TUMOR-NECROSIS-FACTOR-ALPHA ALTERS MATERNAL AND EMBRYONIC ZINC-METABOLISM AND IS DEVELOPMENTALLY TOXIC IN MICE

We tested the hypothesis that tumor necrosis factor-alpha (TNF-alpha) would be teratogenic in mice due in part to its effects on zinc metabolism. In Experiment 1, nonpregnant mice were injected with a single dose of TNF-alpha (40,000 U) or PBS and then received a Zn-65-labeled meal. Mice killed 10 h after TNF-alpha treatment had high liver Zn-65 and low plasma Zn-65, compared with controls. In Experiment 2, gestation day 8 (GD 8) mice were injected with PBS or TNF-alpha and then received a Zn-65-labeled meal. Darns killed 10 h after TNF-alpha treatment had higher liver and kidney Zn-65 and lower plasma and embryonic Zn-65 accumulation than controls. In Experiment 3, TNF-alpha dosing from GD 7-12 was associated with high maternal liver Zn and metallothionein concentrations on GD 13 and a high frequency of exencephaly on GD 18. In Experiment 4, dams fed diets containing 4.5, 12.5 or 50.0 mu g Zn/g were given PBS or TNF-alpha on GD 7-12. Gross fetal defects were not observed in the PBS-treated litters evaluated on GD 18. In contrast, TNF-alpha-treated litters were characterized by multiple defects, with the incidence and severity being highest in the low Zn diet group. In Experiment 5, embryos cultured in serum from TNF-alpha-treated animals exhibited a high frequency of defects; the developmental toxicity of this serum was ameliorated when it was supplemented with Zn. Thus, the developmental toxicity of TNF-alpha is due in part to its influence on Zn metabolism.