Prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development.
Prenatal alcohol exposure triggers ceramide-induced apoptosis in neural crest-derived tissues concurrent with defective cranial development.
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DOI：
10.1038/cddis.2010.22
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发表时间：
2010-05-27
影响因子：
9
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中科院分区：
文献类型：
--
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胎儿酒精综合症（FAS）是由母亲在怀孕期间饮酒引起的。特定胚胎组织对乙醇敏感的原因尚不清楚。我们发现，在 E10 小鼠胚胎第一鳃弓的神经嵴衍生细胞 (NCC) 培养物中，用乙醇孵育可使凋亡细胞数量增加五倍。凋亡细胞对神经酰胺染色强烈，表明神经酰胺诱导的细胞凋亡介导乙醇对 NCC 的损伤。与 CDP-胆碱（胞二磷胆碱）一起孵育可减少细胞凋亡，CDP-胆碱是神经酰胺转化为鞘磷脂的前体。与 NCC 培养物一致，对怀孕小鼠进行乙醇插管会导致体内神经酰胺升高和 NCC 细胞凋亡增加。乙醇还会增加前列腺细胞凋亡反应 4 (PAR-4) 的蛋白质水平，PAR-4 是神经酰胺诱导细胞凋亡的敏化剂。 E18 天时，20% 的胚胎在产前乙醇暴露的同时会出现顶骨畸形。脑膜是一种源自 NCC 的组织复合体，它被破坏并产生水平降低的 TGF-β1（一种对骨骼和大脑发育至关重要的生长因子）。乙醇诱导的 NCC 细胞凋亡导致脑膜缺陷，这可能解释了 FAS 中同时存在颅骨畸形和认知迟缓的情况。此外，我们的数据表明，CDP-胆碱治疗可以减轻酒精引起的组织损伤。
Fetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy. The reason why specific embryonic tissues are sensitive toward ethanol is not understood. We found that in neural crest-derived cell (NCC) cultures from the first branchial arch of E10 mouse embryos, incubation with ethanol increases the number of apoptotic cells by fivefold. Apoptotic cells stain intensely for ceramide, suggesting that ceramide-induced apoptosis mediates ethanol damage to NCCs. Apoptosis is reduced by incubation with CDP-choline (citicoline), a precursor for the conversion of ceramide to sphingomyelin. Consistent with NCC cultures, ethanol intubation of pregnant mice results in ceramide elevation and increased apoptosis of NCCs in vivo. Ethanol also increases the protein level of prostate apoptosis response 4 (PAR-4), a sensitizer to ceramide-induced apoptosis. Prenatal ethanol exposure is concurrent with malformation of parietal bones in 20% of embryos at day E18. Meninges, a tissue complex derived from NCCs, is disrupted and generates reduced levels of TGF-β1, a growth factor critical for bone and brain development. Ethanol-induced apoptosis of NCCs leading to defects in the meninges may explain the simultaneous presence of cranial bone malformation and cognitive retardation in FAS. In addition, our data suggest that treatment with CDP-choline may alleviate the tissue damage caused by alcohol.
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