Mechanisms Involved in A/J Mouse Lung Tumorigenesis Induced by Inhalation of an Environmental Tobacco Smoke Surrogate

Abstract

Lung tumors have been reproducibly induced in A/J mice exposed to a surrogate for experimental environmental tobacco smoke (ETSS) in a 5-mo inhalation period followed by 4 mo without further exposure. In order to increase our mechanistic understanding of this model, male mice were whole-body exposed for 6 h/d, 5 d/wk to ETSS with a particulate matter concentration of 100 mg/m(3). Food restriction regimens were included to model or exceed the ETSS-related impairment of body weight development. Half of the mice were pretreated with a single ip injection of urethane to study the effect of the above treatments on lung tumor development induced by this substance. At 5 mo, the tumor response was statistically the same for all groups of non-pretreated mice; however, the expected urethane-induced lung tumorigenesis was significantly inhibited by approximately 25% by ETSS and food restriction. This inhibition was accompanied by a threefold increase in blood corticosterone as a common stress marker for both ETSS and food restriction. At 9 mo, in mice not pretreated, the lung tumor incidence and multiplicity were significantly increased by twofold in the ETSS group; in the urethane-treated groups, the same high tumor multiplicity was reached regardless of previous treatment. The predominant tumor type in all groups was bronchiolo-alveolar adenoma. There was no induction of a specific K-ras mutation pattern by ETSS exposure. These data suggest a stress-induced inhibition of lung tumorigenesis in this model, explaining the need for the posttreatment period.

Indole-3-carbinol Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Plus Benzo(a)pyrene–Induced Lung Tumorigenesis in A/J Mice and Modulates Carcinogen-Induced Alterations in Protein Levels

“…Although calorie restriction is the most potent cancer prevention regimen (24), effects of calorie restriction and reduced body weight gain on lung tumor development have not been extensively studied. In one study, restriction of food intake by 40% and 60% reduced body weight by about 23% and 34%, respectively, but lung tumor multiplicity was reduced only by 25% in both groups (25).…”

Chronic Nose-only Inhalation Study in Rats, comparing Room-aged Sidestream Cigarette Smoke and Diesel Engine Exhaust

“…The A/J model has several poorly understood properties: Strong carcinogens caused a dose-related increase in lung tumor multiplicity, but concomitant exposure to ETS surrogate postponed lung tumor development during the exposure period (Witschi et al, 1997). In addition, commonly used tumor inhibitors were not effective in this model (Witschi, 2000), and stress hormones seem to modulate the outcome of tumorigenicity studies (Stinn et al, 2005). Because it is not currently known which aspect of the human carcinogenicity process is addressed by the A/J model, mechanistic studies are currently underway in several laboratories.…”

“…However, at 20 times higher doses, an ETS surrogate (whole smoke as well as gas phase) and MS exposure led to increased lung tumor multiplicity (Curtin et al, 2004;Stinn et al, 2005;Witschi et al, 2004). Studies using DEE at such exaggerated doses are not feasible because of technical limitations (Reed et al, 2004).…”

Secondhand Tobacco Smoke

“…Several studies reported no increase in lung tumour incidence or multiplicity in mice exposed to simulated secondhand tobacco smoke for 5-9 months and killed immediately thereafter (Witschi et al, 1995(Witschi et al, , 1997aFinch et al, 1996). It was suggested that the lack of tumour response in simulated secondhand tobacco smoke-exposed mice might be due to treatment-induced stress (as determined by the increased plasma corticosterone level) that has been shown to attenuate lung tumorigenesis (Stinn et al, 2005a).…”