Altered zinc metabolism occurs in murine lethal milk syndrome

The lethal milk (lm) mutation in mice causes Zn deficiency in pups nursed by lm dams. To examine tissue Zn distribution and Zn transport to milk and pups, 65Zn was administered to lactating normal and lm dams. Transport of 65Zn to milk of lm dams was approximately 50% of that transported to milk of normal dams. The lower milk 65Zn resulted in significantly less 65Zn uptake by tissues of the nursing pups. The decrease in 65Zn transport to the milk was accompanied by a significant increase in 65Zn 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 65Zn in vitro compared with proteins from normal mammary gland. Normal pups nursed by dams of the lm 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.