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Translating mouse exposure studies into human health effects

Institution: University of California, Riverside
Investigator(s): Manuela Martins-Green, Ph.D.
Award Cycle: 2019 (Cycle 28) Grant #: 28PT-0080S Award: $719,347
Subject Area: Environmental Exposure/Toxicology
Award Type: Integrated Research Project

Initial Award Abstract
This application is a logical extension of our work in the 2nd phase of Consortium funding and responds to the current RFA: (1) 'Human subject Translatability of THS markers or biomarkers' and (2) Human exposure studies Our data show that THS-exposed mice have alterations in multiple organ systems and excrete levels of a tobacco-specific carcinogen that are similar to those found in children exposed to SHS (and consequently to THS). Specifically, (1) In liver, causes increased lipid levels causing fatty liver disease, a precursor to cirrhosis and cancer and a contributor to heart disease. (2) In lung, it stimulates fibrosis and high levels of inflammatory molecules, with implications for diseases such as asthma. (3) In wounded skin, it causes problems found in the poor healing of surgical incisions in human smokers. (4) In behavior, THS-exposed mice become hyperactive. Also, (5) we determined the minimum exposure time and dose of THS needed to detect differences in specific biological markers of harm to health. (6) We have also shown that THS-exposure affects insulin metabolism. (7) We also found that exposure to THS in utero and during lactating results in smaller litters and smaller mice. The goals of this research project are: Project 1 Determine dose-dependent effects of THS exposure in mice at different ages; Project 2, identifying effects of THS-exposure damages mitochondrial DNA so that future studies can be performed to determine whether that damage is passed on to the next generation. Mitochondria are critical parts of cells because they produce the energy the cells use to function; Project 3 perform Proof-of-Concept studies in children using Biological Markers of Harm induced by THS exposure that we identified in mouse tissue, serum and urine. We will also measure levels of cotinine in the saliva of the parents and their children measured in the Dr.'s office during the visit to provide in real-time feedback to the parent/caregiver so that smoke cessation measure could be put in place. Significance/innovation: This is the first-time research will be done to determine whether the effects of THS are age dependent to determine if younger ages more susceptible to the exposure. We will also show if the parts of the cell that are critical to proper function are affected by THS exposure. We will detect cotinine levels in the saliva for doctors to advise parents in real-time that their children are being exposed to THS and can be affected by their smoking. Translational impact: The impact of these studies is three-fold. We will: (a) determine whether younger ages are more susceptible to THS-exposure; (b) determine whether THS exposure leads to malfunction of cells in the body that can lead to disease; (c) provide toxicological evidence to design clinical trials that can be performed in humans; (d) help in the design of policies that mitigate exposure of infants, children, the elderly and workers in places where smoking is allowed.