TERATOGENIC EFFECTS OF SODIUM VALPROATE IN MICE AND RATS AT MIDGESTATION AND AT TERM

Citation
E. Menegola et al., TERATOGENIC EFFECTS OF SODIUM VALPROATE IN MICE AND RATS AT MIDGESTATION AND AT TERM, Teratogenesis, carcinogenesis, and mutagenesis, 16(2), 1996, pp. 97-108
Citations number
35
Categorie Soggetti
Genetics & Heredity",Toxicology,Oncology
ISSN journal
02703211
Volume
16
Issue
2
Year of publication
1996
Pages
97 - 108
Database
ISI
SICI code
0270-3211(1996)16:2<97:TEOSVI>2.0.ZU;2-T
Abstract
This experiment was carried out with the aims of comparing the embryot oxic potential of valproic acid (VPA) in rats and mice, better definin g the malformation pattern in these species, and comparing the embryot oxic 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 gestati on, and at 08:00 and 16:00 on day 8 of gestation with 0, 75, 150, or 3 00 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, an d skeletal malformations. A very high frequency (84%) of malformed emb ryos was recorded in the group of mice treated with 300 mg/kg, includi ng open brain folds (73%), somite defects (36%), and heart malformatio ns (20%). The rat embryos were less sensitive: only 43% of them were m alformed after treatment with 300 mg/kg, however, the pattern of malfo rmations was quite similar to that observed in mice. The treatment wit h 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%. Exe ncephaly and skeletal malformations were also recorded in mouse fetuse s 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 30 0 mg/kg, while the lowest dose produced only sporadic malformations. T hese results confirm that the mouse is the more sensitive species for the teratogenic effects of VPA. Furthermore, it has been shown that, i n both species, the axial skeleton is a system which is very sensitive to the teratogenic effects of VPA. The observed alterations show a po ssible link between axial specification and VPA and suggest further st udies of embryos exposed to VPA for the expression of genes controllin g the identity of vertebral segments. (C) 1996 Wiley-Liss, Inc.