Cadmium-induced mRNA expression of Hsp32 is augmented in metallothionein-I and -II knock-out mice.

Cadmium is toxic and carcinogenic to humans and animals. The testis and lung are the target organs for cadmium carcinogenesis. Heat shock proteins (HSPs) as well as metallothionein (MT) and glutathione (GSH) play an important role in protection against its toxicity. HSP32, also known as heme oxygenase-1, is a 32-kDa protein induced by heme, heavy metals, oxidative stresses, and heat. We investigated expression of the Hsp32 gene of various organs (the liver, lung, heart, stomach, kidney, and testis) in transgenic mice deficient in the MT-I and -II genes (MT-KO) and in control mice (MT-W) after an injection of cadmium chloride (CdCl2). Survival of MT-W mice after a subcutaneously injection of CdCl2 was higher than that of MT-KO mice, while no significant difference was observed in the level of GSH in each organ between MT-W and MT-KO mice. Northern blot analysis showed that the MT-I mRNA was more extensively induced in the liver, kidney, and heart than other organs 6 h after an injection of CdCl2 (30 micromol/kg body wt, sc). There was little increase of the MT-I mRNA in the testis when induced by CdCl2. Expression of the Hsp32 gene in the liver and kidney in response to CdCl2 was more extensively augmented in MT-KO mice than in MT-W mice. In the lung and testis, there was little induction and no augmentation in expression of the Hsp32 gene induced by CdCl2 in both MT-W and MT-KO mice. In the stomach, there was little induction of the Hsp32 mRNA in MT-W mice, but was increased in MT-KO mice. Immunohistochemical staining revealed that the HSP32 protein was strongly expressed in the kidney and liver of MT-W mice 24 h after an injection of CdCl2 (20 micromol/kg body wt, sc), while the expression of HSP32 protein was not increased in the testis. In metabolically active organs such as the liver and kidney, expression of the Hsp32 gene as well as the MT-I gene was extensively induced by cadmium in MT-W mice, and more eminently induced in MT-KO mice. We suggest that organs of low stress response to cadmium such as the testis and lung may be vulnerable target sites for cadmium toxicity and carcinogenesis.