Metabolite Profiling of Whole Murine Embryos Reveals Metabolic Perturbations Associated with Maternal Valproate-induced Neural Tube Closure Defects

Overview

Journal Birth Defects Res

Specialties Reproductive Medicine
Toxicology

Date 2016 Nov 19

PMID 27860192

Citations 7

Authors

Darya Akimova

Bogdan J Wlodarczyk

Ying Lin

M Elizabeth Ross

Richard H Finnell

Qiuying Chen

Steven S Gross

Affiliations

Soon will be listed here.

Abstract

Background: Valproic acid (VPA) is prescribed therapeutically for multiple conditions, including epilepsy. When taken during pregnancy, VPA is teratogenic, increasing the risk of several birth and developmental defects including neural tube defects (NTDs). The mechanism by which VPA causes NTDs remains controversial and how VPA interacts with folic acid (FA), a vitamin commonly recommended for the prevention of NTDs, remains uncertain. We sought to address both questions by applying untargeted metabolite profiling analysis to neural tube closure (NTC) stage mouse embryos.

Methods: Pregnant SWV dams on either a 2 ppm or 10 ppm FA supplemented diet were injected with a single dose of VPA on gestational day E8.5. On day E9.5, the mouse embryos were collected and evaluated for NTC status. Liquid chromatography coupled to mass spectrometry metabolomics analysis was performed to compare metabolite profiles of NTD-affected VPA-exposed whole mouse embryos with profiles from embryos that underwent normal NTC from control dams.

Results: NTDs were observed in all embryos from VPA-treated dams and penetrance was not diminished by dietary FA supplementation. The most profound metabolic perturbations were found in the 10ppm FA VPA-exposed mouse embryos, compared with the other three treatment groups. Affected metabolites included amino acids, nucleobases and related phosphorylated nucleotides, lipids, and carnitines.

Conclusion: Maternal VPA treatment markedly perturbed purine and pyrimidine metabolism in E9.5 embryos. In combination with a high FA diet, VPA treatment resulted in gross metabolic changes, likely caused by a multiplicity of mechanisms, including an apparent disruption of mitochondrial beta-oxidation. Birth Defects Research 109:106-119, 2017. © 2016 Wiley Periodicals, Inc.

Citing Articles

Secretome profiling reveals acute changes in oxidative stress, brain homeostasis, and coagulation following short-duration spaceflight.

Houerbi N, Kim J, Overbey E, Batra R, Schweickart A, Patras L Nat Commun. 2024; 15(1):4862.

PMID: 38862464 PMC: 11166969. DOI: 10.1038/s41467-024-48841-w.

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review.

Ornoy A, Echefu B, Becker M Int J Mol Sci. 2024; 25(1).

PMID: 38203562 PMC: 10779436. DOI: 10.3390/ijms25010390.

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress.

Liang Y, Wang Y, Zhang X, Jin S, Guo Y, Yu Z Acta Biochim Biophys Sin (Shanghai). 2023; 56(1):23-33.

PMID: 38062774 PMC: 10875364. DOI: 10.3724/abbs.2023234.

Global metabolomic profiling reveals hepatic biosignatures that reflect the unique metabolic needs of late-term mother and fetus.

Saini N, Virdee M, Helfrich K, Kwan S, Smith S Metabolomics. 2021; 17(2):23.

PMID: 33550560 PMC: 8543356. DOI: 10.1007/s11306-021-01773-8.

Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease).

Sindelar M, Dyke J, Deeb R, Sondhi D, Kaminsky S, Kosofsky B Sci Rep. 2018; 8(1):15229.

PMID: 30323181 PMC: 6189193. DOI: 10.1038/s41598-018-33449-0.

