Role of the maternal acute phase response and tumor necrosis factor alpha in the developmental toxicity of lipopolysaccharide in the CD-1 mouse.
The acute phase response (APR) functions to reset metabolic homeostasis following infectious, toxic, or traumatic insult. TNF-alpha, a putative mediator of the APR, has been associated with fetal death in rodents and preterm labor and delivery in humans. We hypothesized that physiologic changes associated with the maternal APR may play a role in adverse embryo/fetal outcome. Pregnant CD-1 mice injected i.p. with lipopolysaccharide (LPS), a model inducer of the APR, on gestation day (gd) 9 showed a dose-related increase in embryo death on gd 10. Histology indicated placental infarct and necrosis. Maternal serum TNF-alpha levels, measured by ELISA following administration of 0.05 mg/kg LPS on gd 9, were found to increase significantly and peak within 1 to 1.5 h. Pretreatment with 0.01 mg/kg LPS on gd 8 ameliorated embryotoxicity of the 0.05 mg/kg LPS treatment on gd 9 and also eliminated the increase in serum TNF-alpha. Direct LPS exposure in whole embryo culture was nontoxic. These data support a maternally mediated mechanism of LPS embryolethality, and suggest that TNF-alpha may be an important mediator of this developmental toxicity.
Leazer
Tyra M
TM
Curriculum in Toxicology, University of North Carolina at Chapel Hill, USA. tleazer@kumc.edu
Barbee
Brenda
B
Ebron-McCoy
Marian
M
Henry-Sam
Gerelyn A
GA
Rogers
John M
JM
D000210:Acute-Phase Reaction / Q000503:physiopathology*; D000818:Animals; D004622:Embryo, Mammalian / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005313:Fetal Death / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D009924:Organ Culture Techniques; D011247:Pregnancy; D012486:Salmonella typhimurium / Q000737:chemistry*; D013723:Teratogens / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D008070:Lipopolysaccharides; D013723:Teratogens; D014409:Tumor Necrosis Factor-alpha