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 65Zn-labeled meal. Mice killed 10 h after TNF-alpha 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-alpha and then received a 65Zn-labeled meal. Dams killed 10 h after TNF-alpha treatment had higher liver and kidney 65Zn and lower plasma and embryonic 65Zn 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 micrograms 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.
Taubeneck
M W
MW
Department of Nutrition, University of California, Davis 95616-8669, USA.
Daston
G P
GP
Rogers
J M
JM
Gershwin
M E
ME
Ansari
A
A
Keen
C L
CL
D000014:Abnormalities, Drug-Induced; D000818:Animals; D004622:Embryo, Mammalian / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D005314:Embryonic and Fetal Development / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005333:Fetus / Q000187:drug effects; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008668:Metallothionein / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D011247:Pregnancy; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000633:toxicity*; D015032:Zinc / Q000378:metabolism*; D015037:Zinc Radioisotopes
D014409:Tumor Necrosis Factor-alpha; D015037:Zinc Radioisotopes; D008668:Metallothionein; D015032:Zinc