McDougall Melissa, Choi Jaewoo, Truong Lisa, Tanguay Robert, Traber Maret G
Linus Pauling Institute, Oregon State University, Corvallis, OR 97330, USA; College of Public Health and Human Sciences, Oregon State University, Corvallis, OR 97330, USA.
Linus Pauling Institute, Oregon State University, Corvallis, OR 97330, USA.
Free Radic Biol Med. 2017 Sep;110:250-260. doi: 10.1016/j.freeradbiomed.2017.06.012. Epub 2017 Jun 20.
Vitamin E (α-tocopherol; VitE) is a lipophilic antioxidant required for normal embryonic development in vertebrates, but the long-term effects of embryonic VitE deficiency, and whether they are ameliorated by feeding VitE-adequate diets, remain unknown. We addressed these questions using a zebrafish (Danio rerio) model of developmental VitE deficiency followed by dietary remediation. Adult zebrafish maintained on VitE-deficient (E-) or sufficient (E+) diets were spawned to obtained E- and E+ embryos, respectively, which we evaluated up to 12 days post-fertilization (dpf). The E- group suffered significantly increased morbidity and mortality as well as altered DNA methylation status through 5 dpf when compared to E+ larvae, but upon feeding with a VitE-adequate diet from 5 to 12 dpf both the E- and E+ groups survived and grew normally; the DNA methylation profile also was similar between groups by 12 dpf. However, 12 dpf E- larvae still had behavioral defects. These observations coincided with sustained VitE deficiency in the E- vs. E+ larvae (p < 0.0001), despite adequate dietary supplementation. We also found in E- vs. E+ larvae continued docosahexaenoic acid (DHA) depletion (p < 0.0001) and significantly increased lipid peroxidation. Further, targeted metabolomics analyses revealed persistent dysregulation of the cellular antioxidant network, the CDP-choline pathway, and glucose metabolism. While anaerobic processes were increased, aerobic metabolism was decreased in the E- vs. E+ larvae, indicating mitochondrial damage. Taken together, these outcomes suggest embryonic VitE deficiency causes lasting behavioral impairments due to persistent lipid peroxidation and metabolic perturbations that are not resolved via later dietary VitE supplementation.
维生素E（α-生育酚；VitE）是脊椎动物正常胚胎发育所需的亲脂性抗氧化剂，但胚胎期维生素E缺乏的长期影响以及这些影响是否能通过喂食维生素E充足的饮食得到改善，目前尚不清楚。我们使用斑马鱼（Danio rerio）发育性维生素E缺乏模型并进行饮食补救来解决这些问题。将维持在维生素E缺乏（E-）或充足（E+）饮食的成年斑马鱼进行产卵，分别获得E-和E+胚胎，我们在受精后12天（dpf）内对其进行评估。与E+幼虫相比，E-组在5 dpf时发病率和死亡率显著增加，DNA甲基化状态也发生改变，但在5至12 dpf期间喂食维生素E充足的饮食后，E-组和E+组均存活且生长正常；到12 dpf时，两组之间的DNA甲基化谱也相似。然而，12 dpf的E-幼虫仍存在行为缺陷。这些观察结果与E-幼虫与E+幼虫相比持续存在维生素E缺乏（p < 0.0001）相一致，尽管饮食补充充足。我们还发现E-幼虫与E+幼虫相比二十二碳六烯酸（DHA）持续消耗（p < 0.0001）且脂质过氧化显著增加。此外，靶向代谢组学分析显示细胞抗氧化网络、CDP-胆碱途径和葡萄糖代谢持续失调。与E+幼虫相比，E-幼虫的无氧代谢增加，有氧代谢减少，表明线粒体受损。综上所述，这些结果表明胚胎期维生素E缺乏会导致持久的行为障碍，原因是持续的脂质过氧化和代谢紊乱，而后期饮食补充维生素E并不能解决这些问题。
