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首页> 外文期刊>Toxicological sciences: An official journal of the Society of Toxicology >A system-based comparison of gene expression reveals alterations in oxidative stress, disruption of ubiquitin-proteasome system and altered cell cycle regulation after exposure to cadmium and methylmercury in mouse embryonic fibroblast.
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A system-based comparison of gene expression reveals alterations in oxidative stress, disruption of ubiquitin-proteasome system and altered cell cycle regulation after exposure to cadmium and methylmercury in mouse embryonic fibroblast.

机译：基因表达的基于系统的比较揭示了小鼠胚胎成纤维细胞中的镉和甲基汞暴露后，氧化应激的改变，泛素-蛋白酶体系统的破坏以及细胞周期调控的改变。

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Environmental and occupational exposures to heavy metals such as methylmercury (MeHg) and cadmium (Cd) pose significant health risks to humans, including neurotoxicity. The underlying mechanisms of their toxicity, however, remain to be fully characterized. Our previous studies with Cd and MeHg have demonstrated that the perturbation of the ubiquitin-proteasome system (UPS) was associated with metal-induced cytotoxicity and apoptosis. We conducted a microarray-based gene expression analysis to compare metal-altered gene expression patterns with a classical proteasome inhibitor, MG132 (0.5 microM), to determine whether the disruption of the UPS is a critical mechanism of metal-induced toxicity. We treated mouse embryonic fibroblast cells at doses of MeHg (2.5 microM) and Cd (5.0 microM) for 24 h. The doses selected were based on the neutral red-based cell viability assay where initial statistically significant decreases in variability were detected. Following normalization of the array data, we employed multilevel analysis tools to explore the data, including group comparisons, cluster analysis, gene annotations analysis (gene ontology analysis), and pathway analysis using GenMAPP and Ingenuity Pathway Analysis (IPA). Using these integrated approaches, we identified significant gene expression changes across treatments within the UPS (Uchl1 and Ube2c), antioxidant and phase II enzymes (Gsta2, Gsta4, and Noq1), and genes involved in cell cycle regulation pathways (ccnb1, cdc2a, and cdc25c). Furthermore, pathway analysis revealed significant alterations in genes implicated in Parkinson's disease pathogenesis following metal exposure. This study suggests that these pathways play a critical role in the development of adverse effects associated with metal exposures.
机译：甲基汞（MeHg）和镉（Cd）等重金属的环境和职业暴露对人类构成重大的健康风险，包括神经毒性。然而，其毒性的潜在机制尚待充分表征。我们以前对Cd和MeHg的研究表明，泛素-蛋白酶体系统（UPS）的扰动与金属诱导的细胞毒性和细胞凋亡有关。我们进行了基于微阵列的基因表达分析，将金属改变的基因表达模式与经典的蛋白酶体抑制剂MG132（0.5 microM）进行比较，以确定UPS的破坏是否是金属诱导毒性的关键机制。我们以MeHg（2.5 microM）和Cd（5.0 microM）的剂量处理了小鼠胚胎成纤维细胞24小时。选择的剂量是基于中性红细胞活力检测，其中检测到了最初的统计学上显着的变异性降低。在对阵列数据进行标准化之后，我们使用了多级分析工具来探索数据，包括组比较，聚类分析，基因注释分析（基因本体分析）以及使用GenMAPP和Ingenuity Pathway Analysis（IPA）进行的路径分析。使用这些整合的方法，我们确定了UPS（Uchl1和Ube2c），抗氧化剂和II期酶（Gsta2，Gsta4和Noq1）以及涉及细胞周期调控途径的基因（ccnb1，cdc2a和cdc25c）。此外，通路分析显示，金属暴露后，与帕金森氏病发病机制有关的基因发生了显着变化。这项研究表明，这些途径在与金属暴露相关的不良反应的发展中起着至关重要的作用。

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