Induction of Congenital Anomalies in the Progeny After Germ Cell Exposure to Radiation and Chemicals.

众所周知，辐射和化学物质会在高等植物和动物中产生可见的和致命的突变。特别是在小鼠中通过特定位点方法等进行了广泛的工作，但通过这些既定方法测试各种化学品需要大量动物。最近，野村发现，父母暴露于辐射会导致下一代小鼠先天性畸形。此外，F_1代的诱发畸形与人类相似。本课题期间所取得的实验结果总结如下。(1)先天性畸形生殖系突变检测方法的建立及其在化学品中的应用：用ENU、DMBA和4NQO及X射线进行孕前处理，可引起F_1代明显的先天性畸形。与X射线相比，精原细胞阶段对ENU的敏感性高于减数分裂后阶段，因为ENU发生在特定的位点突变。(2)用基因突变检测胎儿功能缺陷：父母暴露于ENU和X线可引起F_1胎儿呼吸窘迫，其中半数胎儿不伴形态畸形。(3)后代中诱导畸形的遗传率：侏儒症和尾部异常作为显性性状遗传，表现力降低。(4)对精子受精能力的损害：极低剂量的AS和LAS中断了人和小鼠精子对金黄地鼠卵的受精能力。(5)WHO建议：采用F_1代生殖系变异引起先天畸形作为遗传危害的检测方法。(6)未来的问题：应进行临床和流行病学调查。功能缺陷在人类中将变得更加重要。

Radiation and chemicals are well known to produce visible and lethal mutations in higher plants and animal. Especially, extensive works have been done by specific loci method, etc. In mice, but large numbers of animals are necessary to test a variety of chemicals by these established methods. Recently, Nomura found that parental exposure to radiation can cause congenital malformations in the next generation in mice. Furthermore, induced malformations in F_1 offspring were similar to those found in humans. Experimental results obtained in the term of this project were summa-rized as follows.(1) Establishment of a method to detect germ-line mutation causing congenital malformation and its application to chemicals : Preconceptional treatment with ENU, DMBA and 4NQO as well as X-rays induced a significant incidence of congenital malformations in the F_1 offspring. In contrast to X-rays, spermatogonial stage was more sensitive to ENU than post-meiotic stages as it was in the specific locus mutation.(2) Detection of functional defects by germinal mutation : Parental exposure to ENU and X-rays caused a significant incidence of respiratory distress in F_1 fetuses, and a half of them were not accompanied with morphological malformations.(3) Heritability of induced malformations in the offspring : Dwarfism and tail anomalies inherited as a dominant trait with reduced expressivity.(4) Damage to fertilization capacity of the sperm : Very low doses of AS and LAS interrupted fertilization capacity of the human and mouse sperm to golden hamster eggs.(5) WHO recommendation : Germ-line alterations causing congenital malformation in F_1 offspring was adopted as a method to detect genetic hazards.(6) Future problems : Clinical and epidemiological survey should be performed. Functional defects will become more important in human population.