Valproic acid-induced fetal malformations are reduced by maternal immune stimulation with granulocyte-macrophage colony-stimulating factor or interferon-gamma.
Valproic acid, a drug commonly used to treat seizures and other psychiatric disorders, causes neural tube defects (NTDs) in exposed fetuses at a rate 20 times higher than in the general population. Failure of the neural tube to close during development results in exencephaly or anencephaly, as well as spina bifida. In mice, nonspecific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes-induced NTDs. We hypothesized that nonspecific activation of the maternal immune system with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce valproic acid (VA)-induced defects as well. Female CD-1 mice were given immune stimulant prebreeding: either IFN-gamma or GM-CSF. Approximately half of the control and immune-stimulated pregnant females were then exposed to 500 mg/kg VA on the morning of gestational day 8. The incidence of developmental defects was determined on gestational day 17 from at least eight litters in each of the following treatment groups: control, VA only, IFN-gamma only, IFN-gamma+VA, GM-CSF only, and GM-CSF+VA. The incidence of NTDs was 18% in fetuses exposed to VA alone, compared to 3.7% and 2.9% in fetuses exposed to IFN-gamma+VA, or GM-CSF+VA respectively. Ocular defects were also significantly reduced from 28.0% in VA exposed groups to 9.8% in IFN-gamma+VA and 12.5% in GM-CSF+VA groups. The mechanisms by which maternal immune stimulation prevents birth defects remain unclear, but may involve maternal or fetal production of cytokines or growth factors which protect the fetus from the dysregulatory effects of teratogens.
Hrubec
Terry C
TC
Department of Biomedical Science, E. Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia 24060, USA. thrubec@vcom.vt.edu
Yan
Mingjin
M
Ye
Keying
K
Salafia
Carolyn M
CM
Holladay
Steven D
SD
D000014:Abnormalities, Drug-Induced / Q000517:prevention & control*; D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005141:Eyelid Diseases / Q000139:chemically induced / Q000517:prevention & control; D005143:Eyelids / Q000002:abnormalities / Q000187:drug effects; D005260:Female; D005313:Fetal Death; D005327:Fetal Resorption; D020567:Fetal Weight / Q000187:drug effects; D005865:Gestational Age; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced / Q000517:prevention & control*; D010920:Placenta / Q000187:drug effects; D011247:Pregnancy; D013997:Time Factors; D014635:Valproic Acid / Q000633:toxicity*
D000276:Adjuvants, Immunologic; D000927:Anticonvulsants; D014635:Valproic Acid; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor