title: Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency.
abstract: Valproate (VPA) treatment in pregnancy leads to congenital anomalies, possibly by disrupting folate or homocysteine metabolism. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate interconversion and homocysteine metabolism, we addressed the possibility that VPA might have different teratogenicity in Mthfr(+/+) and Mthfr(+/-) mice and that VPA might interfere with folate metabolism through MTHFR modulation. Mthfr(+/+) and Mthfr(+/-) pregnant mice were injected with VPA on gestational day 8.5; resorption rates and occurrence of neural tube defects (NTDs) were examined on gestational day 14.5. We also examined the effects of VPA on MTHFR expression in HepG2 cells and on MTHFR activity and homocysteine levels in mice. Mthfr(+/+) mice had increased resorption rates (36%) after VPA treatment, compared to saline treatment (10%), whereas resorption rates were similar in Mthfr(+/-) mice with the two treatments (25-27%). NTDs were only observed in one group (VPA-treated Mthfr(+/+)). In HepG2 cells, VPA increased MTHFR promoter activity and MTHFR mRNA and protein (2.5- and 3.7-fold, respectively). Consistent with cellular MTHFR upregulation by VPA, brain MTHFR enzyme activity was increased and plasma homocysteine was decreased in VPA-treated pregnant mice compared to saline-treated animals. These results underscore the importance of folate interconversion in VPA-induced teratogenicity, since VPA increases MTHFR expression and has lower teratogenic potential in MTHFR deficiency.
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal Children's Hospital, Montreal, Quebec, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Roy
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D000818:Animals; D001921:Brain / Q000201:enzymology; D045744:Cell Line, Tumor; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D013723:Teratogens; D015854:Up-Regulation / Q000187:drug effects*; D014635:Valproic Acid / Q000009:adverse effects*
chemical_list: D013723:Teratogens; D006710:Homocysteine; D014635:Valproic Acid; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)