Circulatory metabolites trigger ex vivo arterial endothelial cell dysfunction in population chronically exposed to diesel exhaust

Particle and Fibre Toxicology

Shuguang Leng¹  Xiaoya Ji²  Jianzhong Zhang²  Jinling Gao²  Jinglong Tang²  Wenting Cheng²  Yanting Li²  Yuxin Zheng²  Matthew J. Campen³  Dunqiang Ren⁴  Nathaniel Rothman⁵  Qing Lan⁵  Huanhuan Pang⁶  Zeping Hu⁶ 

[1] Department of Internal Medicine, School of Medicine, University of New Mexico;Department of Occupational and Environmental Health, School of Public Health, Qingdao University;Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico;Department of Respiratory Medicine, Affiliated Hospital of Medical College of Qingdao University, Qingdao University;Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health;School of Pharmaceutical Sciences, Tsinghua University;

关键词: Diesel exhaust;    Endothelial cell dysfunction;    Circulatory metabolites;    Cardiovascular disease risk;   

DOI  :  10.1186/s12989-022-00463-0

来源: DOAJ

【 摘 要 】

Abstract Background Chronic exposure to diesel exhaust has a causal link to cardiovascular diseases in various environmental and occupational settings. Arterial endothelial cell function plays an important role in ensuring proper maintenance of cardiovascular homeostasis and the endothelial cell dysfunction by circulatory inflammation is a hallmark in cardiovascular diseases. Acute exposure to diesel exhaust in controlled exposure studies leads to artery endothelial cells dysfunction in previous study, however the effect of chronic exposure remains unknown. Results We applied an ex vivo endothelial biosensor assay for serum samples from 133 diesel engine testers (DETs) and 126 non-DETs with the aim of identifying evidence of increased risk for cardiovascular diseases. Environmental monitoring suggested that DETs were exposed to high levels of diesel exhaust aerosol (282.3 μg/m3 PM2.5 and 135.2 μg/m3 elemental carbon). Surprisingly, chronic diesel exhaust exposure was associated with a pro-inflammatory phenotype in the ex vivo endothelial cell model, in a dose-dependent manner with CCL5 and VCAM as most affected genes. This dysfunction was not mediated by reduction in circulatory pro-inflammatory factors but significantly associated with a reduction in circulatory metabolites cGMP and an increase in primary DNA damage in leucocyte in a dose-dependent manner, which also explained a large magnitude of association between diesel exhaust exposure and ex vivo endothelial biosensor response. Exogenous cGMP addition experiment further confirmed the induction of ex vivo biosensor gene expressions in endothelial cells treated with physiologically relevant levels of metabolites cGMP. Conclusion Serum-borne bioactivity caused the arterial endothelial cell dysfunction may attribute to the circulatory metabolites based on the ex vivo biosensor assay. The reduced cGMP and increased polycyclic aromatic hydrocarbons metabolites-induced cyto/geno-toxic play important role in the endothelial cell dysfunction of workers chronic exposure to diesel exhaust.

【 授权许可】

Unknown