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ROLE OF METALLOTHIONEIN INDUCTION AND ALTERED ZINC STATUS AS MATERNAL MEDIATORS OF DEVELOPMENTAL TOXICITY IN RATS: COMPARISON OF THE EFFECTS OF URETHANE AND STYRENE
Citation:
Daston, G., G. Overman, L. Lehman-McKeeman, J. Rogers, AND C. Keen. ROLE OF METALLOTHIONEIN INDUCTION AND ALTERED ZINC STATUS AS MATERNAL MEDIATORS OF DEVELOPMENTAL TOXICITY IN RATS: COMPARISON OF THE EFFECTS OF URETHANE AND STYRENE. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-91/307 (NTIS PB92124635).
Description:
We hypothesize that maternal metallothionein (MT) induction by toxic dosages of chemicals may contribute to or cause developmental toxicity by the following chain of events: ) maternal hepatic MT induction; 2) redistribution of Zn to the newly synthesized MT; 3) decreased circulating Zn due to hepatic MT binding: leading to 4) a transient by developmentally toxic decrease in Zn availability to the embryo. his hypothesis was tested by evaluating hepatic MT induction, maternal and embryonic Zn status end developmental toxicity after exposure to urethane, a developmental toxicant, or styrene, which is not a developmental toxicant. regnant Sprague Dawley rats were given 0 or 1 g/kg urethane ip, or 0 to 300 mg/kg styrene in corn oil po, on gestation day 11. hese were maternally toxic dosages. s both treatments decreased food consumption, separate pair-fed control groups were also evaluated for effects on MT and Zn status, and development. ubsets of dams in each group were killed 18 hours after treatment to measure hepatic MT concentration, liver, plasma and embryo Zn concentrations, and Zn distribution to maternal and embryonic tissues. he remainder of the dams were killed on gestation day 20, and their fetuses were examined for developmental toxicity. n addition, gestation day 11 rat embryos were exposed to urethane in vitro for 20 hours at concentrations up to 2250 ug/ml, in order to determine whether urethane is directly embryo toxic. rethane treatment induced hepatic MT 14-fold over control, styrene induced MT 2.5-fold. he MT induction by styrene was similar to that observed in 1 pair-fed untreated group. owever, the level of MT induction by urethane was much greater than that produced by decreased food intake alone. epatic Zn concentration, particularly in the cytosol, was increased in the presence of increased hepatic MT concentration. lasma Zn concentration was significantly greater, but distribution to embryonic tissues was significantly lower, than in pair-fed or ad lib-fed controls. tyrene treatment had no effect on 65Zn distribution. rethane was developmentally toxic, causing an 18% decrease in fetal weight and a significant delay in skeletal ossification. rethane was not toxic to rat embryos in vitro. upporting the concept that urethane produces developmental toxicity by an indirect mechanism. tyrene was not developmentally toxic. he changes observed after urethane treatment, namely substantial hepatic MT induction and altered maternal and embryonic Zn status, and the lack of direct embryotoxicity or urethane Zn status support the hypothesis that the maternal effects contribute to developmental toxicity. he lack of similar changes in styrene- intoxicated dams provides an explanation for its low developmental toxicity at maternally toxic dosages.
