Date Created

2011

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. While 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 due to 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.

Document Type

Article

Publication Title

Toxicological Sciences

ISSN

1096-6080

Volume

116

Issue

2

First Page

632

Last Page

639

DOI

10.1093/toxsci/kfq140

Keywords

Valproic acid; Teratology; Inbred strain; Maternal effect; Histone deacetylase

Place of Publication

United Kingdom

Rights Statement

Copyright is held by the publisher. See Notes for more information.

Notes

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Toxicological Sciences following peer review. The definitive publisher-authenticated version [Toxicological Sciences (2011) 116(2): 632-639. DOI: 10.1093/toxsci/kfq140] is available online at: http://toxsci.oxfordjournals.org/content/116/2/632.full

Extent

21 pages (in manuscript)

Digital Origin

Born digital

Language

English

Publisher

Oxford University Press

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