Preneoplastic and neoplastic lesions in the lung, liver and urinary tract of mice exposed to environmental cigarette smoke and UV light since birth

Abstract

It is difficult to reproduce the carcinogenicity of cigarette smoke (CS) in animal models. Recently, we showed that exposure of mice to mainstream CS (MCS) for 120 days, starting immediately after birth, resulted in an early and potent carcinogenic response. In parallel, we implemented studies evaluating intermediate biomarkers and tumors in mice exposed to environmental CS (ECS). To this purpose, we used 263 newborn CD-1 mice born from 27 dams. The whole-body exposure to ECS for 120 days, starting within 12 hr after birth, resulted in an early appearance of preneoplastic lesions in lung, which however tended to attenuate after discontinuing exposure. When the experiment was stopped, after 330 days, the number of lung adenomas was higher in ECSexposed mice as compared to sham-exposed mice, but such increase was statistically significant only in mice co-exposed to smoke and halogen light mimicking solar irradiation. Moreover, exposure to ECS produced extensive histopathological changes, mainly parenchymatous degeneration, in liver. The alterations produced in both lung and liver require that exposure to ECS starts immediately after birth, no effect being observed when exposure started 8 days later. In contrast, induction by ECS of alterations in the urinary tract, such as microadenomas and adenomas in renal pelvis and kidney, papillary hyperplasia of urothelium, and urinary bladder papillomas, were unrelated to the exposure time after birth. The results obtained with ECS cannot be directly compared to those previously obtained with MCS, since the latter involved shorter daily exposures to more massive CS doses.

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

“…The tumorigenic response observed in the present study in neonatal mice exposed to ECS for a longer period of time is more convincing than that observed in our previous study, in which the neonatal mice had been exposed to ECS for 4 months only followed by 7 months in filtered air (23). In fact, in the previous study, the increase of lung tumor yield became statistically significant only in mice coexposed to ECS and light (23).…”

“…In fact, in the previous study, the increase of lung tumor yield became statistically significant only in mice coexposed to ECS and light (23). In any case, carcinogenicity of ECS was much less striking than that obtained with MCS in neonatal mice (20).…”

“…Histopathologic analyses showed that the incidences of bronchial and alveolar hyperplasias and of lung adenomas were increased in ECS-exposed mice compared with sham-exposed mice. However, the tumorigenic response was rather weak (23).…”

Upregulation of stem cell antigen-1 in the lung of neonatal mice exposed to environmental cigarette smoke

“…This conclusion is consistent with our previous findings that exposure to ECS upregulates vascular endothelial growth factors (VEGFs), endothelin, and other angiogenesis-related genes or proteins in rodent tissues, including the fetus liver of transplacentally exposed Swiss mice (14), the lung of A/J mice, both wildtype and P53 mutant (26), and the lung of Sprague-Dawley rats (27). Moreover, exposure of mice to either MCS or ECS induced blood vessel proliferation in the lung as well as in liver and kidney (13,17). Sca-1-positive cells and their derived cells demonstrated significant recruitment to Lewis lung carcinoma in a syngenic bone marrow transplantation mouse model, although these cells were not found to functionally contribute to tumor neovascularization (28).…”

“…When the infant mice became post-weanling, ~5 weeks after birth, they were distinguished by gender. All dams (5-7/ group) and sub-groups of 10 post-weanling mice (5 males and 5 females/group) were deeply anesthesized and sacrificed by cervical dislocation, while all remaining mice were kept alive for a long-term study (17). Body fluids and various organs were collected and used for evaluating a variety of intermediate biomarkers in the hematopoietic system and respiratory tract (6) and in the cardiovascular system (7).…”