Regulation of the ontogeny of rat liver metallothionein mRNA by zinc

Abstract

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...

Nutrient-gene interactions: a single nutrient and hundreds of target genes

“…As addressed above, metallothioneins (MTs) are also considered to act as ROS scavengers and Zn deficiency caused an almost complete down-regulation of the MT-I mRNA in rat liver (Andrews et al, 1987;tom Dieck et al, 2003) that in turn could again increase the hepatic ROS burden. That gene expression of metallothioneins is not only dependent on the Zn status but also on oxidative stress has been established (Dalton et al, 1996;) and one factor that links ROS status and MT expression could be the metal transcription factor 1.…”

Insulino-mimetic and anti-diabetic effects of zinc

“…In this sense, they help protect cells and tissues against heavy metal toxicity, facilitate the exchange of metals functioning as anti-oxidants in tissues, as well as protecting the cell against hydroxyl free radicals, which can cause an oxidative stress induced apoptosis (87;88). It has been suggested that MT play an important role in Zn-induced cell proliferation and differentiation (89), since they are over expressed in proliferating tissues, such as regenerating and developing rat livers, and certain types oftumors (90)(91)(92)(93). MT also play a role in metal exchange with Zn dependant enzymes, such as carbonic anhydrase (CA), a zinc metalloenzyme that catalyzes the reversible conversion between carbon dioxide and the bicarbonate ion, tlrrough the hydration of carbon dioxide (C02) (94)(95)(96).…”

Analysis of hepatic copper, zinc, metallothionein and metallothionein‐Ia mRNA in developing sheep

“…Thus the protein may be serving as a source of zinc for metabolism in the foetal liver and a protective role in the neonate. Andrews et al [14] reported, however, that in zinc-deficient rats the concentration of hepatic metallothionein mRNA was reduced in foetal and neonatal rats suggesting that in both foetus and neonate metallothionein may be primarily protecting the liver from zinc accumulation. This result is consistent with our suggestion that zinc is the most probable inducer in the neonates [Ill; however, it differs from our conclusions and those of Quaife and Palmiter [12] concerning the regulation of metallothionein genes in the late foetal period.…”