Towards the validation of a lung tumorigenesis model with mainstream cigarette smoke inhalation using the A/J mouse

Abstract

A generally accepted and validated laboratory model for smoking-associated pulmonary tumorigenesis would be useful for both basic and applied research applications, such as the development of early diagnostic endpoints or the evaluation of modified risk tobacco products, respectively. The A/J mouse is susceptible for developing both spontaneous and induced lung adenomas and adenocarcinomas, and increased lung tumor multiplicities were also observed in previous cigarette smoke inhalation studies. The present study was designed to collect data useful towards the validation of an 18-month mainstream smoke (MS) inhalation model. Male and female A/J mice were exposed whole-body at three MS concentration levels for 6h/day, and the results were compared to a previous study in the same laboratory and with a similar design. A linear MS concentration-dependent increase in lung tumorigenesis was observed with similar slopes for both sexes and both studies and a maximal 5-fold increase in multiplicity beyond sham control. The minimal detectable difference in lung tumor multiplicity for the current study was 37%. In the larynx, papillomas were detectable in all MS-exposed groups in a non-concentration dependent manner. No other extra-pulmonary MS-dependent neoplastic lesions were found. Gene expression signatures of lung tumor tissues allowed a clear differentiation of sham- and high dose MS-exposed mice. In combination with data from previous smoke inhalation studies with A/J mice, the current data suggest that this model for MS inhalation-induced pulmonary tumorigenesis is reliable and relevant, two crucial requirements towards validation of such a model.

Lung tumor promotion by chromium-containing welding particulate matter in a mouse model

“…It also continues to be useful for evaluation of chemointerventive agents of lung neoplasia [24,26,27]. This strain is susceptible to both chemically-induced and spontaneous lung adenomas compared to the resistant B6 mouse [23].…”

Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model

“…The current study was a sub-study of an A/J mouse validation study, and its design has been previously described in detail (Stinn et al , 2013a ; Stinn et al , 2013b ). Briefly, male A/J mice aged between 8 and 12 weeks received whole-body exposure to MS at concentrations of 75, 150, and 300 mg/m 3 of total particulate matter (TPM) (animal groups MS-75, MS-150, and MS-300, respectively) from the 3R4F reference cigarette (University of Kentucky, Lexington, KY, USA) for 6 h/day and 5 days/week for 18 months.…”

“…Histopathologic evaluation was conducted on mice exposed to air (sham control, N=27) and to MS of the 3R4F cigarette smoke, (N=33, 37, and 34 mice of the MS-75, MS-150 and MS-300 groups, respectively) by a certified pathologist, who was blinded to the individual treatment of the animals, as reported previously (Stinn et al , 2013a ).…”

“…Although a considerable number of studies failed to produce significant increases of either tumor incidence or multiplicity in A/J mice that were chronically exposed to cigarette smoke, other studies, including those that were performed by our group, successfully demonstrated significantly more lung tumors following exposure to MS or the combination of MS and SS relative to sham (Stinn et al , 2010 ; Stinn et al , 2005 ). Moreover, an 18-month MS exposure regimen has been shown to be sufficient in eliciting a concentration-dependent lung tumor response (Stinn et al , 2013a ). This is in contrast to the previously reported exposure regimen that included a 5-month exposure followed by a 4-month post-inhalation period which was thought to be required and optimal for the full development of cigarette smoke-associated pulmonary lesions in this mouse model (Witschi, 2005 ).…”

Pharmacological Modulation of Lung Carcinogenesis in Smokers: Preclinical and Clinical Evidence

“…This drawback depends on the general difficulty to test complex mixtures rather than individual compounds in experimental settings as well as on various problems inherent to exposure by inhalation of rodents, such as the different anatomy of the upper respiratory tract and the fact that rodents are obligate nose-only breathers. As a consequence, most carcinogenicity studies in a variety of animal species showed that inhaled CS is either negative or just weakly positive [7–10]. Our attempts to use transgenic mice, such as p53 mutant mice [11], failed to enhance the carcinogenic response.…”