Effect of multifactorial genetic liability to exencephaly on the teratogenic effect of valproic acid in mice.
The present study shows that the multifactorial genetic liability to spontaneous exencephaly in the SELH/Bc mouse strain (10-20% of embryos) also confers an elevated risk of exencephaly induced by valproic acid. Treatment of pregnant dams (600 mg/kg sodium valproate in distilled water, i.p.) during the critical period on day 8 (D8) of gestation resulted in D14 exencephaly frequencies of 69% in SELH/Bc contrasted with 39% in each of the SWV/Bc and ICR/Bc strains. Analysis of these data under the assumptions of the threshold model indicated that the valproic acid-induced-shift in mean liability was similar for all three strains, and therefore the effects of genotype and teratogen were additive, not synergistic. A similar exencephaly response pattern for the same three strains was observed previously with retinoic acid [Tom et al. (1991) Teratology 43:27-40], a pattern that, combined with the data of Finnell et al. [(1988) Teratology 38:313-320], argues that strain differences in exencephaly response are not due to strain differences in teratogen metabolism. SWV/Bc and ICR/Bc embryos differ in location of the Closure 2 initiation site of cranial neural tube closure [Juriloff et al. (1991) Teratology 44:225-233], but the observation that they do not differ in risk of exencephaly produced by either valproic acid or retinoic acid contradicts the hypothesis that this particular morphological difference underlies strain differences in exencephaly risk. The high exencephaly response of SELH/Bc to two teratogens predicts that human conceptuses with a genetically determined elevated risk for neural tube defects could be easily tipped into high risk by mild teratogens.
Hall
J L
JL
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Harris
M J
MJ
Juriloff
D M
DM
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000196:embryology; D004198:Disease Susceptibility; D005260:Female; D005313:Fetal Death; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity*; D014635:Valproic Acid / Q000633:toxicity*
D013723:Teratogens; D014635:Valproic Acid