Hatori A, Shigematsu A, McCormick A M, Willhite C C, Sharma R P
Toxicology Program, Utah State University, Logan 84322.
Exp Mol Pathol. 1991 Aug;55(1):38-54. doi: 10.1016/0014-4800(91)90017-r.
The temporal relationship between the distribution of retinoic acid, a known human and rodent teratogen, and that of cellular retinoic acid-binding protein (CRABP) was investigated from Day 11 to Day 14 of hamster prenatal development. The 11,12-(3)H2 and 15(-14C) forms of all-trans-retinoic acid were used for quantitative distribution studies and autoradiography, respectively, and were evaluated 15 min after a single intravenous injection. Radioactivity was detected in all fetal tissues examined (brain, liver, heart, spinal cord, limb, and skin), and at Day 14, approximately 66% of the total radioactivity was present as parent all-trans-retinoic acid. High concentrations of total radioactivity were observed by autoradiography in the midbrain and hindbrain (mesencephalon, metencephalon, and myelencephalon) and spinal cord, but not in the forebrain. At the earliest time studied, limb buds showed relatively high concentrations of radioactivity. Levels of radioactivity were also high in portions of the developing face, nose, and tongue. Immunohistochemical analyses indicated that the amount of CRABP in Day 14 tissues was the highest in spinal cord followed by limb and skin; heart and liver contained only relatively small amounts of this protein. From Day 11 to Day 14, the amount of CRABP, as measured by high-performance size-exclusion liquid chromatography, in the whole body decreased as gestation progressed. Microscopic immunohistochemical localization of CRABP found the highest concentration in the ventral midbrain and in the ventral and lateral sides of the hindbrain and spinal cord; CRABP was also abundant in tongue, limb, and skin. The distribution of CRABP-positive cells in the central nervous system was similar to the distribution of retinoic acid. The data presented here indicate that fetal CRABP appears to play a role in differential accumulation of retinoic acid in certain structures of the developing hamster. The patterns of tissue retinoid and CRABP distribution observed here are consistent with the patterns of congenital malformations induced by prenatal retinoid exposure.
在仓鼠产前发育的第11天至第14天期间，研究了已知的人类和啮齿类动物致畸剂视黄酸的分布与细胞视黄酸结合蛋白（CRABP）的分布之间的时间关系。全反式视黄酸的11,12-(3)H2和15(-14C)形式分别用于定量分布研究和放射自显影，并在单次静脉注射后15分钟进行评估。在所有检查的胎儿组织（脑、肝、心、脊髓、肢体和皮肤）中均检测到放射性，在第14天，约66%的总放射性以母体全反式视黄酸的形式存在。通过放射自显影观察到中脑和后脑（中脑、后脑和延髓）以及脊髓中总放射性浓度较高，而前脑中没有。在最早研究的时间点，肢芽显示出相对较高的放射性浓度。发育中的面部、鼻子和舌头的部分区域放射性水平也很高。免疫组织化学分析表明，第14天组织中CRABP的含量在脊髓中最高，其次是肢体和皮肤；心脏和肝脏中仅含有相对少量的这种蛋白质。从第11天到第14天，通过高效尺寸排阻液相色谱法测量，随着妊娠进展，全身CRABP的含量下降。CRABP的微观免疫组织化学定位发现，腹侧中脑以及后脑和脊髓的腹侧和外侧浓度最高；CRABP在舌头、肢体和皮肤中也很丰富。CRABP阳性细胞在中枢神经系统中的分布与视黄酸的分布相似。此处提供的数据表明，胎儿CRABP似乎在发育中的仓鼠某些结构中视黄酸的差异积累中起作用。此处观察到的组织类视黄醇和CRABP分布模式与产前视黄醇暴露诱导的先天性畸形模式一致。
