Metallothionein Induction and Pulmonary Responses to Inhaled Cadmium Chloride in Rats and Mice

Abstract

et al., 1985; NTP, 1993; Nikula et al., 1995;Heinrich et al., Inhaled CdCl 2 is a pulmonary carcinogen in rats but not in mice. 1995). Different strains of rats and mice have been used We hypothesized that pulmonary metallothionein (MT) induction in the different studies with cadmium and solid particles, may be different in both species and thereby may lead to different including the standard strains for chronic NTP bioassays, levels of protection from Cd-induced lung injury. Fisher-344 rats and i.e., Fischer-344 rats and B6C3F 1 mice. The species-specific B6C3F 1 mice were exposed for 4 weeks to CdCl 2 aerosols of 0, 30, lung tumor response was found in all of them and we de- cided, therefore, to use those standard strains in our subseAnimals from each exposure group were terminated at 1, 30, and quent studies. With respect to particle-induced lung tumors 133 days after the end of exposure. The lungs were lavaged for cell in rats, a condition of lung particle overload is thought to and biochemical analyses. Cadmium and MT in lavagate and lung tissue were measured. The retention half-time of pulmonary Cd was be the basis (Oberdörster, 1995), yet this condition does not greater in mice (290 vs 90 days, p õ 0.05). Cd exposure provoked occur after low-level Cd exposure. Thus, the reasons for an inflammatory response which was dose-dependent in both species, these species differences in tumorigenic response to inhaled and while it was only short-lived in rats, it persisted throughout the Cd are not known yet and studying them provides a unique observation period in mice at the high exposure concentrations. Mice opportunity to gain a better understanding of the mechanisms were found to have a greater baseline level of MT (18.04 { 6.96 vs important for Cd carcinogenesis, which may include species 11.7 { 1.98 mg MT/g control lung, p õ 0.05). Mice showed greater differences in metallothionein (MT) induction and turnover. inducibility of MT for a given CdCl 2 exposure concentration; how-MT is a low-molecular-weight protein which is highly ever, both species had a similar relationship between retained pulmoconserved throughout the animal kingdom. The major role nary Cd and MT induction though mice maintained increased MT levels for a longer period of time. The greater pulmonary baseline of MT appears to be its involvement with essential metal MT together with the longer presence of Cd-induced pulmonary MT homeostasis, specifically its physiologic association with may result in greater protection from Cd carcinogenicity in spite of zinc and copper metabolism. It has also been suggested that the greater pulmonary Cd-induced inflammation in mice. ᭧ 1996 MT plays a role in protecting cells from heavy metal toxicity Society of Toxicology(e.g., Cd, Hg) and oxidant stresses and, moreover, that MT may protect cells from the carcinogenic effect of Cd by sequestering Cd. The reader is referred to several reviews Inhaled cadmium (Cd) has been linked with lung cancer in for further details of the role of MT with respect to heavy human...

Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs

“…The cellular and molecular mechanisms of Cd-induced carcinogenesis have been reviewed elsewhere (Waisberg et al 2003;Liu et al 2009;Joseph 2009). As already mentioned, mice having a higher content of MT in the lungs exhibited less Cd-induced toxicity and a lower incidence of lung cancer than rats expressing less MT (Kenaga et al 1996;McKenna et al 1998), whereas Cd-treated MT-null mice exhibited an increased incidence of hepatic carcinoma in comparison with WT mice (Habeebu et al 2000a; reviewed in Klaassen et al 2009). In these cases, sequestering Cd and scavenging ROS during Cd-induced oxidative stress may be the major role of MT, and these functions protect from triggering further events, such as activation of oncogenes, stress-response genes and transcription factors, and inhibition of DNA damage repair, which finally lead to apoptosis (programmed cell death) or uncontrolled cell proliferation (reviewed in: Waisberg et al 2003;Liu et al 2009;Joseph 2009).…”

“…Within the cells, Cd can bind to the existing MT, and can induce synthesis of new MT. Adult rats exhibit less MT in the lung cells than mice, and this phenomenon may explain a higher resistance of mice to toxic and carcinogenic actions of Cd (Hart et al 1995;Kenaga et al 1996;McKenna et al 1998). MT in the lung cells may play a significant role as a ROS scavenger in protection and survival from oxidative injury by various inducers; MT-null mice exhibited much higher senstivity to oxidative stress (Hart et al 2001;Takano et al 2004;Wesselkamper et al 2006).…”

Inhalation Toxicity of Propineb. Part II: Results of Mechanistic Studies in Rats

“…Cellular responses to inhaled Zn-organic substances include the induction of proteins that function to prevent adverse effects, for example, metallothionein (MT). The induction of MT protein by exposure to this metal has been well characterized, and studies have demonstrated an involvement of MT protein in its chelation and detoxification (Cosma et al, 1992;Hart et al, 1995;Kenaga et al, 1996;Coyle et al, 2002). This investigation included the quantification of foamy alveolar macrophages and concomitant phospholipidotic changes (Reasor, 1981) and MT induction in bronchoalveolar cells.…”

Metallothionein induction in the liver, kidney, heart and aorta of cadmium and isoproterenol treated rats

“…It has been shown that MT is efficiently induced in many human and animal organs, particularly in liver tissue, in response to heavy metals such as Zn or Cd (Piscator, 1964;Norberg, 1979;Kagi and Kojima, 1987) and agents which cause oxidative stress such as starvation (Kagi 1991), heat (Lazo et al, 1995), restraint (Hidalgo et al, 1988), Zn-or Cu-deficient diets and inflammation (Kagi and Shaffer, 1988;Brady, 1991). The effect of cadmium, one of the inducers most used, has been investigated widely (Onosaka and Cherian, 1981;Vasconcelos et al, 1996;Kenaga et al, 1996;Iszard et al, 1995;Eaton et al, 1980;Klaassen and Liu, 1998;Minami et al, 1996). Even though the induction of MT has been demonstrated in adult rat liver after injection of high amounts of Cd, little is known about MT induction in other tissues.…”

“…The aim of this study was to investigate the capacity of cadmium and isoproterenol, two well-known inducers of MT in the liver (Brady, 1991;Brady and Helvig, 1984;Lazo et al, 1995;Kenaga et al, 1996;Iszard et al, 1995;Eaton et al, 1980;Klaassen and Liu, 1998;Onosaka and Cherian, 1981), to induce in vivo MT in the heart, aorta and kidney. In order to develop an experimental procedure for enhancing these tissue MT levels, different doses of Cd and isoproterenol and the time of responses were studied.…”