Taubeneck M W, Daston G P, Rogers J M, Gershwin M E, Ansari A, Keen C L
Department of Nutrition, University of California, Davis 95616-8669, USA.
J Nutr. 1995 Apr;125(4):908-19. doi: 10.1093/jn/125.4.908.
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.
我们验证了这样一个假说，即肿瘤坏死因子-α（TNF-α）在小鼠体内具有致畸性，部分原因是其对锌代谢的影响。在实验1中，给未怀孕的小鼠注射单剂量的TNF-α（40,000单位）或磷酸盐缓冲液（PBS），然后给予含65锌标记的食物。与对照组相比，在TNF-α处理10小时后处死的小鼠肝脏中65锌含量高，而血浆中65锌含量低。在实验2中，给妊娠第8天（GD 8）的小鼠注射PBS或TNF-α，然后给予含65锌标记的食物。在TNF-α处理10小时后处死的母鼠，其肝脏和肾脏中的65锌含量高于对照组，而血浆和胚胎中的65锌积累量低于对照组。在实验3中，从GD 7至12给予TNF-α，与GD 13时母体肝脏锌和金属硫蛋白浓度高以及GD 18时无脑儿发生率高有关。在实验4中，给在GD 7至12期间喂食含4.5、12.5或50.0微克锌/克饲料的母鼠注射PBS或TNF-α。在GD 18评估的PBS处理的窝中未观察到明显的胎儿缺陷。相比之下，TNF-α处理的窝具有多种缺陷，在低锌饮食组中发生率和严重程度最高。在实验5中，在来自TNF-α处理动物的血清中培养的胚胎出现缺陷的频率很高；当补充锌时，这种血清的发育毒性得到改善。因此，TNF-α的发育毒性部分归因于其对锌代谢的影响。
