The concentrations of zinc, copper, metallothionein and metallothionein-Ia mRNA in sheep livers during development was determined. It was found that early sheep foetuses (30-40 days gestation) had very high concentrations of hepatic zinc (2305f814 pg/g dry mass), and that these levels declined steadily to 644*304 pg/g near to term. The copper concentrations in the foetal livers were not higher than those in the adult. The concentrations of metallothionein and metallothionein-Ia mRNA were also very high in the foetal livers and declined steadily during gestation from 261 94 molecules/pg RNA to 71 f 18 molecules/pg near to term. Metallothionein-Ia mRNA concentrations were closely correlated with hepatic zinc concentrations but not with copper. Metallothionein concentrations also decreased during gestation : e.g. 3044 pg/g (wet mass) in one foetus on day 34 of gestation to 862 pg/g on day 125. After birth, however, the concentrations of metallothionein declined to less than 100 pg/g and this decline occurred despite the presence of significant quantities of mRNA. The ratio of metallothionein/metallothionein-Ia mRNA decreased from 1.3 to 3.2 x lo5 molecules metallothionein/molecule of metallothionein-la mRNA during gestation to between 0.28 -0.64 x lo5 molecules/molecule in the postnatal animals. We conclude that the major function of metallothioneins in the foetal liver is protection of the liver against the potentially toxic accumulation of zinc. In the postnatal sheep there appears to be a decreased synthesis or increased degradation of metallothionein.The livers of developing mammals contain elevated concentrations of zinc and copper [l -31 and a high proportion of these metals is bound to metallothioneins [l, 4, 51. These low-molecular-mass cysteine-rich proteins are thought to play an important role in copper and zinc metabolism and also in protection against heavy metal toxicity [6, 71. The reason for the accumulation of copper and zinc in the liver during development is unclear. It has been suggested, at least for rodents, that it serves as a store of copper and zinc to provide for the period of rapid post-natal growth when supplies from the milk may be limiting [5, 81. Alternatively it is possible that the copper and zinc accumulate because the adult homeostatic mechanisms (e.g. biliary excretion and intestinal absorption) are not fully developed and metallothioneins provide a means of detoxifying the metals [4, 91. Perhaps the most interesting possibility is that metallothioneins provide the zinc required for hepatic cell differentiation [lo].One approach to clarifying the role of metallothioneins in the developing liver is to examine the nature of the inducers of the gene during development. In previous work we determined the levels of metallothionein mRNA, copper and zinc in the livers of developing rats and found evidence for two phases of mRNA induction, one late foetal and the other neonatal [ll]. Reduction of zinc entry into the foetal liver, by means of a Cd block to placental transport, did not sig...
