Naphthalene (NA) is an acute respiratory toxicant and a potential human lung carcinogen. Human exposure to NA is widespread, but human susceptibility to NA toxicity is poorly understood. The verdict on human susceptibility to NA toxicity will have a significant impact on public health, could save many lives, but involves economic costs. The overall theme of this ViCTER program is to study mechanisms of lung toxicity, including tolerance, induced by NA, in order to improve assessment of human lung cancer risks from NA and other related toxicants.
Three Aims are proposed, 1) to define whether NA is a genotoxic carcinogen through a direct mechanism; 2) to test the role of inflammatory cell estrogen production in NA-induced lung toxicity and tolerance; and 3) to identify cellular stress response for NA-induced lung toxicity and tolerance.
These Aims significantly expand the scope of the current project by studying molecular and cellular events downstream of the initial bio-activation step, while the parent grant is focused on the NA bio-activation step. The consortium allows extensive collaborations among the participants, in sharing of animal models, unique skills (e.g., airway dissection), instruments, and molecular, cellular, and genotoxic perspectives. Data from the Aims will provide complementary views of the complex, multi-step process of NA-induced tissue damage and repair that lead to preneoplastic changes and eventual carcinogenesis.
Aim 1 will provide much needed data on whether NA induces stable DNA adducts in the lung in vivo, and will translate our studies to a more human-like model system. The results would drive risk estimation, guide future mechanistic studies, and provide methodology and approaches for testing other carcinogens.
Aim 2 will produce a novel knockout mouse model and establish role of macrophage-derived estrogen in NA-induced hyper proliferative response and tolerance, which precedes development of hyperplastic/dysplastic nodules.
Aim 3 will identify the specific reactive oxygen species damage driving acute lung toxicity and signaling pathways that allow for NA-induced tolerance. The results would provide insight for potential mitigating agents and biomarkers for future translational studies to identify and protect at-risk individuals.
Naphthalene, a lung toxicant and possible human carcinogen, is a ubiquitous environmental pollutant with widespread human exposure. The proposed studies will define the key events that influence the risks of naphthalene-mediated lung toxicity in exposed individuals, and aid in the identification of at-risk individuals for intervention and in te design of effective approaches to disease prevention.
|Van Winkle, Laura S; Kelty, Jacklyn S; Plopper, Charles G (2017) Preparation of Specific Compartments of the Lungs for Pathologic and Biochemical Analysis of Toxicologic Responses. Curr Protoc Toxicol 71:24.5.1-24.5.26|
|Li, Lei; Carratt, Sarah; Hartog, Matthew et al. (2017) Human CYP2A13 and CYP2F1 Mediate Naphthalene Toxicity in the Lung and Nasal Mucosa of CYP2A13/2F1-Humanized Mice. Environ Health Perspect 125:067004|
|Li, Lei; Bao, Xiaochen; Zhang, Qing-Yu et al. (2017) Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice. Drug Metab Dispos 45:977-981|
|Sheng, Jonathan; Wang, Yi; Turesky, Robert J et al. (2016) Novel Transgenic Mouse Model for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure. Chem Res Toxicol 29:797-809|
|Carratt, S A; Morin, D; Buckpitt, A R et al. (2016) Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice. Toxicol Lett 246:35-41|
|Xie, Fang; Ding, Xinxin; Zhang, Qing-Yu (2016) An update on the role of intestinal cytochrome P450 enzymes in drug disposition. Acta Pharm Sin B 6:374-383|
|Turesky, Robert J; Konorev, Dmitri; Fan, Xiaoyu et al. (2015) Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice. Chem Res Toxicol 28:2400-10|
|Pinkerton, Kent E; Harbaugh, Mary; Han, MeiLan K et al. (2015) Women and Lung Disease. Sex Differences and Global Health Disparities. Am J Respir Crit Care Med 192:11-6|
|Kültz, Dietmar; Li, Johnathon; Sacchi, Romina et al. (2015) Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene. Proteomics 15:2655-68|
|Liu, Zhihua; Li, Lei; Wu, Hong et al. (2015) Characterization of CYP2B6 in a CYP2B6-humanized mouse model: inducibility in the liver by phenobarbital and dexamethasone and role in nicotine metabolism in vivo. Drug Metab Dispos 43:208-16|
Showing the most recent 10 out of 11 publications