Placental improvement and reduced distal limb defects by maternal interferon-gamma injection in methylnitrosourea-exposed mice.
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.
Laudermilch
Chelsea Lee
CL
Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Department of Biomedical Sciences and Pathobiology, Blacksburg, VA 24061, USA.
Holladay
Steven David
SD
Sponenberg
Dan Phillip
DP
Saunders
Geoffrey Kirk
GK
Ward
Daniel Lee
DL
Prater
Mary Renee
MR
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
D000276:Adjuvants, Immunologic; D013723:Teratogens; D008770:Methylnitrosourea; D007371:Interferon-gamma