metallothionein and Thymus-Neoplasms

In order to elucidate the involvement of metallothionein (MT) in radiation carcinogenesis, we examined the susceptibility of MT-I/II null mice to carcinogenesis and oxidative DNA damage resulting from X-irradiation. Eight-week-old female MT-I/II null mice and wild-type mice were exposed to whole-body X-irradiation at doses of 1.0, 1.5 or 2.0 Gy once a week for 6 weeks. Incidence of thymic lymphoma was determined at 24 weeks after the first exposure to X-irradiation. The frequency of thymic lymphomas induced by X-irradiation (at 1.5 and 2.0 Gy) was significantly higher in MT-I/II null mice than in wild-type mice. In addition, although the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were increased in the serum and urine of both strains of mice 24 hr after exposure to a single bout of whole body X-irradiation, these increases were significantly greater in the MT-I/II null mice than in the wild-type mice. Thus, the present results suggest that MT plays a protective role against carcinogenesis and oxidative DNA damage caused by X-irradiation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Deoxyguanosine; DNA Damage; Female; Lymphoma; Metallothionein; Mice; Mice, Knockout; Neoplasms, Radiation-Induced; Thymus Neoplasms; X-Rays

Metallothionein functions as a radical scavenger protecting cells from the indirect effect of radiations. We investigated the effect of bismuth nitrate, an efficient inducer of metallothionein, on acute and late effects of radiation in mice. Metallothionein contents were examined in several organs after the administration of bismuth nitrate. The content in bone marrow increased 2-fold in the treated as compared to the control mice. This treatment protected irradiated mice from bone marrow death and increased the number of endogenous spleen colonies. The metallothionein content in the ileum did not change after treatment with bismuth nitrate. Mice were not protected by bismuth nitrate when exposed to 9 Gy of X-rays. This suggests that this agent does not protect from gastrointestinal death. The incidence of X-ray-induced thymic lymphomas was lowered by the administration of bismuth nitrate in mice exposed to four fractionated doses of 1.3 Gy of X-rays. These results indicate that bismuth nitrate effectively modified both acute and late effects of X-rays by inducing metallothionein in the target tissues.

Topics: Animals; Bismuth; Metallothionein; Mice; Mice, Inbred C57BL; Neoplasms, Radiation-Induced; Nitrates; Radiation-Protective Agents; Thymoma; Thymus Neoplasms

Mouse thymus and some thymus-derived cell lines do not normally express metallothioneins (MTs), but these genes can be activated in at least one line (S49) by treatment with carcinogens. Almost half of cells converted to MT expression by carcinogens co-express both MT-I and MT-II, and levels of steady-state RNA from those activated genes are coordinately regulated by Cd. Nuclear transcription studies demonstrate that gene activation and regulation occurs at the level of transcription. Demethylation occurs 5' to each gene in lines expressing MTs. We detected no insertions, deletions, amplifications or rearrangements of the MT locus in lines expressing MTs.

Topics: Carcinogens; Cell Line; Chromosome Mapping; DNA; Gene Expression Regulation; Lymphoma; Metallothionein; Methylation; RNA, Messenger; Thymus Neoplasms; Transcription, Genetic; Transcriptional Activation

Using an immunofluorescence (IF) assay, the presence of metallothionein (MT) was investigated in sections of normal and pathologic human thymuses as well as in cultures of thymic epithelial cells. This protein, known to have a high binding affinity for class II B transitional metals, such as zinc, was detected in the epithelial component of the thymus. Moreover, double labeling experiments with the anti-MT and an anti-thymulin monoclonal antibody showed that all cells containing thymulin, a thymic hormone whose active structure is known to contain zinc, also exhibited large amounts of metallothionein. These results, together with the fact that zinc and thymulin have been detected in the same type of cell organelles, lead to the conclusion that the MT present in thymic epithelial cells might be involved in the mechanism of zinc storage in these cells, thus favoring the secretion of thymulin in its biologically active, zinc-containing form.

Topics: Animals; Biological Assay; Child, Preschool; Cross Reactions; Fluorescent Antibody Technique; Humans; Immune Sera; Infant; Metallothionein; Mice; Mice, Inbred C57BL; Thymic Factor, Circulating; Thymoma; Thymus Gland; Thymus Hormones; Thymus Neoplasms; Zinc