To investigate the role of metals in the regulation of the ontogenic expression of rat liver metallothionein (MT) mRNA, the concentrations of zinc, MT and MT mRNA were determined in livers of fetal and newborn rats from dams whch were fed with a control or zinc-deficient or copper-deficient or iron-deficient diet from day 12 of gestation. The liver samples were analyzed for MT-mRNA levels using a mouse MT-I cRNA probe. Although the newborn hepatic levels of each metal (zinc or copper or iron) was specifically reduced corresponding to the respective mineral deficiencies, the hepatic concentrations of total MT and MT-I mRNA were significantly decreased only in pups born from zinc-deficient dams. Injection of the zinc-deficient newborn pups with 20 mg Zn as ZnS04/kg restored with MT-I mRNA levels to slightly above control values within 5 h of injection. The hepatic zinc, MT and MT-I mRNA levels were observed to increase significantly in control fetal rat liver on days 17-21 of gestation but there were little changes in either zinc or MT in fetal livers from zinc-deficient dams during the late gestational period. The h4T-I mRNA level also did not show an increase on days 18 and 20 of gestation in zinc-deficient fetal liver as compared to controls. These results demonstrate a direct role of zinc in hepatic MT gene expression in rat liver during late gestation. Immunohistochemical localization of MT using a specific antibody to rat liver MT showed that the staining for MT in zinc-deficient pup liver was mainly in the cytosol in contrast to the significant nuclear MT staining observed in control newborn rat liver. The results suggest that maternal zinc deficiency has a marked effect not only in decreasing the levels of hepatic MT and MT-I mRNA but also in the localization of MT in newborn rat liver.The deposition of zinc and the synthesis of metallothionein (MT) in mammalian liver both depend on the stage of development as well as certain changes in physiological conditions. Levels of zinc and MT in rat liver are high during the late fetal and early neonatal periods but decrease dramatially by weaning [l -41. Although there is very little basal synthesis of MT in the livers of control adult animals, synthesis can be induced by injection of certain metals and by various other stress conditions. The ontogeny of expression of murine MT showed high amounts of MT-mRNA in visceral and parietal yolk sac [5] and subsequently in developing liver [5, 61. Metallothionein mRNA was also abundant in certain hepatomas and differentiated teratocarcinoma cells [5].The large concentrations of MT present in the early developmental stages correlate with increased hepatic zinc levels [3] suggesting that MT may play a role in the storage of zinc which is required for the rapid fetal and neonatal growth [7, 81. Previous studies provide evidence that maternal zinc status may be one of the important factors which can influence the levels of hepatic zinc and MT in newborn rats [9].However, the mechanisms of MT gene regulation in fetal and neo...

Somatostatin analogues such as octreotide have been shown in experimental systems to exhibit antineoplastic activity. Further laboratory and clinical research is needed to clarify the mechanism of action of somatostatin analogues as antineoplastics, and to determine if the encouraging preclinical results will lead to novel endocrine approaches to the treatment of breast cancer. Copyright 0 1992 by W.B. Saunders Company T HE ROLE OF HORMONES such as estrogen in stimulating the proliferation of endocrine-dependent human breast cancer is well established.' Furthermore, endocrine treatments currently used to palliate metastatic breast cancer are among the most useful antineoplastic therapies available. Recent basic research concerning the dependence of neoplasms on peptide hormones and growth factors suggests that it may be possible to develop approaches that will extend the usefulness of this modality of cancer treatment. ' An important example of this is the current interest in the role of somatostatin in the regulation of cellular proliferation and the potential for therapeutic intervention using Sandostatin@, a long-acting synthetic analogue of this natural inhibitory peptide.

The effects of maternal Zn, Cu, or Fe deficiencies during late gestation on hepatic levels of metals and metallothionein (MT) and the binding of Zn and Cu to protein fractions were investigated in newborn rats. Timed pregnant rats were fed one of the following diets: Zn deficient (Zn-D), Cu-D, Fe-D, or control from day 12 of gestation until birth. The specific nutritional deficiency status of the dams was confirmed by low plasma levels of the deficient metal. Livers from pups were analyzed for MT, metal content, and metal-protein binding. Maternal Zn-D resulted in a greater than 50% reduction of hepatic MT levels in pups, whereas Cu-D and Fe-D had no significant effects. Pups in each deficient group showed a significant decrease in the hepatic levels of the respective metals. Fractionation of hepatic cytosols from the pups by Sephadex G-75 gel filtration showed that in both Fe-D and Cu-D pups the respective metals were depleted from the high molecular weight protein fraction, whereas in Zn-D pups the Zn was depleted mainly from the MT fraction (Ve/V0 approximately 2). Incorporation of [35S] cysteine into MT fractions was significantly lower in Zn-D pups as compared with control pups. These results indicate that there is a specific effect of the maternal Zn-D on the hepatic storage of Zn as MT in newborn rats.

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