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ROLE OF THE MATERNAL ACUTE PHASE RESPONSE AND TUMOR NECROSIS FACTOR ALPHA IN THE DEVELOPMENTAL TOXICITY OF LIPOPOLYSACCHARIDE IN THE CD-1 MOUSE
Leazer, T. M., B D. Barbee, M. EbronMcCoy, G. A. HenrySam, AND J M. Rogers. ROLE OF THE MATERNAL ACUTE PHASE RESPONSE AND TUMOR NECROSIS FACTOR ALPHA IN THE DEVELOPMENTAL TOXICITY OF LIPOPOLYSACCHARIDE IN THE CD-1 MOUSE. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 16(2):173-179, (2002).
The acute phase response (APR) functions to reset metabolic homeostasis following infectious, toxic or traumatic insult. TNF- , a putative mediator of the APR, has been associated with fetal death in rodents and preterm labor and delivery in humans. We hypothesized that physiological 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- levels, measured by ELISA following administration of 0.05 mg/kg LPS on gd 9, were found to increase significantly and peak within 1-1.5 hr. Pretreatment with 0.01 mg/kg LPS on gd 8 ameliorated embryo toxicity of the 0.05 mg/kg LPS treatment on gd 9 and also eliminated the increase in serum TNF- . Direct LPS exposure in whole embryo culture was non-toxic. These data support a maternally-mediated mechanism of LPS embryolethality, and suggest that TNF- may be an important mediator of this developmental toxicity.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
REPRODUCTIVE TOXICOLOGY DIVISION
DEVELOPMENTAL BIOLOGY BRANCH