Department of Food Science, Rutgers Center for Lipid Research, and New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, New Jersey, 08901, United States.
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065, United States.
Sci Rep. 2018 Jun 11;8(1):8834. doi: 10.1038/s41598-018-27071-3.
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 produced via the 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 the Bco2Rbp4 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 in Bco2Rbp4 but not Bco1Bco2Rbp4 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.
维生素 A 缺乏仍然是一个公共卫生问题，影响着数百万孕妇和儿童。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。胚胎可以在母体循环β-胡萝卜素的作用下生成视黄醛，然后通过对称裂解酶β-胡萝卜素 15,15'-加氧酶（BCO1）将其氧化为视黄酸。另一种裂解酶，β-胡萝卜素 9',10'-加氧酶（BCO2），在成人组织中不对称地裂解β-胡萝卜素，以防止其线粒体毒性，生成β-脱辅基-10'-视黄醛，它可以通过 BCO1 转化为视黄醇（维生素 A 及其代谢物）。然而，BCO2 在哺乳动物胚胎发生中的作用尚不清楚。我们发现，在维生素 A 缺乏易感遗传背景（Rbp4）下缺乏 BCO2 的小鼠会产生严重畸形的维生素 A 缺乏胚胎。尽管 BCO1 表达，但母体β-胡萝卜素补充会损害生育能力，并且不能恢复 Bco2Rbp4 小鼠正常的胚胎发育。这些数据表明，在严重维生素 A 缺乏的情况下，BCO2 可以防止β-胡萝卜素的毒性。相比之下，β-脱辅基-10'-视黄醛剂量依赖性地恢复了 Bco2Rbp4 但不是 Bco1Bco2Rbp4 小鼠的正常胚胎发育，这表明β-脱辅基-10'-视黄醛作为 BCO1 催化的视黄醇形成的底物有助于胚胎发生。这些发现为 BCO2 在胚胎发育中的重要作用提供了一个原理证明，并邀请考虑将β-脱辅基-10'-视黄醛作为一种营养补充剂，以维持维生素 A 缺乏的孕妇的正常胚胎发育。
