Valproic acid-induced fetal malformations are reduced by maternal immune stimulation with granulocyte-macrophage colony-stimulating factor or interferon-γ
Valproic acid-induced fetal malformations are reduced by maternal immune stimulation with granulocyte-macrophage colony-stimulating factor or interferon-γ
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DOI：
10.1002/ar.a.20397
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发表时间：
2006-12-01
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影响因子：
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通讯作者：
Holladay, Steven D.
中科院分区：
文献类型：
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作者：
Hrubec, Terry C.;Yan, Mingjin;Holladay, Steven D.
丙戊酸，一种通常用于治疗癫痫和其他精神疾病的药物，在暴露的胎儿中导致神经管缺陷(NTD)的比率比普通人群高20倍。神经管在发育过程中不能关闭会导致脑外畸形或无脑畸形，以及脊柱裂。在小鼠中，母体免疫系统的非特异性激活可以减少由各种原因引起的胎儿异常，包括糖尿病引起的NTDS。我们推测，用干扰素-γ和粒细胞-巨噬细胞集落刺激因子非特异性激活母体免疫系统也可以减少丙戊酸(VA)诱导的缺陷。雌性CD-1小鼠在繁殖前给予免疫刺激剂：干扰素-伽马或GM-CSF。在妊娠第8天的早晨，大约一半的对照组和免疫刺激组的雌性受试者接受500 mg/kg的维生素A。在妊娠第17天，每组至少8只母鼠的发育缺陷发生率被确定：对照组、单纯VA组、单纯干扰素组、单纯干扰素+VA组、仅GM-CSF组和GM-CSF+VA组。在单独暴露于VA的胎儿中，NTDS的发生率为18%，而在暴露于干扰素-γ+VA或GM-CSF+VA的胎儿中，NTDS的发生率分别为3.7%和2.9%。眼部缺损率也从暴露组的28.0%下降到干扰素-γ-干扰素+VA组的9.8%和GM-CSF+VA组的12.5%。母体免疫刺激预防出生缺陷的机制尚不清楚，但可能涉及母体或胎儿产生细胞因子或生长因子，以保护胎儿免受畸形物的失调影响。
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.