苯并(a)芘-7,8-二氢二醇-9,10-环氧化物(BPDE)通过p53-SLC7A11-ALOX12/p53-SAT1-ALOX15通路诱导大鼠皮质神经元铁凋亡。

IF 2.8 4区 医学 Q3 TOXICOLOGY
Chaoli Zhou, Zhaomeng Xu, Shihan Ding, Xiaohui Li, Hui Wang, Hui He, Hongyu Sun, Xiaomin Tong, Tingyu Ji, Yi Lyu, Jinping Zheng
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引用次数: 0

摘要

苯并(a)芘-7,8-二氢二醇-9,10-环氧化物(BPDE)是苯并(a)芘的最终代谢物,与诱导神经元细胞死亡有关。我们之前的研究证实,BPDE会引发神经母细胞瘤SH-SY5Y细胞的铁下垂;然而,潜在的机制仍然难以捉摸。本研究检测了bpde诱导的大鼠初级皮质神经元铁下垂,发现细胞内活性氧(ROS)和Fe2+浓度显著增加。暴露于0.5 μM BPDE后,观察到线粒体明显的形态学变化,表明铁下垂。观察到丙二醛(MDA)表达上调,同时暴露后谷胱甘肽(GSH)水平、谷胱甘肽过氧化物酶(GSH- px)活性和超氧化物歧化酶(SOD)活性下调。此外,死铁相关蛋白ACSL4和COX2的表达增加,而SLC7A11和GPX4的表达降低。值得注意的是,脂质过氧化抑制剂和铁螯合剂的应用,如去铁胺(DFO)和他铁素-1 (Fer-1),部分减轻了这些影响。这些结果表明,BPDE能够诱导大鼠原代神经元铁下垂。从机制上讲,暴露于BPDE导致p53表达上调,SLC7A11水平降低,ALOX12、SAT1和ALOX15的表达增加。相比之下,使用p53特异性抑制剂聚氟乙烯酯-μ治疗导致SLC7A11水平升高,ALOX12、SAT1和ALOX15水平显著降低,从而减轻了bpde诱导的铁下垂。综上所述,这些发现表明BPDE通过p53-SLC7A11-ALOX12和p53-SAT1-ALOX15通路诱导大鼠皮层原代神经元铁凋亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) Induces Ferroptosis in Rat Cortical Neurons via p53-SLC7A11-ALOX12/p53-SAT1-ALOX15 Pathways

Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), the ultimate metabolite of benzo(a)pyrene, has been implicated in the induction of neuronal cell death. Our previous research established that BPDE initiates ferroptosis in neuroblastoma SH-SY5Y cells; however, the underlying mechanisms remain elusive. This study examines BPDE-induced ferroptosis in rat primary cortical neurons, revealing a significant increase in intracellular reactive oxygen species (ROS) and Fe2+ concentrations. Following exposure to 0.5 μM BPDE, distinctive morphological changes in mitochondria, indicative of ferroptosis, were observed. An upregulation of malondialdehyde (MDA) expression was observed, alongside a downregulation of glutathione (GSH) levels, glutathione peroxidase (GSH-PX) activity, and superoxide dismutase (SOD) activity postexposure. Additionally, there was an increase in the expression of ferroptosis-associated proteins ACSL4 and COX2, whereas the levels of SLC7A11 and GPX4 were reduced. Notably, the application of lipid peroxidation inhibitors and iron chelators, such as deferoxamine (DFO) and ferrostatin-1 (Fer-1), partially mitigated these effects. These findings suggest that BPDE is capable of inducing ferroptosis in primary rat neurons. Mechanistically, exposure to BPDE resulted in the upregulation of p53 expression, a reduction in SLC7A11 levels, and the promotion of ALOX12, SAT1, and ALOX15. In contrast, treatment with the p53-specific inhibitor Pifithrin-μ led to an increase in SLC7A11 levels and a significant decrease in ALOX12, SAT1, and ALOX15 levels, thereby mitigating BPDE-induced ferroptosis. In summary, these findings indicate that BPDE induces ferroptosis in primary rat cortical neurons via the p53-SLC7A11-ALOX12 and p53-SAT1-ALOX15 pathways.

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来源期刊
CiteScore
7.00
自引率
6.10%
发文量
145
审稿时长
1 months
期刊介绍: Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.
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