β-apo-10'-carotenoids support normal embryonic development during vitamin A deficiency.
β-apo-10'-carotenoids support normal embryonic development during vitamin A deficiency.
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β-apo-10-类胡萝卜素支持维生素 A 缺乏期间的正常胚胎发育。
DOI：
10.1038/s41598-018-27071-3
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发表时间：
2018
影响因子：
4.6
通讯作者：
Quadro,Loredana
中科院分区：
文献类型：
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作者：
Spiegler,Elizabeth;Kim,Youn-Kyung;Hoyos,Beatrice;Narayanasamy,Sureshbabu;Jiang,Hongfeng;Savio,Nicole;CurleyJr,RobertW;Harrison,EarlH;Hammerling,Ulrich;Quadro,Loredana
维生素A缺乏症仍然是影响数百万孕妇和儿童的一个公共卫生问题。视黄酸是维生素A的活性形式，对哺乳动物胚胎的正常发育至关重要。胚胎可以从母体循环中的β-胡萝卜素经维生素对称裂解酶β-胡萝卜素15，15 ′-加氧酶（BCO 1）产生的视黄醇氧化生成视黄酸。另一种裂解酶β-胡萝卜素9′，10 ′-加氧酶（BCO 2）在成体组织中不对称地裂解β-胡萝卜素以防止其线粒体毒性，产生β-apo-10′-胡萝卜醛，其可通过BCO 1转化为类维生素A（维生素A及其代谢产物）。然而，BCO 2在哺乳动物胚胎发生中的作用尚不清楚。我们发现，缺乏维生素A缺乏易感遗传背景（Rbp 4 −/−）的小鼠产生严重畸形的维生素A缺乏胚胎。母体补充β-胡萝卜素会损害生育能力，尽管BCO 1表达，但BCO 2 −/− Rbp 4 −/−小鼠的胚胎发育并没有恢复正常。这些数据表明，在严重维生素A缺乏的情况下，BCO 2可防止胚胎发生过程中β-胡萝卜素的毒性。相比之下，β-apo-10′-胡萝卜素醛剂量依赖性地恢复了Bco 2 −/− Rbp 4 −/−小鼠的正常胚胎发育，但Bco 1 −/− Bco 2 −/− Rbp 4 −/−小鼠没有，这表明β-apo-10′-胡萝卜素醛作为Bco 1催化的类维生素A形成的底物促进了胚胎发生。这些发现为BCO 2在胚胎发育中的重要作用提供了原则证明，并邀请考虑将β-apo-10′-胡萝卜素醛作为营养补充剂，以维持维生素A缺乏的孕妇的正常胚胎发育。
Vitamin A deficiency is still a public health concern affecting millions of pregnant women and children. Retinoic acid, the active form of vitamin A, is critical for proper mammalian embryonic development. Embryos can generate retinoic acid from maternal circulating β-carotene upon oxidation of retinaldehyde producedviathe symmetric cleavage enzyme β-carotene 15,15′-oxygenase (BCO1). Another cleavage enzyme, β-carotene 9′,10′-oxygenase (BCO2), asymmetrically cleaves β-carotene in adult tissues to prevent its mitochondrial toxicity, generating β-apo-10′-carotenal, which can be converted to retinoids (vitamin A and its metabolites) by BCO1. However, the role of BCO2 during mammalian embryogenesis is unknown. We found that mice lacking BCO2 on a vitamin A deficiency-susceptible genetic background (Rbp4−/−) generated severely malformed vitamin A-deficient embryos. Maternal β-carotene supplementation impaired fertility and did not restore normal embryonic development in theBco2−/−Rbp4−/−mice, despite the expression of BCO1. These data demonstrate that BCO2 prevents β-carotene toxicity during embryogenesis under severe vitamin A deficiency. In contrast, β-apo-10′-carotenal dose-dependently restored normal embryonic development inBco2−/−Rbp4−/−but notBco1−/−Bco2−/−Rbp4−/−mice, suggesting that β-apo-10′-carotenal facilitates embryogenesis as a substrate for BCO1-catalyzed retinoid formation. These findings provide a proof of principle for the important role of BCO2 in embryonic development and invite consideration of β-apo-10′-carotenal as a nutritional supplement to sustain normal embryonic development in vitamin A-deprived pregnant women.