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
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.