Zinc treatment prevents lipopolysaccharide-induced teratogenicity in mice.
BACKGROUND
During pregnancy, exposure to lipopolysaccharide (LPS) can lead to abortion, preterm delivery, and teratogenicity. The mechanisms underlying these effects are unclear. Both LPS and ethanol are potent inducers of liver metallothionein (MT), a key Zn binding protein. The teratogenic effects of ethanol have been linked to MT-induced changes in maternal-fetal Zn homeostasis, leading tofetal deficiency. This study was designed to assess whether the teratogenic effects of LPS are also related to MT induction and changes in Zn homeostasis.


METHODS
Non-pregnant normal (MT +/+) and MT-null (MT -/-) mice were injected subcutaneously with 0.5 microg/gm LPS and killed over 48 hr. In MT +/+ mice, liver MT concentrations were elevated from 6 hr, and were maximal at 24 hr (30-fold basal), whereas liver Zn levels were also increased from 6 hr. Plasma Zn concentrations decreased by 80% at 6 hr, and were below normal between 6 and 24 hr. In MT -/- mice, plasma Zn levels were increased from basal between 6 and 16 hr. Dams were injected with LPS, saline, or LPS and ZnSO4 (2 microg/gm, MT +/+ only) on Day 8 of gestation (GDS), killed on GD18, and the fetuses examined for malformations.


RESULTS
External abnormalities were most prevalent in fetuses from MT +/+ dams exposed to LPS, where 34% of fetuses in each litterwere affected. MT +/+ dams treated with LPS and ZnSO4, and MT -/- dams treated with LPS had litters in which 5.4 and 4.8% of fetuses were abnormal respectively.


CONCLUSIONS
The findings of this study strongly support the hypothesis that LPS teratogenicity is mediated at least in part by MT-induced changes in maternal Zn homeostasis,which compromises fetal Zn supply.
Carey
Luke C
LC
Division of Clinical Biochemistry, Institute of Medical and Veterinary Science, Adelaide, Australia.
Berbée
Paulien L
PL
Coyle
Peter
P
Philcox
Jeffrey C
JC
Rofe
Allan M
AM
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D004926:Escherichia coli; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D015032:Zinc / Q000097:blood / Q000627:therapeutic use*
D008070:Lipopolysaccharides; D008668:Metallothionein; D015032:Zinc