Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung

• Type of Material: Article
• Authors: Xin Hu, Emory University; Joshua Chandler, Emory University; Soojin Park, Georgia State University; Ken Liu, Emory University; Jolyn Fernandes, Emory University; Michael Orr, Emory University; Matthew R. Smith, Emory University; Chunyu Ma, Emory University; Sang-Mooo Kang, Georgia State University; Karan Uppal, Emory University; Dean Jones, Emory University; Young-Mi Go, Emory University
• Language: English
• Date: 2019-02-01
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.freeradbiomed.2018.12.005
• Title of Journal or Parent Work: FREE RADICAL BIOLOGY AND MEDICINE
• Volume: 131
• Start Page: 209
• End Page: 217
• Grant/Funding Information: This study was supported by NIEHS Grants R01 ES023485 (DPJ and YMG), R21 ES025632 (DPJ and YMG), P30 ES019776 (DPJ) and U2C ES026560 (DPJ), and NIH S10 OD018006 (DPJ).
• Keywords: MWAS; REDOX PROTEOMICS; DYSFUNCTION; Biochemistry & Molecular Biology; URINARY CADMIUM; Redox proteomics; PLASMA; HRM; INFLAMMATION; EXPOSURE; Endocrinology & Metabolism; Environmental toxicant; Science & Technology; METABOLOMICS; OXIDATION; Life Sciences & Biomedicine; VIRUS-INFECTION; Metal; CARDIOLIPIN
• Research Categories: Chemistry, Biochemistry; Health Sciences, Nutrition

Abstract

Cadmium (Cd) causes acute and chronic lung toxicities at occupational exposure levels, yet the impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Health concerns arise because humans do not have an effective Cd elimination mechanism, resulting in a long (10- to 35-y) biological half-life. Previous studies showed increased mitochondrial oxidative stress and cell death by Cd yet the details of mitochondrial alterations by low levels of Cd remain unexplored. In the current study, we examined the impacts of Cd burden at a low environmental level on lung metabolome, redox proteome, and inflammation in mice given Cd at low levels by drinking water (0, 0.2, 0.6 and 2.0 mg Cd/L) for 16 weeks. The results showed that mice accumulated lung Cd comparable to non-smoking humans and showed inflammation in lung by histopathology at 2 mg Cd/L. The results of high resolution metabolomics combined with bioinformatics showed that mice treated with 2 mg Cd/L increased levels of lipids in the lung, accompanied by disruption in mitochondrial energy metabolism. In addition, targeted metabolomic analysis showed that these mice had increased accumulation of mitochondrial carnitine and citric acid cycle intermediates. The results of redox proteomics showed that Cd at 2 mg/L stimulated oxidation of isocitrate dehydrogenase, malate dehydrogenase and ATP synthase. Taken together, the results showed impaired mitochondrial function and accumulation of lipids in the lung with a Cd dose response relevant to non-smokers without occupational exposures. These findings suggest that dietary Cd intake could be an important variable contributing to human pulmonary disorders.