White J C, Shankar V N, Highland M, Epstein M L, DeLuca H F, Clagett-Dame M
School of Pharmacy, University of Wisconsin, Madison, WI 53706, USA.
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13459-64. doi: 10.1073/pnas.95.23.13459.
Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 micrograms of atRA per g of diet (230 micrograms per rat per day) or 250 micrograms of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 micrograms of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 micrograms of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 micrograms/g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 micrograms of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 micrograms of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 micrograms of atRA per g of diet fed to VAD dams (approximately 4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.
维生素A对于生殖和正常胚胎发育是必需的。我们已经确定，全反式维甲酸（atRA）能够支持维生素A缺乏（VAD）大鼠体内的哺乳动物胚胎发育至分娩。在胚胎第（E）0.5天，给VAD母鼠喂食每克饲料含12微克atRA（每只大鼠每天230微克）或每克饲料含250微克atRA（每只大鼠每天4.5毫克）的纯化饲料，或者喂食补充了视黄醇来源（每天100单位棕榈酸视黄酯）的纯化饲料。另外一组同时喂食每克饲料含250微克atRA和棕榈酸视黄酯。所有组胚胎存活至E12.5的情况相似。然而，每克饲料喂食12微克atRA组的胚胎发育严重异常。最显著的缺陷出现在后脑区域，包括后颅神经（IX、X、XI和XII）和耳后咽弓缺失，以及异位耳泡和前主静脉肿胀。通过喂食药理剂量的atRA（每克饲料250微克）或补充棕榈酸视黄酯，可预防E12.5时所有胚胎异常。每克饲料接受12微克atRA的VAD母鼠所产胚胎在E18.5时被吸收，而每克饲料喂食250微克atRA组的胚胎存活至分娩，但随后不久死亡。使用商业级atRA或已纯化以消除任何潜在中性类视黄醇（如视黄醇）污染的atRA可获得相同结果。因此，给VAD母鼠喂食每克饲料250微克atRA（每只大鼠每天约4.5毫克）可防止胚胎在妊娠中期死亡，并预防VAD母鼠喂食不足量atRA时出现的早期胚胎异常。
