Genetic and Maternal Effects on Valproic Acid Teratogenesis in C57BL/6J and DBA/2J Mice

Abstract

Valproic acid (VPA) is used worldwide to treat epilepsy, migraine headaches, and bipolar disorder. However, VPA is teratogenic and in utero exposure can lead to congenital malformations. Using inbred C57BL/6J (B6) and DBA/2J (D2) mice, we asked whether genetic variation could play a role in susceptibility to VPA teratogenesis. Whereas B6 fetuses were more susceptible than D2 fetuses to digit and vertebral malformations, D2 fetuses were more susceptible to rib malformations. In a reciprocal cross between B6 and D2, genetically identical F1 mice carried in a B6 mother had a greater percentage of vertebral malformations following prenatal VPA exposure than F1 mice carried in a D2 mother. This reciprocal F1 difference is known as a maternal effect and shows that maternal genotype/uterine environment is an important mediator of VPA teratogenecity. VPA is a histone deacetylase inhibitor, and it is possible that the differential teratogenesis in B6 and D2 is because of strain differences in histone acetylation. We observed strain differences in acetylation of histones H3 and H4 in both embryo and placenta following in utero VPA exposure, but additional studies are needed to determine the significance of these changes in mediating teratogenesis. Our results provide additional support that genetic factors, both maternal and fetal, play a role in VPA teratogenesis. Lines of mice derived from B6 and D2 will be a useful model for elucidating the genetic architecture underlying susceptibility to VPA teratogenesis.

A proapoptotic effect of valproic acid on progenitors of embryonic stem cell-derived glutamatergic neurons

“…4, 18, 19 However, there are contradictory reports regarding the effects of VPA on apoptotic death of NPCs at developmentally critical periods. 28, 32 Studies have shown that the reduced (Go et al 28 ) or increased (Kataoka et al 32 ) apoptotic deaths of NPCs by VPA treatment underlie neurodevelopmental defects.…”

“…17 Several studies have proposed that HDAC inhibition by VPA is closely related to teratogenesis in vertebrate embryos. 4, 18, 19 A growing body of evidence suggests that VPA has neuroprotective and neurotrophic effects on neural progenitor cells (NPCs) and neurons, apart from its function as an AED. It promotes neuroplasticity, neurogenesis and cell survival.…”

Teratogenicity and Teratogenic Factors

“…26 The teratogenic effects of VPA could involve altered micro RNAs expression. 27,28 Various forms of VPA, and more importantly, newer generation of AEDs like lamotrigine, topiramate, and gabapentin show signals for either congenital jaw or oral malformation. 29 About half a century ago, thalidomide was widely prescribed to pregnant women as a sedative and anti-nauseant but it proved to be teratogenic, causing multiple birth defects particularly limb malformations.…”

Differences between NMRI and DBA/2J mice in the development of somites and susceptibility to methylnitrosourea-induced skeleton anomalies

“…A study by Downing et al (2010) also found differences in the teratogenic response of C57BL/6J and DBA/2J mice to a single dose of valproic acid given on GD 9, i.e., while C57BL/6J fetuses were more susceptible than DBA/2J fetuses to induction of digit (fused or missing digits) and vertebral anomalies (fused, missing and asymmetrical arches and centra), the latter strain was more susceptible than the former mouse strain for the induction of rib anomalies (fused, missing, bifurcated, and wavy/ bulbous ribs). Since the authors did not determine the number of somite pairs, inter-strain differences IBRAHIM CHAHOUD and FRANCISCO J.R. PAUMGARTTEN of developmental stages at the time of treatment cannot be ruled out as contributing factors for these differences in susceptibility to VPA-induced teratogenicity.…”

“…Moreover, it is known that, in polytocous mammals, the stage of development of individual embryos varies within the litter and between litters at a same gestational age. Nonetheless, a strain-dependent difference in the development of embryos of the same age has seldom been considered as a possible cause for inter-strain differences in susceptibility to teratogens (Linval et al 1982, Moreno and Epstein 1987, Biddle 1988, Juriloff et al 1991, Biddle et al 1993, Hall et al 1997, Datta et al 2008, Downing et al 2010. Along this line, it should be mentioned that a comparative study of the embryo development in four mouse strains (NMRI, BALB/cJ, DBA/2J and C57BL/6J) revealed remarkable differences among them in somite counts on defined gestation times (GD) between GD9 and GD12 (Thiel et al 1993).…”