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 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 65Zn 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 mumol/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 mumol/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 mumol/kg and higher. Plasma Zn concentration decreased after alpha-hederin treatment to a level approximately 75% of control at a dosage of 30 mumol/kg and 50% of control at 300 mumol/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 65Zn 8 h after treatment with 0, 30, or 300 mumol/kg alpha-hederin on gestation day 11, and measuring 65Zn levels 18 h after treatment. The fraction of 65Zn distributed to the liver of treated rats (either dosage) was twice that of control, but distribution of 65Zn to other maternal tissues was decreased. 65Zn 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 mumol/kg increased resorption incidence, and 300 mumol/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.(ABSTRACT TRUNCATED AT 400 WORDS)
Daston
G P
GP
Miami Valley Laboratories, Procter & Gamble Co., Cincinnati, Ohio.
Overmann
G J
GJ
Baines
D
D
Taubeneck
M W
MW
Lehman-McKeeman
L D
LD
Rogers
J M
JM
Keen
C L
CL
D000818:Animals; D002570:Ceruloplasmin / Q000187:drug effects; D046508:Culture Techniques; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D008668:Metallothionein / Q000187:drug effects; D008670:Metals / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives*; D009961:Orosomucoid / Q000187:drug effects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism*
D008670:Metals; D009961:Orosomucoid; D012503:Saponins; C010177:beta-hederin; D009828:Oleanolic Acid; D008668:Metallothionein; D002570:Ceruloplasmin; D015032:Zinc