The embryolethality of lipopolysaccharide in CD-1 and metallothionein I-II null mice: lack of a role for induced zinc deficiency or metallothionein induction.
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.
Leazer
Tyra M
TM
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. tleazer@kumc.edu
Daston
George P
GP
Keen
Carl L
CL
Rogers
John M
JM
D000210:Acute-Phase Reaction / Q000139:chemically induced; D000818:Animals; D004357:Drug Synergism; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D005865:Gestational Age; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008668:Metallothionein / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011247:Pregnancy; D012486:Salmonella typhimurium / Q000276:immunology; D013045:Species Specificity; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D008070:Lipopolysaccharides; D008668:Metallothionein; D015032:Zinc