类似的结果。由于NHEJ是容易出错的，DNA-PKCS和NHEJ的诱导可能通过苯有助于诱变和白血病。据我们所知，该研究首次展示了苯和代谢物第一次诱导CYP4F3A和DNA-PKC在体内和体外。基因的诱导可能在苯血管毒性的发病机制中发挥作用，并用作苯暴露的生物标志物。

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