Effects of ATP7A overexpression in mice on copper transport and metabolism in lactation and gestation.

Placentae and mammary epithelial cells are unusual in robustly expressing two copper "pumps", ATP7A and B, raising the question of their individual roles in these tissues in pregnancy and lactation. Confocal microscopic evidence locates ATP7A to the fetal side of syncytiotrophoblasts, suggesting a role in pumping Cu towards the fetus; and to the basolateral (blood) side of lactating mammary epithelial cells, suggesting a role in recycling Cu to the blood. We tested these concepts in wild-type C57BL6 mice and their transgenic counterparts that expressed hATP7A at levels 10-20× those of endogenous mAtp7a. In lactation, overexpression of ATP7A reduced the Cu concentrations of the mammary gland and milk ~50%. Rates of transfer of tracer (64)Cu to the suckling pups were similarly reduced over 30-48 h, as was the total Cu in 10-day -old pups. During the early and middle periods of gestation, the transgenic litters had higher Cu concentrations than the wild-type, placental Cu showing the reverse trend; but this difference was lost by the first postnatal day. The transgenic mice expressed ATP7A in some hepatocytes, so we investigated the possibility that metalation of ceruloplasmin (Cp) might be enhanced. Rates of (64)Cu incorporation into Cp, oxidase activity, and ratios of holo to apoceruloplasmin were unchanged. We conclude that in the lactating mammary gland, the role of ATP7A is to return Cu to the blood, while in the placenta it mediates Cu delivery to the fetus and is the rate-limiting step for fetal Cu nutrition during most of gestation in mice.