Tetrabromobisphenol-A induces apoptotic death of auditory cells and hearing loss.
Phenolic tetrabromobisphenol-A (TBBPA) and its derivatives are commonly used flame-retardants, in spite of reported toxic effects including neurotoxicity, immunotoxicity, nephrotoxicity, and hepatotoxicity. However, the effects of TBBPA on ototoxicity have not yet been reported. In this study, we investigated the effect of TBBPA on hearing function in vivo and in vitro. Auditory Brainstem Response (ABR) threshold was markedly increased in mice after oral administration of TBBPA, indicating that TBBPA causes hearing loss. In addition, TBBPA induced the loss of both zebrafish neuromasts and hair cells in the rat cochlea in a dose-dependent manner. Mechanistically, hearing loss is largely attributed to apoptotic cell death, as TBBPA increased the expression of pro-apoptotic genes but decreased the expression of anti-apoptotic genes. We also found that TBBPA induced oxidative stress, and importantly, pretreatment with NAC, an anti-oxidant reagent, reduced TBBPA-induced reactive oxygen species (ROS) generation and partially prevented cell death. Our results show that TBBPA-mediated ROS generation induces ototoxicity and hearing loss. These findings implicate TBBPA as a potential environmental ototoxin by exerting its hazardous effects on the auditory system.
Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, South Korea; Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Channy
C
Park
Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea.
Se-Jin
SJ
Kim
Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Won Kyo
WK
Lee
Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Sung Kyun
SK
Moon
Zoonosis Research Center, Wonkwang University School of Medicine, Jeonbuk, South Korea.
SeongAe
S
Kwak
Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk, South Korea. Electronic address: seongkyu642@wku.ac.kr.
Seong-Kyu
SK
Choe
Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, South Korea. Electronic address: rkpark@gist.ac.kr.
Raekil
R
Park
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005411:Flame Retardants / Q000633:toxicity; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000187:drug effects* / Q000378:metabolism; D034381:Hearing Loss / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053403:Lateral Line System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism; D008813:Mice, Inbred ICR; D008856:Microscopy, Fluorescence; D009925:Organ of Corti / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish
D051017:Apoptosis Regulatory Proteins; D005411:Flame Retardants; D016166:Free Radical Scavengers; D015850:Interleukin-6; D011075:Polybrominated Biphenyls; D017382:Reactive Oxygen Species; C020806:tetrabromobisphenol A; D000111:Acetylcysteine
Apoptosis; Hair cells; Hearing loss; TBBPA; Zebrafish neuromast