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  2. AHR/ROS-mediated mitochondria apoptosis contributes to benzo[a]pyrene-induced heart defects and the protective effects of resveratrol

AHR/ROS-mediated mitochondria apoptosis contributes to benzo[a]pyrene-induced heart defects and the protective effects of resveratrol

  • Toxicology. 2021 Oct;462:152965. doi: 10.1016/j.tox.2021.152965.
Yujie Huang 1 Jie Zhang 1 Yizhou Tao 1 Cheng Ji 2 Stanley Aniagu 3 Yan Jiang 4 Tao Chen 5
Affiliations

Affiliations

  • 1 School of Public Health, Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
  • 2 School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China.
  • 3 Toxicology, Risk Assessment, and Research Division, Texas Commission on Environmental Quality, 12015 Park 35 Cir, Austin, TX, USA.
  • 4 School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China. Electronic address: yjiang@suda.edu.cn.
  • 5 School of Public Health, Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China. Electronic address: tchen@suda.edu.cn.
Abstract

Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon, is widely present in the environment. BaP-induced heart defects have been frequently reported, but the underlying molecular mechanisms remain elusive. Here, we found that BaP increased heart malformations in zebrafish embryos in a concentration-dependent manner, which were attenuated by supplementation with either CH223191 (CH), an Aryl Hydrocarbon Receptor (AHR) inhibitor, or N-acetyl-l-cysteine (NAC), a Reactive Oxygen Species (ROS) scavenger. While CH and NAC both inhibited BaP-induced ROS generation, NAC had no effect on BaP-induced AHR activation. We further demonstrated that BaP increased mitochondrial ROS, decreased mitochondrial membrane potential, and caused endogenous Apoptosis, with all these effects being counteracted by supplementation with either CH or NAC. Resveratrol (RSV), a natural AHR antagonist and ROS scavenger, also counteracted the heart malformations caused by BaP. Further experiments showed that RSV attenuated BaP-induced oxidative stress, mitochondrial damage and Apoptosis, but had no significant effect on AHR activation. In conclusion, our findings show that BaP induces oxidative stress via AHR activation, which causes mitochondria-mediated intrinsic Apoptosis, resulting in heart malformations in zebrafish embryos, and that RSV had a protective effect against BaP-induced heart defects mainly by inhibiting oxidative stress rather than through antagonism of AHR activity.

Keywords

AHR; Benzo[a]pyrene; Heart development; Resveratrol; Zebrafish.

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