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UC Riverside Electronic Theses and Dissertations (2022)

Abstract of the Dissertation

Clinical Investigations on Human Health Responses to Thirdhand Smoke and Electronic Cigarette Exposure by Shane Sakamaki-Ching Doctor of Philosophy, Graduate Program in Cell, Molecular, and Developmental Biology University of California, Riverside, March 2022 Dr. Prue Talbot, Chairperson

Background: Cigarette smoking causes diseases such as cancer, heart disease, and stroke. The diseases associated with electronic cigarettes (ECs) are not as well understood. Cigarette smoking leaves a residue, thirdhand smoke (THS), on indoor surfaces. The health effects of THS on humans is limited to one study. Our purposes were to: (1) identify urinary biomarkers of potential harm and exposure and correlate these to metal concentrations in urine from cigarette smokers and EC users; (2) determine the responses of humans dermally exposed to THS; and (3) identify molecular changes in keratinocytes exposed to THS extract.

Methods: In Chapter 1, urine from non-smokers, EC users, and cigarette smokers was evaluated for biomarkers of exposure, effect, and potential harm. In Chapter 2, human participants were exposed dermally to clothing impregnated with filtered clean air or THS; their urine was analyzed for biomarkers of exposure and harm, and their plasma was analyzed using proteomics. In Chapter 3, molecular responses of keratinocytes to extracts from THS impregnated fabric were determined.

Results: In Chapter #1, urinary biomarkers of exposure, effect, and potential harm were elevated in EC users and cigarette smokers; increased EC usage was correlated with elevated metal concentrations, which correlated with oxidative DNA damage. In Chapter #2, THS-exposure significantly elevated urinary 8-OHdG, 8-isoprostane, and protein carbonyls and activated pathways associated with inflammation, oxidative stress, and skin disease initiation. In Chapter #3, THS in keratinocytes caused proinflammation, and oxidative stress, mitochondrial damage, and elevated keratin 5 levels.

Conclusion: Cigarette smoking and EC vaping elevated DNA damage by oxidization which was correlated with total metal concentrations in the urine of cigarette smokers and EC vapers, a change which may lead to disease. Dermal THS exposure significantly increased oxidative damage to DNA, lipids, and proteins in humans. Inflammation was elevated at 3 hours and persisted for 22 hours, which could in the long-term lead to disease. Keratinocytes exposed to THS extracts had elevated molecular risk factors for developing inflammatory skin diseases, including cancer. THS-induced responses in keratinocytes were similar to those in cigarette smokers, implicating THS as an environmental hazard that should be monitored.

    Cover page: Clinical Investigations on Human Health Responses to Thirdhand Smoke and Electronic Cigarette ExposureCreative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    UC Riverside Previously Published Works (2022)

    Background

    Thirdhand smoke (THS) exposure correlated with significant metabolism of carcinogenic chemicals and the potential to cause detrimental health effects. Human harm research of THS exposure is limited to one other study and overall, there is a general lack of knowledge of the human health responses to THS exposure.

    Methods

    This was a clinical investigation to evaluate the health effects of 3-h dermal THS exposure from urine and plasma. 10 healthy, non-smoking subjects were recruited for dermal exposure for 3 h exposed to clothing impregnated with filtered clean air or THS. Exposures to clean air or THS occurred 20-30 days apart.

    Findings

    In THS-exposed group, there was a significant elevation of urinary 8-OHdG, 8-isoprostane, protein carbonyls. The THS 3-h exposure identified proteomics pathways of inflammatory response (p=2.18 × 10-8), adhesion of blood cells (p=2.23 × 10-8), atherosclerosis (p=2.78 × 10-9), and lichen planus (p=1.77 × 10-8). Nine canonical pathways were significantly activated including leukocyte extravasation signaling (z-score=3.0), and production of nitric oxide and reactive oxygen in macrophages (z-score=2.1). The THS 22-h proteomics pathways revealed inflammation of organ (p=3.09 × 10-8), keratinization of the epidermis (p=4.0 × 10-7), plaque psoriasis (p=5.31 × 10-7), and dermatitis (p=6.0 × 10-7). Two activated canonical pathways were production of nitric oxide and reactive oxygen in macrophages (z-score=2.646), and IL-8 signaling (z-score=2.0).

    Interpretation

    This is a clinical study demonstrating that acute dermal exposure to THS mimics the harmful effects of cigarette smoking, alters the human plasma proteome, initiates mechanisms of skin inflammatory disease, and elevates urinary biomarkers of oxidative harm.

    Funding

    Funding was provided by the Tobacco Related Disease Research Program (TRDRP) 24RT-0037 TRDRP, 24RT-0039 TRDRP, and 28PT-0081 TRDRP.
      Cover page: Dermal thirdhand smoke exposure induces oxidative damage, initiates skin inflammatory markers, and adversely alters the human plasma proteome
      • Article
      • Peer Reviewed
      UC Riverside Previously Published Works (2020)

      Objectives

      To determine if urinary biomarkers of effect and potential harm are elevated in electronic cigarette users compared with non-smokers and if elevation correlates with increased concentrations of metals in urine.

      Study design and setting

      This was a cross-sectional study of biomarkers of exposure, effect and potential harm in urine from non-smokers (n=20), electronic cigarette users (n=20) and cigarette smokers (n=13). Participant's screening and urine collection were performed at the Roswell Park Comprehensive Cancer Center, and biomarker analysis and metal analysis were performed at the University of California, Riverside.

      Results

      Metallothionein was significantly elevated in the electronic cigarette group (3761±3932 pg/mg) compared with the non-smokers (1129±1294 pg/mg, p=0.05). 8-OHdG (8-hydroxy-2'-deoxyguanosine) was significantly elevated in electronic cigarette users (442.8±300.7 ng/mg) versus non-smokers (221.6±157.8 ng/mg, p=0.01). 8-Isoprostane showed a significant increase in electronic cigarette users (750.8±433 pg/mg) versus non-smokers (411.2±287.4 pg/mg, p=0.03). Linear regression analysis in the electronic cigarette group showed a significant correlation between cotinine and total metal concentration; total metal concentration and metallothionein; cotinine and oxidative DNA damage; and total metal concentration and oxidative DNA damage. Zinc was significantly elevated in the electronic cigarette users (584.5±826.6 µg/g) compared with non-smokers (413.6±233.7 µg/g, p=0.03). Linear regression analysis showed a significant correlation between urinary zinc concentration and 8-OHdG in the electronic cigarette users.

      Conclusions

      This study is the first to investigate biomarkers of potential harm and effect in electronic cigarette users and to show a linkage to metal exposure. The biomarker levels in electronic cigarette users were similar to (and not lower than) cigarette smokers. In electronic cigarette users, there was a link to elevated total metal exposure and oxidative DNA damage. Specifically, our results demonstrate that zinc concentration was correlated to oxidative DNA damage.
        Cover page: Correlation between biomarkers of exposure, effect and potential harm in the urine of electronic cigarette users
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