Birth Defect Amelioration and Placental Cytokine Expression in Mnu-exposed Dams Treated with Ifn-γ

BACKGROUND: Methylnitrosourea (MNU), an alkylating agent derived from creatinine metabolism, is cytotoxic, genotoxic, and mutagenic. Mid-gestational exposure to MNU leads to distal limb defects in mice. Previous studies have shown that nonspecific maternal immune stimulation protects against MNU-induced teratogenesis. A role for immune-mediated placental improvement in this effect remains uncertain. METHODS: The immune system of timed-pregnant C57BL/6N and CD-1 mice was stimulated by gestation day (GD) 7 intraperitoneal (IP) injection with the cytokine, interferon-gamma (IFN-γ). A teratogenic dose of MNU was then administered by IP injection on the morning of GD 9 to disrupt distal limb formation. Fetal limb length, body length, digital deformities and placental integrity were evaluated on GD 14. RESULTS: The incidence of syndactyly, polydactyly, and interdigital webbing in MNU-exposed mice was decreased by maternal IFN-γ treatment. In C57BL/6N mice, these defects were reduced by 47%, 100%, and 63%, respectively; as compared to previous reports in CD-1 mice, by 39%, 71%, and 20% respectively. Administration of IFN-γ significantly diminished MNU-induced endothelial and trophoblast placental damage in both strains of