Menegola E, Broccia M L, Nau H, Prati M, Ricolfi R, Giavini E
Department of Biology, University of Milan, Italy.
Teratog Carcinog Mutagen. 1996;16(2):97-108. doi: 10.1002/(SICI)1520-6866(1996)16:2<97::AID-TCM4>3.0.CO;2-A.
This experiment was carried out with the aims of comparing the embryotoxic potential of valproic acid (VPA) in rats and mice, better defining the malformation pattern in these species, and comparing the embryotoxic effects detectable in mid-pregnancy to those observed in fetuses at term. Pregnant CD:Crl rats were treated subcutaneously (s.c.) at 08:00, 16:00, and 00:00 on day 9 of gestation with 0, 150, or 300 mg/ kg VPA; pregnant NMRI mice were treated s.c. at 00:00 on day 7 of gestation, and at 08:00 and 16:00 on day 8 of gestation with 0,75, 150, or 300 mg/kg VPA. Groups of females were killed on day 9 (mice) or day 11 (rats) of pregnancy and their embryos were carefully examined under a dissecting microscope. The remaining females were killed 1 day before parturition and their fetuses were examined for external, visceral, and skeletal malformations. A very high frequency (84%) of malformed embryos was recorded in the group of mice treated with 300 mg/kg, including open brain folds (73%), somite defects (36%), and heart malformations (20%). The rat embryos were less sensitive: only 43% of them were malformed after treatment with 300 mg/ kg, however, the pattern of malformations was quite similar to that observed in mice. The treatment with 150 mg/kg produced about 32% malformed embryos in mice and only 8.5% in rats. More than 84% of mouse fetuses from mothers treated with the highest dose showed a severe form of exencephaly. The axial skeleton was also severely affected. The postimplantation loss reached 52%. Exencephaly and skeletal malformations were also recorded in mouse fetuses from mothers exposed to 150 mg/kg. The dose of 75 mg/kg was without effects. Exencephaly was not observed in rat fetuses at term. In this species the axial skeleton was the most severely affected region at 300 mg/kg, while the lowest dose produced only sporadic malformations. These results confirm that the mouse is the more sensitive species for the teratogenic effects of VPA. Furthermore, it has been shown that, in both species, the axial skeleton is a system which is very sensitive to the teratogenic effects of VPA. The observed alterations show a possible link between axial specification and VPA and suggest further studies of embryos exposed to VPA for the expression of genes controlling the identity of vertebral segments.
本实验旨在比较丙戊酸（VPA）对大鼠和小鼠的胚胎毒性潜力，更好地确定这些物种中的畸形模式，并比较妊娠中期可检测到的胚胎毒性效应与足月胎儿中观察到的效应。妊娠第9天的CD:Crl孕鼠于08:00、16:00和00:00皮下注射（s.c.）0、150或300mg/kg VPA；妊娠第7天的NMRI孕鼠于00:00皮下注射，妊娠第8天的08:00和16:00皮下注射0、75、150或300mg/kg VPA。在妊娠第9天（小鼠）或第11天（大鼠）处死一组雌性动物，并在解剖显微镜下仔细检查其胚胎。其余雌性动物在分娩前1天处死，并检查其胎儿的外部、内脏和骨骼畸形。在接受300mg/kg治疗的小鼠组中记录到非常高频率（84%）的畸形胚胎，包括开放性脑褶（73%）、体节缺陷（36%）和心脏畸形（20%）。大鼠胚胎较不敏感：用300mg/kg治疗后只有43%畸形，然而，畸形模式与在小鼠中观察到的相当相似。150mg/kg的治疗在小鼠中产生约32%的畸形胚胎，在大鼠中仅产生8.5%。来自接受最高剂量治疗的母亲的小鼠胎儿中超过84%表现出严重的无脑畸形形式。轴向骨骼也受到严重影响。植入后损失达到52%。在暴露于150mg/kg的母亲的小鼠胎儿中也记录到无脑畸形和骨骼畸形。75mg/kg的剂量没有影响。足月大鼠胎儿中未观察到无脑畸形。在该物种中，轴向骨骼是在300mg/kg时受影响最严重的区域，而最低剂量仅产生散发性畸形。这些结果证实小鼠对VPA的致畸作用更敏感。此外，已经表明，在这两个物种中，轴向骨骼是对VPA的致畸作用非常敏感的系统。观察到的改变显示了轴向特化与VPA之间的可能联系，并建议对暴露于VPA的胚胎进行进一步研究，以研究控制椎骨节段身份的基因的表达。
