Genotoxic effects of 1-nitropyrene in macrophages are mediated through a p53-dependent pathway involving cytochrome c release, caspase activation, and PARP-1 cleavage

Ecotoxicology and Environmental Safety

Rosa Huang-Liu¹  Chun-Hung Su²  Kun-Lin Yeh³  Chien-Ying Lee⁴  Yung-Chuan Ho⁵  Yu-Hsiang Kuan⁶  Wen-Ying Chen⁷  Yi-Ching Li⁷  Shiuan-Shinn Lee⁸  Sheng-Wen Wu⁹  Ching-Chi Tseng^1,10  Yun-Wei Chiang^1,11  Chun-Jung Chen^1,12 

[1] Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan;The School of Medicine, Chung Shan Medical University, Taichung, Taiwan;Aerospace Center Hospital, Peking University, Beijing, China;Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan;Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan;Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan;Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan;Department of life sciences, National Chung-Hsing University, Taichung, Taiwan;Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan;School of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan;School of Nutrition, Chung Shan Medical University, Taichung, Taiwan;School of Public Health, Chung Shan Medical University, Taichung, Taiwan;

关键词: 1-Nitropyrene;    Genotoxicity;    p53-dependent pathway;    Macrophage;   

DOI  :  

来源: DOAJ

【 摘 要 】

Genotoxic stress from environmental pollutants plays a critical role in cytotoxicity. The most abundant nitro-polycyclic aromatic hydrocarbon in environmental pollutants, 1-nitropyrene (1-NP), is generated during fossil fuel, diesel, and biomass combustion under sunlight. Macrophages, the key regulators of the innate immune system, provide the first line of defense against pathogens. The toxic effects of 1-NP on macrophages remain unclear. Through a lactate dehydrogenase assay, we measured the cytotoxicity induced by 1-NP. Our results revealed that 1-NP induced genotoxicity also named DNA damage, including micronucleus formation and DNA strand breaks, in a concentration-dependent manner. Furthermore, 1-NP induced p53 phosphorylation and nuclear accumulation; mitochondrial cytochrome c release; caspase-3 and -9 activation and cleavage; and poly (ADP-ribose) polymerase-1 (PARP-1) cleavage in a concentration-dependent manner. Pretreatment with the PARP inhibitor, 3-aminobenzamide, significantly reduced cytotoxicity, genotoxicity, and PARP-1 cleavage induced by 1-NP. Pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, and caspase 3 activation induced by 1-NP. Pretreatment with the p53 inhibitor, pifithrin-α, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, caspase 3 activation, and p53 phosphorylation induced by 1-NP. We propose that cytotoxicity and genotoxicity induced by 1-NP by PARP-1 cleavage via caspase-3 and -9 activation through cytochrome c release from mitochondria and its upstream p53-dependent pathway in macrophages.

【 授权许可】

Unknown