Premium
TNF‐α Expression in Embryos Exposed to a Teratogen
Author(s) -
IVNITSKY IRENA,
TORCHINSKY ARKADY,
GORIVODSKY MARAT,
ZEMLIAK ILONA,
ORENSTEIN HASIDA,
SAVION SHOSHANA,
SHEPSHELOVICH JEANE,
CARP HOWARD,
FEIN AMOS,
TODER VLADIMIR
Publication year - 1998
Publication title -
american journal of reproductive immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.071
H-Index - 97
eISSN - 1600-0897
pISSN - 1046-7408
DOI - 10.1111/j.1600-0897.1998.tb00430.x
Subject(s) - tumor necrosis factor alpha , embryo , teratology , andrology , biology , craniofacial , in situ hybridization , immunostaining , messenger rna , medicine , endocrinology , pregnancy , gestation , immunology , immunohistochemistry , microbiology and biotechnology , biochemistry , genetics , gene
PROBLEM: The role of tumor necrosis factor (TNF)‐α produced by embryonic cells in normal and abnormal development is poorly understood. To assess to what extent TNF‐α may be involved in the process of induced dysmorphogenesis, the expression of TNF‐α and TNF‐α receptor (TNFRI) mRNA as well as TNF‐α protein was evaluated in embryos responding to a cyclophosphamide (CP)‐induced teratogenic insult. The effect of maternal immunostimulation increasing the embryo's tolerance to CP on TNF‐α expression was also investigated. METHOD OF STUDY: ICR female mice were treated intraperitoneally with 40 mg/kg CP on day 12 of pregnancy. The immunostimulator, xenogeneic rat splenocytes, was injected intrauterine 21 days before mating. Embryos were collected on days 13, 14, or 15 of pregnancy. TNF‐α mRNA, TNFRI mRNA, and TNF‐α protein expression were evaluated by in situ hybridization and immunostaining techniques in control, teratogen‐treated, and immuno‐stimulated teratogen‐treated embryos. RESULTS: CP‐treated embryos showed severe external brain and craniofacial anomalies already visible on day 14 of pregnancy. TNF‐α mRNA transcripts were detected in cells of the brain and the head of 13‐day embryos, which preceded the occurrence of CP‐induced external craniofacial anomalies. On day 15 of pregnancy, when severe craniofacial anomalies increased, a significant increase in the intensity of TNF‐α, TNFR1 mRNA transcripts, and TNF‐α protein expression were observed in cells of the malformed regions of the head and the brain. In other nonmalformed organs of CP‐treated embryos such as the liver (not macroscopically different from controls), neither TNF‐α nor TNFR1 transcripts were detected. Immunostimulation substantially diminished the severity of CP‐induced brain and craniofacial anomalies, decreased the resorption rate, and was associated with decreased intensity of TNF‐α mRNA transcripts detected on day 15 of pregnancy in the head and the brain of CP‐treated embryos. CONCLUSIONS: TNF‐α expressed in the embryo may be one of the molecules promoting the formation of CP‐induced brain and craniofacial anomalies. The decrease of TNF‐α expression in embryos of immunostimulated females may be one of the mechanisms responsible for the increased tolerance to the teratogenic insult.