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Tumor Necrosis Factor- Alters Maternal and Embryonic Zinc Metabolism and Is Developmentally Toxic in Mice^1,2,

Marie Weldon Taubeneck^*, George P. Daston^**, John M. Rogers, M. Eric Gershwin, Aftab Ansari^# and Carl L. Keen^*,,3

^* Department of Nutrition Department of Internal Medicine, University of California, Davis, CA 95616-8669 The^** Procter and Gamble Co., Miami Valley Laboratories, Cincinnati, OH 45239 Developmental Toxicology Division, Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 ^# Department of Pathology, Emory University, Atlanta, GA 30322

We tested the hypothesis that tumor necrosis factor- (TNF-) 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- (40,000 U) or PBS and then received a ⁶⁵Zn-labeled meal. Mice killed 10 h after TNF- treatment had high liver ⁶⁵Zn and low plasma ⁶⁵Zn, compared with controls. In Experiment 2, gestation day 8 (GD 8) mice were injected with PBS or TNF- and then received a ⁶⁵Zn-labeled meal. Dams killed 10 h after TNF- treatment had higher liver and kidney ⁶⁵Zn and lower plasma and embryonic ⁶⁵Zn accumulation than controls. In Experiment 3, TNF- 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 µg Zn/g were given PBS or TNF- on GD 7–12. Gross fetal defects were not observed in the PBS-treated litters evaluated on GD 18. In contrast, TNF--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--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- is due in part to its influence on Zn metabolism.

KEY WORDS: • development • mice • zinc • tumor necrosis factor- • metallothionein

¹ Supported by NIH grants HD01743 and HD14388, U.S. Environmental Protection Agency Cooperative Agreement CR816713, and NIH Training Grant DK07355-14.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 2 May 1994. Revision accepted 26 August 1994.