Transcriptomics of single dose and repeated carbon black and ozone inhalation co-exposure highlight progressive pulmonary mitochondrial dysfunction

Particle and Fibre Toxicology

Vince Castranova¹  William T. Goldsmith²  Nairrita Majumder²  Jack R. Harkema³  Quincy A. Hathaway⁴  Amina Kunovac⁴  John M. Hollander⁴  Salik Hussain⁵  Mark V. Pinti⁶ 

[1] Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA;Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA;Department of Physiology and Pharmacology, West Virginia University School of Medicine, PO Box 9229, 64 Medical Center Drive, 26506-9229, Morgantown, WV, USA;Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA;Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV, USA;Mitochondria, Metabolism and Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA;Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA;Mitochondria, Metabolism and Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA;Center for Inhalation Toxicology (iTOX), West Virginia University School of Medicine, Morgantown, WV, USA;Department of Physiology and Pharmacology, West Virginia University School of Medicine, PO Box 9229, 64 Medical Center Drive, 26506-9229, Morgantown, WV, USA;Mitochondria, Metabolism and Bioenergetics Working Group, West Virginia University School of Medicine, Morgantown, WV, USA;West Virginia University School of Pharmacy, Morgantown, WV, USA;

关键词: Ozone;    Carbon black;    Ultrafine/nanoparticle;    Inhalation toxicology;    Mitochondria;    Genomics;    Lung;    Environmental exposure;   

DOI  :  10.1186/s12989-021-00437-8

来源: Springer

【 摘 要 】

BackgroundAir pollution is a complex mixture of particles and gases, yet current regulations are based on single toxicant levels failing to consider potential interactive outcomes of co-exposures. We examined transcriptomic changes after inhalation co-exposure to a particulate and a gaseous component of air pollution and hypothesized that co-exposure would induce significantly greater impairments to mitochondrial bioenergetics. A whole-body inhalation exposure to ultrafine carbon black (CB), and ozone (O3) was performed, and the impact of single and multiple exposures was studied at relevant deposition levels. C57BL/6 mice were exposed to CB (10 mg/m3) and/or O3 (2 ppm) for 3 h (either a single exposure or four independent exposures). RNA was isolated from lungs and mRNA sequencing performed using the Illumina HiSeq. Lung pathology was evaluated by histology and immunohistochemistry. Electron transport chain (ETC) activities, electron flow, hydrogen peroxide production, and ATP content were assessed.ResultsCompared to individual exposure groups, co-exposure induced significantly greater neutrophils and protein levels in broncho-alveolar lavage fluid as well as a significant increase in mRNA expression of oxidative stress and inflammation related genes. Similarly, a significant increase in hydrogen peroxide production was observed after co-exposure. After single and four exposures, co-exposure revealed a greater number of differentially expressed genes (2251 and 4072, respectively). Of these genes, 1188 (single exposure) and 2061 (four exposures) were uniquely differentially expressed, with 35 mitochondrial ETC mRNA transcripts significantly impacted after four exposures. Both O3 and co-exposure treatment significantly reduced ETC maximal activity for complexes I (− 39.3% and − 36.2%, respectively) and IV (− 55.1% and − 57.1%, respectively). Only co-exposure reduced ATP Synthase activity (− 35.7%) and total ATP content (30%). Further, the ability for ATP Synthase to function is limited by reduced electron flow (− 25%) and translation of subunits, such as ATP5F1, following co-exposure.ConclusionsCB and O3 co-exposure cause unique transcriptomic changes in the lungs that are characterized by functional deficits to mitochondrial bioenergetics. Alterations to ATP Synthase function and mitochondrial electron flow underly a pathological adaptation to lung injury induced by co-exposure.

【 授权许可】

CC BY