Hepatic metallothionein gene expression in toxic milk mice

The toxic milk mutation (tx) in mice is an autosomal recessive condition that causes a marked hepatic accumulation of copper in adults and severe copper deficiency in the pups of tx/tx dams. We determined the concentration of metallothionein-I (MT-I) mRNA in mutant and normal animals at various stages of development and following administration of copper and zinc. In two tx/tx males the average MT-I mRNA was 329 molecules/pg RNA compared with 38 molecules/pg in normal animals. In fetal and neonatal animals the concentration of MT-I mRNA was generally the same in normal and mutant mice and was independent of copper status. Copper or zinc administration to 7-d-old pups caused a marked induction of MT-I mRNA. There was an increased response to copper administration in one mutant group, but no clear pattern of hyper-induction of the MT gene in tx/tx animals was demonstrated. The elevation of MT-I mRNA in adult toxic milk mice is likely to be a secondary consequence of copper accumulation and not a primary effect of the mutation, because high MT-I mRNA levels would have been observed in the mutant neonates and fetuses. However, the possibility that the tx mutation causes overexpression of MT in post-weaning animals cannot be excluded by these data. The results also show that copper deficiency has no effect on the fetal or neonatal expression of the MT genes.