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Genetic Susceptibility to Thirdhand Smoke Effects

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Bo Hang, Ph.D.; M.D.
Award Cycle: 2019 (Cycle 28) Grant #: 28PT-0076 Award: $904,744
Subject Area: Environmental Exposure/Toxicology
Award Type: Integrated Research Project

Initial Award Abstract
Thirdhand smoke (THS) has gained public attention in recent years but its health impact is largely unknown. During the last six years of research within the Consortium, we have shown that exposure to THS or its specific chemical constituent NNA causes damage to cellular genetic material (DNA) with covalent binding, changes in cellular metabolites and tumor-forming properties; exposure at early age in mice resulted in significant developmental, immunological abnormalities and lung cancer formation. The goal of this sub-project is to study genetic factors for individual susceptibility to THS-induced effects, especially tumor development, and to develop biomarkers in animal studies and human samples, with an emphasis on carrying out laboratory studies that will help in translating findings to human practice and the public. We hypothesize that (I) genetic susceptibility influences disease risk of THS exposure; (2) the NNA-induced deoxyguanosine (dG)-binding adduct is a biomarker (a tracer of harm inside the body) for THS exposure and the adduct level is associated with disease risk. We will employ an integrative systems biology approach for this project by using the generally diverse Collaborative Cross (CC) mouse resource that recapitulates the genetic diversity of the human population. In Aim 1 we will first investigate the tumor incidence across 20 THS-exposed CC strains and then perform genetic analysis to identify individual genetic susceptibility to these biological and health effects of THS exposure. Translational implications include (1) developing useful animal models for predicting health risk of THS exposure in human population; (2) using genome-wide association analysis together with RNA-sequencing, we will identify gene biomarkers for genetic susceptibility to THS effects, and find related human homologs of these mouse genes that can be used to predict and study human disease risk induced by THS; and (3) identify molecular mechanism for THS-induced disease for ultimately developing strategies for disease prevention and treatment. In Aim 2, we will develop a quantitative LC-MS/MS method for the validation of the NNA adduct 1,N2-NNA-dG as a specific biomarker for THS exposure and indicator of cancer risk in both animals and humans. We will determine whether iso-NNAC is an NNA metabolite in vitro with human liver homogenates. For biomarkers we will perform proof-of-concept studies using available human specimen. Such translational studies will provide novel evidence of THS impact on cancer development in general population and how individual genetics affect vulnerability, and to use both basic science and translational findings to reduce the THS impact in exposed humans and to support policy modeling and development.