In vivo and in vitro developmental toxicity in LPS-induced zinc-deficient rabbits.

Lipopolysaccharide (LPS) was used to induce maternal hypozincemia in order to test the hypothesis that altered zinc homeostasis is developmentally toxic in the rabbit. Treatment of dams on Gestation Day (GD) 8 with LPS (0.67 microgram/kg i.v.) caused total resorption of 78% (7 of 9) of the litters whereas GD 10 treatment increased the percentage of resorbed implantations (18-fold), but resulted in only 14% (1 of 7) totally resorbed litters. Cotreatment with zinc oxide (ZnO) on GD 10 decreased the resorption rate by 44%, indicating that hypozincemia was partially responsible for the resorptions. However, ZnO had no effect on resorption rate in GD 8 LPS-treated dams. No malformations were observed with LPS dosing on either gestation day. To determine whether LPS-induced Zn deficiency had any direct effects on rabbit embryos, normal GD 9 embryos were cultured for 48 h in serum from LPS-treated dams (0.53 +/- 0.01 microgram/mL Zn) or from controls (1.74 +/- 0.07 micrograms/mL Zn). Embryo growth and development were normal in both groups, indicating a lack of any direct embryo effects of Zn deficiency. Finally, maternal plasma progesterone and the Zn content of conceptus tissues were measured 24 h after LPS injection on GD 10. Despite a marked decrease in maternal serum Zn, no significant changes in embryo, visceral yolk sac, yolk sac cavity-exoceolomic fluid, or placental Zn were found. However, maternal progesterone levels were decreased 33 and 28% in the LPS and LPS + ZnO groups, respectively. Taken together, these results indicate that rabbits may differ from rodent species in their lesser susceptibility to the teratogenic potential of transient maternal Zn deficiency, as well as in their resistance to conceptus Zn changes. Nonetheless, Zn deficiency may be responsible for an increase in resorption rate in the rabbit.

Developmental toxicity of dietary zinc deficiency in New Zealand white rabbits.

Chemically induced maternal Zn deficiency has been shown previously to cause terata and increase embryonic loss in rodents. To examine the potential effects of Zn deficiency in the rabbit, a major developmental toxicity test species, rabbit dams were fed an ethylenediamine-tetraacetic acid-washed alfalfa-based Zn-deficient diet (-Zn) or the same diet replete with 80 ppm Zn (control) from Gestation Day (GD) 0 through 20. A third group of animals was pair fed to match the mean daily feed consumption levels of the < 2 ppm Zn group. By GD 7, maternal serum Zn levels of the -Zn dams were decreased 56% and reached a nadir with a 75% decrease of serum Zn by GD 14. Zinc concentrations in the visceral yolk sac and visceral yolk sac-exoceolomic fluid were decreased 30% and 50%, respectively, by GD 11. Although GD 11 embryonic Zn levels were not affected, the embryos from Zn-deficient dams exhibited decreased head length, somite number, and total protein. On GD 28, a significant increase in resorptions/litter was noted in the -Zn group, and the incidence of totally resorbed litters of the -Zn group was greater than laboratory historical control values. No terata were observed in GD 28 fetuses. This study indicates that Zn deficiency occurring during the standard dosing period of guideline rabbit developmental toxicity studies may be associated with a modest increase in resorption rate and a transient inhibition of embryonic growth, but in contrast to rodent species, does not appear to be teratogenic.