Merker H J, Franke L, Günther T
Naunyn Schmiedebergs Arch Pharmacol. 1975;287(4):359-76. doi: 10.1007/BF00500038.
Rats received 20, 50 or 100 mg/animal D-penicillamine i.p. twice daily on days 15, 16, 17, 18, and 19 of gestation, i.e. a total dose of 200, 500 resp. 1000 mg/animal. At all dosages the number of fetal resorptions did not increase significantly. Weight of the 20 day old embryos as well as length of the long bones in the extremities in the 100 mg-group showed a significant decrease. Numerous skeletal alterations could be observed in the 1000 mg-group such as absence, deformations or incomplete mineralisation of bones. Light microscopic examinations revealed an inhibition of the ossification as well as a decrease of number and size of the trabecula and of the thickness of the perichondrial bone sheath. A swelling of the collagenous fibrils can be demonstrated with the electron microscope. The first apatite crystals aggregate in collagen-free areas. The fusion of these aggregates to homogenously mineralized trabecula is inhibitied. In contrast to bones from untreated embryos, mineralized areas show varying content of collagen and apatide crystals. A regular spatial relationship between apatite crystals and collagenous fibrils does not develop. These findings show that even after the so-called "critical period" malformations can be pproduced by substances which disturb synthesis and maturation of the mesenchymal intercellular substance.
在妊娠第15、16、17、18和19天，给大鼠腹腔注射20、50或100mg/只的D-青霉胺，每日两次，即总剂量分别为200、500和1000mg/只。在所有剂量下，胎儿吸收的数量均未显著增加。100mg组中20日龄胚胎的体重以及四肢长骨的长度均显著降低。在1000mg组中可观察到许多骨骼改变，如骨骼缺失、变形或矿化不完全。光学显微镜检查显示骨化受到抑制，小梁的数量和大小以及软骨膜骨鞘的厚度均减少。电子显微镜检查可显示胶原纤维肿胀。第一批磷灰石晶体聚集在无胶原区域。这些聚集体融合成均匀矿化的小梁受到抑制。与未处理胚胎的骨骼相比，矿化区域显示出胶原和磷灰石晶体的含量不同。磷灰石晶体与胶原纤维之间没有形成规则的空间关系。这些发现表明，即使在所谓的“关键期”之后，干扰间充质细胞间物质合成和成熟的物质也可导致畸形。
