title: Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice.
abstract: Metallothionein (MT)-bound zinc accumulates when animals are exposed to excess zinc and is depleted under conditions of zinc deficiency, suggesting that MT serves as a means of sequestering excess zinc as well as a zinc reservoir that can be utilized when zinc is deficient. To examine the importance of MT for these processes, mice with null alleles of both MT I and MT II genes were created and the zinc concentration and histological appearance of multiple organs assessed. At birth, the hepatic zinc concentration of these MT-null mice was lower than that of wild-type controls (0.27 +/- 0.02 vs. 0.65 +/- 0.11 micromol zinc/g tissue, P < 0.05). During the next 3 wk of suckling zinc-replete (95 micrograms zinc/g diet) dams, the hepatic zinc concentration of controls fell to 0.42 +/- 0.04 micromol/g but was unchanged in the MT-null mice (0.28 +/- 0.04 micromol/g). The most prominent histological anomaly observed at 3 wk of age was the presence of swollen Bowman's capsules in the kidneys of MT-null mice. When nursing MT-null dams were fed a severely zinc-deficient (1.5 microg/g) diet, kidney development in the MT-null pups was retarded as indicated by the retention of the nephrogenic zone and incomplete tubule development. We suggest that the lack of a hepatic reservoir of zinc jeopardizes the developing kidney in the MT-null mice. In addition to being more sensitive to dietary zinc restriction, MT-null mice are more sensitive to zinc toxicity. When adult mice were challenged with a ramping dose of zinc up to a total of 3700 micromol zinc/kg body weight, MT-null mice had a greater incidence of pancreatic acinar cell degeneration compared with control mice despite accumulating less zinc (2.72 +/- 0.46 vs. 1.23 +/- 0.52 micromol zinc/g pancreas, control and MT-null, respectively, P < 0.05). The results of these experiments suggest that MT I and MT II can protect against both zinc deficiency and zinc toxicity.
authors.affiliation: Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, 98195-7370, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Kelly
authors.forename: C J
authors.initials: CJ
authors.lastname: Quaife
authors.forename: G J
authors.initials: GJ
authors.lastname: Froelick
authors.forename: R D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism; D004032:Diet; D005838:Genotype; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D015032:Zinc / Q000172:deficiency* / Q000633:toxicity*
chemical_list: D008668:Metallothionein; D015032:Zinc