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

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

doi:10.1016/j.tox.2024.154014

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

Toxicology. 2024 Nov 23:154014. doi: 10.1016/j.tox.2024.154014. Online ahead of print.

Authors

Jui-Ming Liu¹, Shing-Hwa Liu², Shih-Chang Fu³, Wei-Cheng Lai⁴, Kai-Min Fang⁵, Ken-An Lin⁶, Jun-An Ke⁷, Chun-Ying Kuo⁸, Chin-Chuan Su⁹, Ya-Wen Chen¹⁰

Affiliations

¹ Division of Urology, Department of Surgery, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan; Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan.
² Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
³ Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan.
⁴ Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan.
⁵ Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan.
⁶ Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404, Taiwan.
⁷ Department of Medical Education, Changhua Christian Hospital, Changhua City 500, Taiwan.
⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua City 500, Taiwan.
⁹ Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua City 500, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan. Electronic address: 91334@cch.org.tw.
¹⁰ Department of Physiology, College of Medicine, China Medical University, Taichung 404, Taiwan. Electronic address: ywc@mail.cmu.edu.tw.

PMID: 39586487
DOI: 10.1016/j.tox.2024.154014

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.

Keywords: AMPKα; Apoptosis; CHOP; Neurotoxicity; Tetrabromobisphenol A; p38-MAPK.