title: Placental improvement and reduced distal limb defects by maternal interferon-gamma injection in methylnitrosourea-exposed mice.
abstract: 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 GD 7 intraperitoneal (IP) injection with the cytokine interferon-gamma (IFN-gamma). 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-gamma treatment. In C57BL/6N mice, these defects were reduced by 47, 100, and 63%, respectively, as compared to previous reports on CD-1 mice, by 39, 71, and 20%, respectively. Administration of IFN-gamma significantly diminished MNU-induced endothelial and trophoblast placental damage in both strains of mice.
  
  
  CONCLUSIONS
  These findings support a possible link between maternal immunity, placental integrity, and fetal distal limb development. Further, these results suggest that IFN-gamma might act through placental improvement to indirectly protect against MNU-induced fetal limb malformations.
authors.affiliation: Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Department of Biomedical Sciences and Pathobiology, Blacksburg, VA 24061, USA.
authors.forename: Chelsea Lee
authors.initials: CL
authors.lastname: Laudermilch
authors.forename: Steven David
authors.initials: SD
authors.lastname: Holladay
authors.forename: Dan Phillip
authors.initials: DP
authors.lastname: Sponenberg
authors.forename: Geoffrey Kirk
authors.initials: GK
authors.lastname: Saunders
authors.forename: Daniel Lee
authors.initials: DL
authors.lastname: Ward
authors.forename: Mary Renee
authors.initials: MR
authors.lastname: Prater
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D005865:Gestational Age; D007107:Immune System / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D038061:Lower Extremity Deformities, Congenital / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D008431:Maternal-Fetal Exchange; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010920:Placenta / Q000276:immunology*; D011247:Pregnancy; D011897:Random Allocation; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors; D014327:Trophoblasts / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D013723:Teratogens; D008770:Methylnitrosourea; D007371:Interferon-gamma