Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide 通过氧化还原失衡诱导神经母细胞瘤细胞发生铁死亡。,The Journal of Toxicological Sciences

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Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide 通过氧化还原失衡诱导神经母细胞瘤细胞发生铁死亡。
The Journal of Toxicological Sciences ( IF 1.8 ) Pub Date : 2022-01-01 , DOI: 10.2131/jts.47.519
Yi Lyu _{1,

2} , Xue-Ke Ren ₁ , Can-Can Guo ₁ , Zhao-Fei Li ₁ , Jin-Ping Zheng _{1,

3}

Affiliation

作为一种广泛存在的环境污染物，苯并（a）芘-7,8-二醇-9,10-环氧化物（BPDE）诱导的神经毒性越来越受到关注。研究表明，BPDE 诱导的神经变性部分是由于神经细胞凋亡。与细胞凋亡不同，铁死亡是程序性细胞死亡的一种非凋亡形式，但其在 BPDE 神经毒性中的具体作用仍不清楚。在这项工作中，我们使用特定的药理学抑制剂研究了 BPDE 诱导的人神经母细胞瘤细胞系 SH-SY5Y 细胞死亡中的铁死亡。评估了脂质过氧化物、丙二醛产量、谷胱甘肽/谷胱甘肽过氧化物酶活性、超氧化物歧化酶活性和铁含量。与之前的研究一致，我们的数据显示 0. 5 μM BPDE 中毒 24 小时可诱导细胞凋亡，使用凋亡抑制剂可提高细胞存活率。但是随着暴露时间的延长（72 小时）或暴露剂量的增加（1.0 μM），我们已经阐明并验证了 BPDE 在人类 SH-SY5Y 细胞中引发了铁死亡。我们还发现，特定抑制剂 ferrostatin-1 和去铁胺对铁死亡的抑制显着挽救了 BPDE 诱导的铁死亡表型。BPDE 下调 Nrf2 及其与氧化还原调节相关的靶基因 GPX4 和 SLC7A11，但上调 HO-1。我们的结果首先证明了 BPDE 通过细胞凋亡和铁死亡对细胞死亡产生细胞毒性作用。最值得注意的是，由于铁死亡，长期环境暴露于 BPDE 成为一个问题。氧化还原失衡由 Nrf2、SLC7A11 和 HO-1 控制，BPDE 处理后，脂质过氧化物和亚铁离子积累会导致铁死亡。这些发现强调靶向铁死亡可以作为 BPDE 神经毒性的有效保护策略。

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Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide induces ferroptosis in neuroblastoma cells through redox imbalance.

As a widespread environmental pollutant, benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE)-induced neurotoxicity has received increasing attention. Studies have shown that BPDE-induced neurodegeneration is due partly to neuronal apoptosis. Unlike apoptosis, ferroptosis is a non-apoptotic form of programmed cell death, but its specific role in the neurotoxicity of BPDE remains unclear. In this work, we investigated the ferroptosis in BPDE-induced cell death in human neuroblastoma cell line SH-SY5Y using a specific pharmacological inhibitor. Lipid peroxides, malondialdehyde production, glutathione / glutathione peroxidase activity, superoxide dismutase activity, and iron content were evaluated. Consistent with previous studies, our data showed that 0.5 μM BPDE poisoning for 24 hr could induce cell apoptosis and that cell survival could be improved by using apoptosis inhibitors. But with prolonged exposure time (72 hr) or increased exposure dose (1.0 μM), we have elucidated and validated that BPDE triggered ferroptosis in human SH-SY5Y cells. We also revealed that suppression of ferroptosis by specific inhibitors, ferrostatin-1 and deferoxamine, significantly rescued the phenotypes of ferroptosis induced by BPDE. BPDE downregulated Nrf2 and its target genes related to redox regulation, GPX4 and SLC7A11, but upregulated HO-1. Our results first demonstrated that BPDE caused cytotoxic effects on cell death via apoptosis and ferroptosis. Most notably, long-term environmental exposure to BPDE becomes a concern due to ferroptosis. Redox imbalance is controlled by the Nrf2, SLC7A11, and HO-1, through which lipid peroxides and ferrous ion accumulation cause ferroptosis after BPDE treatment. These findings highlight that targeting ferroptosis could serve as an effective protective strategy for neurotoxicity of BPDE.

更新日期：2022-01-01

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