Exposure to polyaromatic hydrocarbons (PAHs) and heavy metal/loid(s) has been demonstrated to induce an oxidative stress response in mammalian cells. The combined effect of PAHs and heavy metal/loid(s) on the oxidative stress response has not been reported extensively. The Nrf2 antioxidant response pathway plays an important role in cellular antioxidant defense against oxidative stress-induced cell damage. In this study, we have determined the combined effect of four PAHs (benzo[a]pyrene (B[a]P), naphthalene (Nap), phenanthrene (Phe) and pyrene (Pyr)) and three heavy metal/loid(s) (arsenic (As), cadmium (Cd) and lead (Pb)) on the Nrf2 antioxidant pathway using the ARE reporter-HepG2 cell line. The mixture study was carried out for binary, ternary, quaternary and seven-component combinations of PAHs and heavy metal/loid(s). Initially, individual dose responses for the PAHs (B[a]P, Nap, Phe and Pyr) and heavy metal/loid(s) (As, Cd and Pb), as well as their respective concentrations that induced an induction ratio of 1.5 (ECIR1.5), were determined. The luciferase assay system was used to quantify the induction of the Nrf2 antioxidant pathway. The individual dose response study showed that both PAHs and heavy metal/loid(s) activated the Nrf2 antioxidant pathway in ARE reporter-HepG2 cells. Among these chemicals, Cd was the most potent inducer, followed by B[a]P and As. Based on the individual dose response findings, PAHs and heavy metal/loid(s) were mixed at equipotent ratios using a fixed concentration ratio, and the effects of the mixtures of PAHs and heavy metal/loid(s) (binary to seven-component) on the Nrf2 antioxidant pathway were determined. The mixture effects were predicted by using the concentration addition (CA) model. Overall, the results showed that the multi-component mixtures of PAHs and heavy metal/loid(s) induced an oxidative stress response in ARE reporter-HepG2 cells, and that the CA model is an appropriate model to predict the interaction effect of these selected mixtures. A human cell line-based reporter gene assay system was successfully used to determine the mixture effects of two groups of common contaminants on oxidative stress response pathway.

中文翻译：

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多环芳烃和重金属/类物质的多组分混合物对 ARE 报告基因 HepG2 细胞中 Nrf2 抗氧化反应元件 (ARE) 途径的影响。

已证明接触多环芳烃 (PAH) 和重金属/类物质会诱导哺乳动物细胞产生氧化应激反应。PAH 和重金属/类物质对氧化应激反应的综合影响尚未得到广泛报道。Nrf2 抗氧化反应途径在细胞抗氧化防御氧化应激诱导的细胞损伤中发挥着重要作用。在这项研究中，我们确定了四种多环芳烃（苯并[a]芘 (B[a]P)、萘 (Nap)、菲 (Phe) 和芘 (Pyr)）和三种重金属/类物质的综合影响使用 ARE 报告基因 HepG2 细胞系研究 Nrf2 抗氧化途径中的砷 (As)、镉 (Cd) 和铅 (Pb)。对多环芳烃和重金属/类物质的二元、三元、四元和七元组合进行了混合物研究。最初，PAH（B[a]P、Nap、Phe 和 Pyr）和重金属/类化合物（As、Cd 和 Pb）的个体剂量反应，以及诱导诱导比为 1.5 的各自浓度(ECIR1.5)，进行了测定。荧光素酶测定系统用于量化 Nrf2 抗氧化途径的诱导。个体剂量反应研究表明，PAH 和重金属/类物质都会激活 ARE 报告基因 HepG2 细胞中的 Nrf2 抗氧化途径。在这些化学物质中，Cd 是最有效的诱导剂，其次是 B[a]P 和 As。根据个体剂量反应结果，使用固定浓度比将多环芳烃和重金属/类物质以等势比混合，以及多环芳烃和重金属/类物质混合物（二元至七组分）的影响）对Nrf2抗氧化途径的影响进行了测定。通过使用浓度加成（CA）模型来预测混合物效应。总体而言，结果表明 PAH 和重金属/类物质的多组分混合物在 ARE 报告基因 HepG2 细胞中诱导氧化应激反应，并且 CA 模型是预测这些选定物质的相互作用效应的合适模型。混合物。基于人类细胞系的报告基因检测系统成功地确定了两组常见污染物对氧化应激反应途径的混合影响。