Lung Tumorigenicity in A/J and rasH2 Transgenic Mice Following Mainstream Tobacco Smoke Inhalation

Abstract

Hypothesizing that their respective genetic backgrounds would confer an increased sensitivity to lung tumorigenesis, the plausibility of selected rodent models for the inhalation testing of mainstream tobacco smoke (MTS) was evaluated. Strain A/J and rasH2 transgenic (Tg) mice were exposed to MTS from Kentucky 1R4F research cigarettes using either a whole-body or nose-only exposure regimen. The whole-body regimen consisted of a 20-week exposure period [0.200 mg wet total particulate matter/liter (WTPM/l), 6 h/day, 5 days/week]; nose-only dosing proceeded for 28 weeks [0.040, 0.125, or 0.400 mg WTPM/l, 3 h/day, 5 days/week]. Both regimens included a 16-week recovery period. Gross and microscopic examinations of the lungs were used to evaluate tumor formation, with experimental results supporting the following conclusions: 1. Evaluation of MTS-induced tumorigenicity based on gross evaluation versus microscopic confirmation provides strikingly disparate results, indicating that serial sectioning is necessary for a definitive assessment of lung tumors. 2. While the dosing regimens employed do not allow for a definitive comparison, whole-body exposure appeared to be more effective for inducing statistical changes in tumor multiplicity and incidence compared to nose-only exposure. 3. Exposure-related stress, evidenced as reductions in both body weight gain and background tumor formation, represents a potential confounder during inhalation testing of MTS tumorigenicity, with additional investigation warranted to validate the specificity of exposure-related responses. 4. Comparative findings between A/J and rasH2 Tg mice suggest that the former may be overly sensitive to exposure-related stress, potentially influencing tumorigenic responses.

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

“…It may in the future be possible to compare the results obtained under whole-body conditions to those from nose-only exposures to address this potential confounder (Curtin et al, 2004;Haussmann et al, 1998b;Ayres et al, 1994).…”

“…Wholebody exposure of A/J mice to MS for 5 mo followed by 4 mo posttreatment failed to induce the lung tumor yield (D'Agostini et al, 2001). In another study with MS with a similar exposure regimen, the lung tumor multiplicity was increased in MSexposed mice, but a statistically significant difference was only seen after serial step lung section analysis (Curtin et al, 2004). Recently, a statistically significant increase in lung tumor incidence was reported for female Fischer F344 rats after lifetime exposure to MS (Mauderly et al, 2004).…”

A/J Mouse As A Model For Lung Tumorigenesis Caused By Tobacco Smoke: Strengths And Weaknesses

“…It is readily apparent that other mouse strains are afflicted by the same difficulties the A mouse has, i.e., very small differences and large standard deviations between exposed and control animals. Likewise, experiments with genetically manipulated mice so far have not given better results [12,57].…”

“…After a 5-month exposure, the animals were allowed to recover in air for another 4 months before evaluation of the lung tumor response. The same protocol was eventually adopted by three other laboratories [10][11][12]. Table 1 summarizes the available data from experiments that had used this protocol.…”

Modulation by Phenethyl Isothiocyanate and Budesonide of Molecular and Histopathologic Alterations Induced by Environmental Cigarette Smoke in Mice

“…The most convincing medium-term bioassay for ECS tumorigenicity has been developed by Witschi et al (7) and validated in four laboratories, including ours, during the last dozen years (8)(9)(10)(11)(12)(13)(14). This model involves the whole-body exposure of A/J mice or other mouse strains to high doses of ECS for 5 months followed by recovery in filtered air for an additional 4 months.…”