Project Abstract
Electronic cigarettes (e-cig) have been promoted as electronic nicotine (NIC) delivery systems (ENDS) without
the adverse effects of tobacco cigarette smoking (CS). However, recent studies have reported a wide range of
e-cig-induced toxicities with severe inflammatory lung disease observed in e-cig users. While there is a strong
association between CS-induced oxidative stress, inflammation and cancer, this has not been established for
e-cig use. E-cig generate toxic species, including free radicals and reactive acetaldehydes with the levels of
these toxicants increased with increasing device power. These toxic chemicals produce reactive oxygen
species (ROS), which can lead to uncontrolled inflammation and DNA damage with dysregulated cell
proliferation that trigger carcinogenesis. In our chronic mouse e-cig exposure model, we observed that e-cig
aerosol, generated from e-cig liquid containing NIC, induced lung tumors in 50% of the mice studied at 50
weeks of exposure, as first detected by micro-CT imaging. Histopathological examination of the tumors
showed adenocarcinoma or adenoma with focal mixed broncho-alveolar neoplastic and pre-malignant cells.
Superoxide radicals, inflammation, DNA damage and stemness markers were detected in the alveoli and
bronchioles, preceding cancer development at earlier exposure times. The free radicals and high levels of
aldehydes in e-cig aerosol, as well as the NIC derived iminium metabolite, can trigger processes of cellular
ROS generation and this may serve as a central trigger of carcinogenesis. Based on the critical public health
implications of this work, it is imperative to expand these observations to measure the exposure
intensity/duration relationships, and the role of e-cig aerosol free radical levels and NIC in cancer development.
Thus, we will perform longitudinal studies with the requisite group size needed to definitively address the
critical questions: 1) What is the exposure intensity and duration required for lung cancer initiation/progression?
2) What is the incidence rate of e-cig-induced lung cancer? 3) Is cancer onset and/or progression NIC-
dependent? 4) How is it effected by device power and resultant aerosol free radical levels? 5) Is cancer onset
and/or progression gender-dependent? 6) What are the mechanisms by which e-cig exposure triggers ROS
generation and inflammation in the lung? Studies with longitudinal micro-CT, MRI, EPR spectroscopy, EPR-
MRI co-imaging and blood tumor markers followed by biochemical assays and histopathology will determine
the role of exposure duration, ENDS power, NIC, and gender on initiation and/or progression of lung cancer.
ROS generation, lung inflammation and secondary epithelial mesenchymal transition will be evaluated as
triggers or steps leading to carcinogenesis. With knowledge of the role of these mechanisms and evaluation of
inhibitors that block them, we will identify therapeutic interventions that could be used to ameliorate e-cig
induced lung inflammation and carcinogenesis. Thus, this research will provide important insights defining the
carcinogenesis risk of e-cig use, and its underlying exposure-dependent triggers and mechanisms.