Ethanol Decreases Zinc Transfer to the Fetus in Normal but Not Metallothionein-Null Mice

Abstract

Background: Ethanol causes significant teratogenicity in normal (MT+/+) but not metallothionein-null (MT−/−) fetuses. Impaired maternal fetal zinc (Zn) transfer is indicated, because ethanol significantly reduces plasma Zn concentrations in MT+/+ dams while increasing concentrations in MT−/− dams. In this study we examined maternal-fetal Zn homeostasis in response to ethanol in MT+/+ and MT−/− mice and the origins of the increase in plasma Zn in MT−/− mice. Methods and Results: Mice were treated with saline or ethanol (0.015 ml/g intraperitoneally at 0 and 4 hr) on day 12 of gestation. An additional subcutaneous injection of 65Zn tracer was administered after the second ethanol injection before mice were killed 3 hr later. Maternal liver MT levels were not different between ethanol and saline MT+/+ mice. Both liver Zn and 65Zn levels were higher in MT+/+ mice. Plasma Zn concentrations were higher in MT−/− mice, with MT−/− ethanol-treated mice having levels greater than those of MT−/− saline-treated controls. MT+/+ ethanol-treated fetuses exhibited lower 65Zn transfer and whole Zn concentrations compared with MT+/+ and MT−/− saline and MT−/− ethanol fetuses. So we could examine changes in plasma Zn after ethanol treatment, MT+/+ and MT−/− mice were injected with 65Zn 3 days before they received ethanol treatment. Muscle and skin showed a decrease in 65Zn retention in both genotypes over 3 hr. There was a trend toward greater 65Zn release from skin and muscle at an earlier time in MT−/− mice: 24% vs. 2% decrease (MT−/− vs. MT+/+) for muscle and 28% vs. 15% decrease (MT−/− vs. MT+/+) for skin at 2 hr. Conclusions: The results show (a) that ethanol interferes with the transfer of Zn to the fetus, and that this is MT dependent, and (b) that the increase in plasma Zn seen in MT−/− mice after ethanol administration is a result of Zn release from the skin and muscle, in the absence of hepatic Zn sequestration.