Title: Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung.
Authors: Hu, Xin; Chandler, Joshua D; Park, Soojin; Liu, Ken; Fernandes, Jolyn; Orr, Michael; Smith, M Ryan; Ma, Chunyu; Kang, Sang-Moo; Uppal, Karan; Jones, Dean P; Go, Young-Mi
Published In Free Radic Biol Med, (2019 02 01)
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.
PubMed ID: 30529385
MeSH Terms: Animals; Cadmium Chloride/toxicity*; Carnitine/metabolism; Citric Acid Cycle/drug effects*; Drinking Water/administration & dosage; Isocitrate Dehydrogenase/metabolism; Lipid Metabolism/drug effects*; Lung/drug effects; Lung/metabolism; Lung/pathology; Malate Dehydrogenase/metabolism; Male; Metabolome; Mice; Mice, Inbred C57BL; Mitochondria/drug effects*; Mitochondria/metabolism; Mitochondrial Proton-Translocating ATPases/metabolism; Oxidation-Reduction; Oxidative Stress; Pneumonia/chemically induced; Pneumonia/metabolism*; Pneumonia/pathology; Proteome/metabolism; Water Pollutants, Chemical/toxicity*