ALTERED ZN STATUS BY ALPHA-HEDERIN IN THE PREGNANT RAT AND ITS RELATIONSHIP TO ADVERSE DEVELOPMENTAL OUTCOME

The hypothesis that an acute-phase reaction in the pregnant animal causes a systemic redistribution of Zn, resulting in a transient but developmentally adverse Zn deficiency in the embryo, was tested by treating pregnant rats during organogenesis with a alpha-hederin, an agent reported to induce substantial metallothionein (MT) synthesis in rat liver, and determining hepatic MT concentration, hepatic and plasma Zn concentration, and systemic distribution of a pulse of Zn-65 after treatment. Developmental toxicity was assessed by evaluating morphologic development in term fetuses. A single dose of alpha-hederin, injected sc at dosages of 3 to 300 mu mol/kg kg, caused an acute phase response, indicated by decreased Fe and Zn, and increased Cu, alpha(1)-acid glycoprotein, and ceruloplasmin concentration in plasma, along with a dosage-related increase in maternal hepatic MT concentration. The maximum induction of MT was 11 to 15-fold greater than control and occurred at dosages of 30 mu mol/kg and higher, and MT concentration reached its peak 12 to 24 h after treatment. Zn concentration in liver and liver cytosol increased along with MT, reaching a maximum level at dosages of 30 mu mol/kg and higher. Plasma Zn concentration decreased after alpha-hederin treatment to a level approximately 75% of control at a dosage of 30 mu mol/kg and 50% of control at 300 mu mol/kg. Therefore, hepatic MT induction was associated with most, but not all, of the decrease in plasma Zn concentration. Zn distribution was evaluated by giving an oral pulse of Zn-65 8 h after treatment with 0, 30, or 300 mu mol/kg alpha-hederin on gestation day 11, and measuring Zn-65 levels 18 h after treatment. The fraction of Zn-65 distributed to the liver of treated rats (either dosage) was twice that of control, but distribution of Zn-65 to other maternal tissues was decreased. Zn-65 accumulation by conceptuses was significantly decreased, attributable to decreased accumulation in decidua, but not in visceral yolk sacs or embryos; however, at this stage of development the decidua accounts for a greater quantity of Zn than either of the other products of conception and may serve as the Zn-storing tissue for the conceptus. Both 30 and 300 mu mol/kg increased resorption incidence, and 300 mu mol/kg also decreased fetal weight and increased the incidence of abnormal fetuses. Serum collected from rats two hours after alpha-hederin treatment (i.e., before the onset of MT synthesis) supported rat embryo development in vitro, whereas serum collected 18 h after treatment did not. Adding Zn to this serum restored normal embryonic development. These data are consistent with the hypothesis that systemic changes in Zn status, brought about by a hepatic acute phase response, including a substantial induction of hepatic MT, may be a mechanism for maternally mediated abnormal development.