Leazer Tyra M, Daston George P, Keen Carl L, Rogers John M
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Toxicol Sci. 2003 Jun;73(2):442-7. doi: 10.1093/toxsci/kfg088. Epub 2003 Apr 15.
Lipopolysaccharide (LPS) is embryolethal in CD-1 mice. LPS induces metallothionein (MT) via cytokines, including TNF-alpha, IL-1, and IL-6, which initiate and maintain the acute phase response. Maternal hepatic MT induction in pregnant rats, by diverse toxicants, can result in maternal hypozincemia and subsequent embryonal zinc (Zn) deficiency. We examined the hypothesis that LPS causes embryo toxicity in CD-1 mice via MT induction and subsequent embryo Zn deficiency by (1) determining whether LPS induces maternal hepatic MT and causes Zn redistribution, (2) assessing the effects of maternal Zn supplementation on LPS developmental toxicity, and (3) assessing the role of MT with MT I-II null mice (MTKO). Timed pregnant CD-1 mice were dosed i.p. with LPS (S. typhimurium) (0.05 mg/kg) on gestation day (gd) 9. Zn supplementation was administered on gd 8 (10 mg/kg, pretreatment) or on gd 9 as a cotreatment (5 or 10 mg/kg). MTKO and wild type (WT) mice were dosed with LPS (0.05 or 0.1 mg/kg) on gd 9, and maternal liver MT and Zn and plasma Zn were measured. In CD-1 mice, maternal hepatic MT was elevated 24 h after LPS treatment, and cotreatment with Zn caused further elevation of MT. Maternal hepatic Zn concentrations paralleled hepatic MT concentrations. Maternal plasma Zn on gd 10 showed no consistent effect of LPS treatment or Zn cotreatment on gd 9. Zn pretreatment (10 mg/kg) on gd 8 did not ameliorate LPS embryolethality, while Zn cotreatment (5 or 10 mg/kg) on gd 9 exacerbated the toxicity of LPS. LPS produced a similar incidence of embryolethality in MTKO and WT strains on gd10. Plasma Zn concentrations were similar in both strains, while hepatic Zn concentrations were significantly higher in WT than in the MTKO strain. In conclusion, while LPS can induce maternal hepatic MT and Zn redistribution in CD-1 mice, this does not appear to be a key mechanism leading to LPS embryotoxicity.
脂多糖（LPS）对CD-1小鼠具有胚胎致死性。LPS通过细胞因子（包括肿瘤坏死因子-α、白细胞介素-1和白细胞介素-6）诱导金属硫蛋白（MT），这些细胞因子启动并维持急性期反应。多种毒物可诱导怀孕大鼠母体肝脏MT生成，这会导致母体低锌血症以及随后的胚胎锌（Zn）缺乏。我们通过以下方式检验了LPS通过诱导MT以及随后导致胚胎锌缺乏从而在CD-1小鼠中引起胚胎毒性这一假说：（1）确定LPS是否诱导母体肝脏MT并导致锌重新分布；（2）评估母体补充锌对LPS发育毒性的影响；（3）利用MT I-II基因敲除小鼠（MTKO）评估MT的作用。在妊娠第9天（gd9），对处于特定时间点的怀孕CD-1小鼠腹腔注射LPS（鼠伤寒沙门氏菌）（0.05 mg/kg）。在gd8（10 mg/kg，预处理）或gd9作为联合处理（5或10 mg/kg）给予锌补充剂。在gd9给MTKO和野生型（WT）小鼠注射LPS（0.05或0.1 mg/kg），并测量母体肝脏MT、锌以及血浆锌含量。在CD-1小鼠中，LPS处理24小时后母体肝脏MT升高，锌联合处理导致MT进一步升高。母体肝脏锌浓度与肝脏MT浓度平行。gd10时母体血浆锌含量未显示出LPS处理或gd9时锌联合处理的一致影响。gd8时锌预处理（10 mg/kg）并未改善LPS胚胎致死性，而gd9时锌联合处理（5或10 mg/kg）加剧了LPS的毒性。在gd10时，LPS在MTKO和WT品系中产生的胚胎致死率相似。两个品系的血浆锌浓度相似，而WT品系的肝脏锌浓度显著高于MTKO品系。总之，虽然LPS可在CD-1小鼠中诱导母体肝脏MT和锌重新分布，但这似乎不是导致LPS胚胎毒性的关键机制。
