Correlation between cadmium-induced pulmonary carcinogenicity, metallothionein expression, and inflammatory processes: A species comparison

Abstract

There is sufficient evidence for pulmonary carcinogenicity of inhaled Cd compounds in rats whereas no such evidence was found in mice and hamsters; the evidence in humans has been termed limited, indicating significant species differences in pulmonary response to inhaled Cd. We hypothesized that expression of metallothionein (MT) protein in the lung after inhalation of Cd differs between species thereby providing different degrees of sequestration of Cd and protection from its effects. Rats and mice were exposed to 100 μg CdCl2 aerosols/m3 for 4 weeks, and the presence of MT was determined in lung and free lung cell homogenates as well as by immunocytochemistry in lung sections up to 28 days postexposure. In addition, pulmonary inflammatory, and cell proliferative responses were determined. Cd exposure significantly increased MT in homogenates of total lung in both species; however, no significant increase of MT in rat lung tissue after removal of free lung cells by lavage was found whereas MT was still significantly increased in lavaged mouse lung tissue throughout the postexposure time. In contrast, exposed rats showed significant increases in MT in the lavageable lung cells and mice did not. Histochemical analysis of lung sections revealed that mainly the epithelial cells of the bronchi, bronchioli, and alveoli of Cd-exposed mice expressed MT. Mice also exhibited a marked and sustained pulmonary inflammatory and cell proliferative response upon CdCl2 exposure which was not observed in rats. The retained Cd dose per gram lung was about 2-fold greater in mice, which is consistent with a greater deposition efficiency of inhaled Cd-aerosols in mice. The pulmonary Cd retention halftime was about twice as long in mice than in rats. The greater MT induction may offer an explanation for the resistance of mice toward the pulmonary carcinogenic effect of inhaled Cd despite a greater pulmonary inflammatory and cell proliferative effect and a greater retention halftime of lung Cd in this species.