Tetrabromobisphenol A induced p38-MAPK/AMPKα activation downstream-triggered CHOP signal contributing to neuronal apoptosis and death

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology Pub Date : 2024-11-23 DOI:10.1016/j.tox.2024.154014

Jui-Ming Liu , Shing-Hwa Liu , Shih-Chang Fu , Wei-Cheng Lai , Kai-Min Fang , Ken-An Lin , Jun-An Ke , Chun-Ying Kuo , Chin-Chuan Su , Ya-Wen Chen

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引用次数: 0

Abstract

Tetrabromobisphenol A (TBBPA), a brominated flame retardant (BFR), has been implicated as the neurotoxic effects in mammalian. However, the exact mechanisms underlying TBBPA-induced neurotoxicity remain unclear. In the present study, Neuro-2a cells, a mouse neural crest-derived cell line, were used to examine the mechanism of TBBPA-induced neuronal cytotoxicity. TBBPA exposure caused alterations in cell viability and mitochondrial membrane potential (MMP) and induction of apoptotic events, such as increased apoptotic cell population and cleaved caspase-3, −7, −9, and poly (ADP-ribose) polymerase (PARP) protein expression). TBBPA exposure triggered CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activation. Transfection with CHOP-specific small interfering RNA (siRNA) obviously prevented the expression of CHOP protein and markedly attenuated MMP loss, and caspase-3 and −7 activation in TBBPA-exposed Neuro-2a cells. In addition, TBBPA exposure significantly evoked the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular-signal regulated kinase1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and AMP-activated protein kinase (AMPK)α proteins. Pretreatment of cells with pharmacological inhibitors of p38-MAPK (SB203580) and AMPK (compound C), but not inhibitors of JNK (SP600125) or ERK1/2 (PD98059), effectively prevented the increase in caspase-3 activity, MMP loss, and activated CHOP and cleaved caspase-3 and −7 protein expression in TBBPA-treated cells. Notably, transfection with either p38α-MAPK- or AMPKα1/2-specific siRNAs markedly attenuated the expression of CHOP, and cleaved caspase-3 and −7. Interestingly, transfection with each siRNA significantly reduced the TBBPA-induced phosphorylation of p38-MAPK and AMPKα proteins. Collectively, these findings suggest that CHOP activation-mediated mitochondria-dependent apoptosis contributes to TBBPA-induced neurotoxicity. An interdependent p38-MAPK and AMPKα signaling-regulated apoptotic pathway may provide new insights into the mechanism understanding TBBPA-elicited neurotoxicity.

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四溴双酚 A 诱导 p38-MAPK/AMPKα 激活，下游触发 CHOP 信号，导致神经元凋亡和死亡

四溴双酚 A（TBBPA）是一种溴化阻燃剂（BFR），被认为会对哺乳动物的神经产生毒性作用。然而，TBBPA 诱发神经毒性的确切机制仍不清楚。本研究使用小鼠神经嵴衍生细胞系 Neuro-2a 细胞来研究 TBBPA 诱导神经细胞毒性的机制。暴露于 TBBPA 会导致细胞活力和线粒体膜电位（MMP）改变，并诱导细胞凋亡事件，如凋亡细胞数量增加、裂解的 Caspase-3、-7、-9 和多（ADP-核糖）聚合酶（PARP）蛋白表达）。暴露于 TBBPA 会引发 CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）的活化。转染CHOP特异性小干扰RNA（siRNA）可明显阻止CHOP蛋白的表达，并显著减轻TBBPA暴露的Neuro-2a细胞中MMP的损失以及Caspase-3和-7的活化。此外，TBBPA 暴露明显诱发了 c-Jun N-terminal kinase（JNK）、extracellular-signal regulated kinase1/2 （ERK1/2）、p38-mitogen-activated protein kinase（p38-MAPK）和 AMP-activated protein kinase（AMPK）α 蛋白的磷酸化。用 p38-MAPK（SB203580）和 AMPK（化合物 C）药理抑制剂，而不是 JNK（SP600125）或 ERK1/2 （PD98059）抑制剂预处理细胞，可有效阻止 TBBPA 处理细胞中的 Caspase-3 活性、MMP 损失、活化的 CHOP 和裂解的 Caspase-3 和 -7 蛋白表达的增加。值得注意的是，转染p38α-MAPK或AMPKα1/2特异性siRNA可明显减少CHOP、裂解的caspase-3和-7的表达。有趣的是，转染每种 siRNA 都能明显减少 TBBPA 诱导的 p38-MAPK 和 AMPKα 蛋白的磷酸化。总之，这些研究结果表明，CHOP激活介导的线粒体依赖性凋亡是TBBPA诱导神经毒性的原因之一。p38-MAPK和AMPKα信号调节的相互依赖的凋亡途径可能会为了解TBBPA诱发神经毒性的机制提供新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.