Cytoplasmic-nuclear redox signaling: Disruption by dietary cadmium levels Our recent research on the redox dependence of the cysteine proteome shows that levels of cadmium (Cd) present in the American diet stimulate translocation of thioredoxin-1 (Trx1) into cell nuclei and potentiate inflammatory signaling by NF-?B. These levels are below recognized toxic levels and so the results must be approached with caution. None-the-less, the finding has substantial health implications because inflammation contributes to many chronic diseases. Epidemiologic studies associate low-level environmental Cd to the risk of lung cancer, emphysema and other lung diseases, as well as heart failure and stroke, osteoporosis, anemia, reproductive failure and other cancers;poor mechanistic understanding of low-level Cd and confounding variables limit use of these findings in risk assessment or policy decisions. The purpose of this basic science project is to improve mechanistic understanding by testing the central hypothesis that dietary Cd levels potentiate inflammatory lung disease through disruption of the redox proteome associated with actin cytoskeleton control and nuclear function. The project is based upon recent advances in redox-sensitive cytoplasmic-nuclear signaling, our recent data on redox proteomics of low-dose Cd and an extensive literature on biologic effects of Cd. We will use molecular and cellular methods along with mass spectrometry-based redox proteomics to study Cd disruption of cytoplasmic-nuclear redox systems in in vitro and in vivo lung disease models. We specifically focus on the lung because of the central role of redox-sensitive transcription in lung function, especially inflammation and fibrosis, and because dietary Cd effects can be exacerbated by Cd inhalation.
Aim 1 is to investigate mechanisms of low-dose Cd on the redox proteome. We will test the hypothesis that Cd effect on actin cytoskeleton proteins causes translocation of Trx1 into nuclei and stimulates activity of transcription factors regulating inflammation and fibrotic responses.
Aim 2 is to determine whether low-dose Cd potentiates profibrosis and proinflammation mechanisms by affecting nuclear redox signaling. Studies will use in vitro cell models of pulmonary diseases using bleomycin and H1N1 influenza virus for profibroitc and inflammatory agents, respectively.
Aim 3 uses mouse models of pulmonary disease paralleling Aim 2, to test whether low-dose Cd potentiates inflammatory and fibrotic signaling by affecting nuclear redox control systems and transcription factor activity in vivo;
the Aim also includes studies of human lung samples to allow direct calibration of model systems to human lung Cd contents. These results will show whether Cd exposures at levels found in the American diet adversely impacts the mechanisms of cytoplasmic-nuclear cell signaling of inflammation and fibrosis. If so, the global proteomic and transcriptomic data, along with calibrated Cd-dependence of markers of inflammation and fibrosis, will provide essential data for targeted evaluation of dietary Cd health risks in humans.

Public Health Relevance

Cadmium is an important element used in batteries and other commercial applications. Research shows that humans are exposed to low levels of cadmium in food, drinking water and other environmental sources. This project is to use powerful new methods to study impact of these low cadmium exposures on lung biology and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES023485-01A1
Application #
8761505
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Heacock, Michelle
Project Start
2014-07-01
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Jones, Dean P (2016) Hydrogen peroxide and central redox theory for aerobic life: A tribute to Helmut Sies: Scout, trailblazer, and redox pioneer. Arch Biochem Biophys 595:13-8
Fernandes, Jolyn; Hao, Li; Bijli, Kaiser M et al. (2016) Manganese Stimulates Mitochondrial H2O2 Production in SH-SY5Y Human Neuroblastoma Cells over Physiologic as well as Toxicologic Range. Toxicol Sci :
Collins, Jeffrey M; Kempker, Russell R; Ziegler, Thomas R et al. (2016) Metabolomics and Mycobacterial Disease: Don't Forget the Bioinformatics. Ann Am Thorac Soc 13:141-2
Rao, Anuradha; Kosters, Astrid; Mells, Jamie E et al. (2016) Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 8:357ra122
Jones, Dean P; Walker, Douglas I; Uppal, Karan et al. (2016) Metabolic Pathways and Networks Associated With Tobacco Use in Military Personnel. J Occup Environ Med 58:S111-6
Jones, Dean P (2016) Sequencing the exposome: A call to action. Toxicol Rep 3:29-45
Chandler, Joshua D; Hu, Xin; Ko, Eun-Ju et al. (2016) Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice. Am J Physiol Regul Integr Comp Physiol 311:R906-R916
Sueblinvong, Viranuj; Mills, Stephen T; Neujahr, David C et al. (2016) Nuclear Thioredoxin-1 Overexpression Attenuates Alcohol-Mediated Nrf2 Signaling and Lung Fibrosis. Alcohol Clin Exp Res 40:1846-56
Chandler, Joshua D; Wongtrakool, Cherry; Banton, Sophia A et al. (2016) Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice. Physiol Rep 4:
Jones, Dean P; Sies, Helmut (2015) The Redox Code. Antioxid Redox Signal 23:734-46

Showing the most recent 10 out of 22 publications