Endosulfan is an organochlorine insecticide and has been implicated in neurotoxicity, hepatotoxicity, immunosuppression and teratogenicity. However, the molecular mechanism of endosulfan toxicity is not yet clear. Recent studies demonstrated that oxidative stress induced by endosulfan is involved in its toxicity and accumulating evidence suggests that endosulfan can modulate the activities of stress-responsive signal transduction pathways including extracellular signal regulated kinases (ERK) 1/2. However, none of the previous studies investigated the ability of endosulfan to modulate activating protein-1 (AP-1) binding and antioxidant response element (ARE)-mediated transcription as an underlying mechanism of endosulfan toxicity. In this report, we show that treatment of HepG2 cells with endosulfan significantly increased oxidative stress-responsive transcription via AP-1 activation. In addition, endosulfan-induced transcription was enhanced in cells depleted of glutathione by buthionine sulfoximine (BSO) treatment. Exposure to endosulfan resulted in a significant increase in the activities of MAPKs, ERK1/2 and p38. Endosulfan-induced increases in enzymatic activities of these MAPKs were consistent with MAPK phosphorylation. Endosulfan exposure also caused an increase in c-Jun phosphorylation. These results suggest a model for endosulfan toxicity in which endosulfan increases ERK1/2 and p38 activities and these activated MAPKs then increase c-Jun phosphorylation. Phosphorylated c-Jun, in turn, increases AP-1 activity, which results in activation of ARE-mediated transcription.

中文翻译：

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硫丹通过在 HepG2 细胞中激活 ERK1/2 和 p38，上调 AP-1 结合和 ARE 介导的转录。

硫丹是一种有机氯杀虫剂，与神经毒性、肝毒性、免疫抑制和致畸性有关。然而，硫丹毒性的分子机制尚不清楚。最近的研究表明，硫丹引起的氧化应激与其毒性有关，而且越来越多的证据表明，硫丹可以调节应激反应性信号转导通路的活动，包括细胞外信号调节激酶 (ERK) 1/2。然而，之前的研究均未将硫丹调节活化蛋白 1 (AP-1) 结合和抗氧化反应元件 (ARE) 介导的转录的能力作为硫丹毒性的潜在机制进行调查。在这份报告中，我们表明，用硫丹处理 HepG2 细胞可通过 AP-1 激活显着增加氧化应激反应性转录。此外，通过丁硫氨酸亚砜亚胺 (BSO) 处理，在耗尽谷胱甘肽的细胞中，硫丹诱导的转录得到增强。接触硫丹导致 MAPK、ERK1/2 和 p38 的活性显着增加。硫丹诱导的这些 MAPK 的酶活性增加与 MAPK 磷酸化一致。接触硫丹还导致 c-Jun 磷酸化增加。这些结果表明了硫丹毒性模型，其中硫丹会增加 ERK1/2 和 p38 的活性，而这些活化的 MAPK 随后会增加 c-Jun 磷酸化。反过来，磷酸化的 c-Jun 会增加 AP-1 的活性，从而激活 ARE 介导的转录。