Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4‐propyl‐4‐pentenoic acid metabolite

Abstract

The teratogenic effects of valproic acid and its 4-propyl-4-pentenoic acid (4-en) metabolite were investigated in three inbred mouse strains that were known to possess differing sensitivity to heat-induced neural tube defects. In the heat-resistant DBA/2J strain, administration of either valproic acid or the metabolite during the critical period of neural tube development failed to produce any abnormal offspring. Similar treatment in the moderately heat-sensitive LM/Bc strain resulted in up to 19.8% exencephalic fetuses. The highly heat-sensitive SWV strain was also very susceptible to the induction of neural tube defects by either valproic acid or its 4-en metabolite. When administered on gestational day 8 plus 12 hours, the parent compound produced 35% exencephalic fetuses, while the metabolite had a response frequency of 32.4%. Thus, the hierarchy of susceptibility for the induction of neural tube defects in these inbred mouse strains was exactly the same whether the teratogen was a physical agent such as hyperthermia or a chemical compound such as valproic acid. If such diverse agents as these should interact to produce malformations, then it is possible that a wide variety of other agents might interact in a similar manner to produce neural tube defects.

Strain-dependent alterations in the expression of folate pathway genes following teratogenic exposure to valproic acid in a mouse model

“…While the highly sensitive SWV fetuses had exencephaly response frequencies approaching 80% affected when the dams received a single intraperitoneal injection of valproic acid, less than 30% of the LM/Bc fetuses were affected following an identical valproic acid exposure. This large difference in the response frequencies to valproic acid-induced exencephaly in the 2 mouse strains suggests that susceptibility to these malformations has a strong genetic component [Finnell et al, 1986[Finnell et al, , 1988Finnell, 1991;Seller et al, 1979]. Given the abundance of highly suggestive clinical and experimental literature published during the last few years linking folates and neural tube defects, we focused our initial efforts to explain the strain differences on a few genes involved in folate transport and metabolism.…”

“…The highly inbred SWV and LM/Bc mouse strains were selected for these studies on the basis of their known differences in sensitivity to valproic acidinduced neural tube defects [Finnell et al, 1988]. The mice were maintained on a 12-hour light cycle in the Laboratory Animal Resources and Research Facility at the College of Veterinary Medicine, Texas A&M University.…”

“…Most clinical and epidemiologic studies show that the incidence of congenital malformations among the offspring of antiepileptic drugtreated women with seizure disorders is approximately 2-3 times the rate observed in either nontreated epileptics, or that of the general population . The nature of the adverse effects of antiepileptic drugs on developing fetuses has been well documented in these human clinical and epidemiologic studies, and many of the clinical observations have been faithfully replicated in experimental animals [Finnell, 1981;Finnell et al, 1988Finnell et al, , 1989; for review see Finnell and Dansky, 1991].…”

“…Given the relationship between valproic acid exposure and neural tube defects in humans, and the wellestablished differences in susceptibility to valproic acid-induced neural tube defects in highly inbred mouse strains [Finnell et al, 1988], we were interested in examining potential differences in gene expression that might explain the observed differences in embryonic sensitivity. We selected the folate binding protein genes (FBP-1 and FBP-2) for examination as they are critical for folate binding and transport into the cytoplasm of the cell.…”

Animal models of neural tube defects

“…Valproic acid causes exencephaly and less commonly spina bifida in genetically normal mouse embryos [Ehlers et al, 1992a;Finnell et al, 1988]. The risk differs among normal genetically different strains and the genes responsible are probably directly involved in neural tube closure, rather than in metabolism of valproic acid [Finnell et al, 1988].…”