ALTERED ZINC-METABOLISM OCCURS IN MURINE LETHAL MILK SYNDROME

The lethal milk (lm) mutation in mice causes Zn deficiency in pups nursed by Im dams. To examine tissue Zn distribution and Zn transport to milk and pups, Zn-65 was administered to lactating normal and Im dams. Transport of Zn-65 to milk of Im dams was approximately 50% of that transported to milk of normal dams. The lower milk Zn-65 resulted in significantly less Zn-65 u take by tissues of the nursing pups. The decrease in Zn-65 transport to the milk was accompanied by a significant increase in Zn-65 uptake and metallothionein mRNA levels in kidney of the lm dams. The elevated Zn uptake and metallothionein expression was tissue specific and could be a reflection of altered zinc transport from mammary gland to milk. Polyacrylamide gel electrophoresis and Western transfer of mammary gland proteins from lm dams showed that a 30-kDa protein bound more Zn-65 in vitro compared with proteins from normal mammary gland. Normal pups nursed by dams of the Im genotype had down-regulated metallothionein expression due to Zn deficiency. The genetic defect in lm mice decreases Zn transport to milk, thus explaining the neonatal Zn deficiency seen in normal mice fostered by lm dams. The greater metallothionein expression in dams of the lm genotype could be a secondary manifestation of altered tissue zinc distribution or a primary effect on a metallothionein regulatory mechanism.