Reactive oxygen species are involved in lipopolysaccharide-induced intrauterine growth restriction and skeletal development retardation in mice.

Abstract

OBJECTIVE:

Maternal infection is a cause of adverse developmental outcomes including embryonic resorption, intrauterine fetal death, and preterm labor. Lipopolysaccharide-induced developmental toxicity at early gestational stages has been well characterized. The purpose of the present study was to investigate the effects of maternal lipopolysaccharide exposure at late gestational stages on intrauterine fetal growth and skeletal development and to assess the potential role of reactive oxygen species in lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation.

STUDY DESIGN:

The timed pregnant CD-1 mice were intraperitoneally injected with lipopolysaccharide (25 to 75 microg/kg per day) on gestational day 15 to 17. To investigate the role of reactive oxygen species on lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation, the pregnant mice were injected with alpha-phenyl-N-t-butylnitrone (100 mg/kg, intraperitoneally) at 30 minutes before lipopolysaccharide (75 microg/kg per day, intraperitoneally), followed by an additional dose of alpha-phenyl-N-t-butylnitrone (50 mg/kg, intraperitoneally) at 3 hours after lipopolysaccharide. The number of live fetuses, dead fetuses, and resorption sites was counted on gestational day 18. Live fetuses in each litter were weighed. Crown-rump and tail lengths were examined and skeletal development was evaluated.

RESULTS:

Maternal lipopolysaccharide exposure significantly increased fetal mortality, reduced fetal weight and crown-rump and tail lengths of live fetuses, and retarded skeletal ossification in caudal vertebrae, anterior and posterior phalanges, and supraoccipital bone in a dose-dependent manner. Alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, almost completely blocked lipopolysaccharide-induced fetal death (63.2% in lipopolysaccharide group versus 6.5% in alpha-phenyl-N-t-butylnitrone + lipopolysaccharide group, P < .01). In addition, alpha-phenyl-N-t-butylnitrone significantly reversed lipopolysaccharide-induced intrauterine growth restriction and skeletal development retardation. However, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, had little effect. Furthermore, lipopolysaccharide-induced intrauterine fetal death, intrauterine fetal growth restriction, and skeletal development retardation were associated with lipid peroxidation and glutathione depletion in maternal liver, placenta, and fetal liver. Alpha-phenyl-N-t-butylnitrone significantly attenuated lipopolysaccharide-induced lipid peroxidation and glutathione depletion in maternal liver, placenta, and fetal liver.

CONCLUSION:

Maternal lipopolysaccharide exposure at late gestational stages results in intrauterine fetal growth restriction and skeletal development retardation in mice. Reactive oxygen species might be, at least in part, involved in lipopolysaccharide-induced intrauterine fetal growth restriction and skeletal development retardation.

• Authors: De-Xiang Xu, Yuan-Hua Chen, Lei Zhao, Hua Wang, Wei Wei
• Journal: American journal of obstetrics and gynecology (Am J Obstet Gynecol) Vol. 195 Issue 6 Pg. 1707-14 (Dec 2006) ISSN: 1097-6868 [Electronic] United States
• PMID: 16769026 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic N-Oxides
• Free Radical Scavengers
• Lipopolysaccharides
• Reactive Oxygen Species
• phenyl-N-tert-butylnitrone
• Glutathione

Topics

• Animals
• Bone Development (drug effects)
• Crown-Rump Length
• Cyclic N-Oxides (pharmacology)
• Dose-Response Relationship, Drug
• Female
• Fetal Death
• Fetal Growth Retardation (chemically induced, metabolism)
• Fetal Weight
• Free Radical Scavengers (pharmacology)
• Gestational Age
• Glutathione (antagonists & inhibitors)
• Lipid Peroxidation (drug effects)
• Lipopolysaccharides (administration & dosage, antagonists & inhibitors, pharmacology)
• Male
• Mice
• Mice, Inbred Strains
• Osteogenesis (drug effects)
• Pregnancy
• Reactive Oxygen Species (metabolism)
• Tail