DESCRIPTION (provided by applicant): 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.