References

Gottlicher M, Minucci S, Zhu P, Kramer O, SCHIMPF A, Giavara S . Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001; 20(24):6969-78. PMC: 125788. DOI: 10.1093/emboj/20.24.6969. View

Jentink J, Loane M, Dolk H, Barisic I, Garne E, Morris J . Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med. 2010; 362(23):2185-93. DOI: 10.1056/NEJMoa0907328. View

Christensen K, Mikael L, Leung K, Levesque N, Deng L, Wu Q . High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015; 101(3):646-58. PMC: 4340065. DOI: 10.3945/ajcn.114.086603. View

Wilde J, Petersen J, Niswander L . Genetic, epigenetic, and environmental contributions to neural tube closure. Annu Rev Genet. 2014; 48:583-611. PMC: 4649936. DOI: 10.1146/annurev-genet-120213-092208. View

Lheureux P, Penaloza A, Zahir S, Gris M . Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?. Crit Care. 2005; 9(5):431-40. PMC: 1297603. DOI: 10.1186/cc3742. View

Wegner C, Nau H . Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. Neurology. 1992; 42(4 Suppl 5):17-24. View

Hansler A, Chen Q, Gray J, Ross M, Finnell R, Gross S . Untargeted metabolite profiling of murine embryos to reveal metabolic perturbations associated with neural tube closure defects. Birth Defects Res A Clin Mol Teratol. 2014; 100(8):623-32. PMC: 4146720. DOI: 10.1002/bdra.23272. View

Sadler T . Embryology of neural tube development. Am J Med Genet C Semin Med Genet. 2005; 135C(1):2-8. DOI: 10.1002/ajmg.c.30049. View

Jentink J, Bakker M, Nijenhuis C, Wilffert B, de Jong-van den Berg L . Does folic acid use decrease the risk for spina bifida after in utero exposure to valproic acid?. Pharmacoepidemiol Drug Saf. 2010; 19(8):803-7. DOI: 10.1002/pds.1975. View

10.

Silva M, Aires C, Luis P, Ruiter J, IJlst L, Duran M . Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis. 2008; 31(2):205-16. DOI: 10.1007/s10545-008-0841-x. View

11.

Tung E, Winn L . Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol. 2011; 80(6):979-87. DOI: 10.1124/mol.111.072314. View

12.

Vaz F, Wanders R . Carnitine biosynthesis in mammals. Biochem J. 2002; 361(Pt 3):417-29. PMC: 1222323. DOI: 10.1042/0264-6021:3610417. View

13.

Ponchaut S, Van Hoof F, Veitch K . In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions. Biochem Pharmacol. 1992; 43(11):2435-42. DOI: 10.1016/0006-2952(92)90324-c. View

14.

Ornoy A . Valproic acid in pregnancy: how much are we endangering the embryo and fetus?. Reprod Toxicol. 2009; 28(1):1-10. DOI: 10.1016/j.reprotox.2009.02.014. View

15.

Hansen D, Grafton T, Dial S, Gehring T, Siitonen P . Effect of supplemental folic acid on valproic acid-induced embryotoxicity and tissue zinc levels in vivo. Teratology. 1995; 52(5):277-85. DOI: 10.1002/tera.1420520506. View

16.

Greene N, Copp A . Neural tube defects. Annu Rev Neurosci. 2014; 37:221-42. PMC: 4486472. DOI: 10.1146/annurev-neuro-062012-170354. View

17.

Elmazar M, Thiel R, Nau H . Effect of supplementation with folinic acid, vitamin B6, and vitamin B12 on valproic acid-induced teratogenesis in mice. Fundam Appl Toxicol. 1992; 18(3):389-94. DOI: 10.1016/0272-0590(92)90137-7. View

18.

Reeves P . Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr. 1997; 127(5 Suppl):838S-841S. DOI: 10.1093/jn/127.5.838S. View

19.

Nau H . Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol Appl Pharmacol. 1985; 80(2):243-50. DOI: 10.1016/0041-008x(85)90081-x. View

20.

Dunning K, Cashman K, Russell D, Thompson J, Norman R, Robker R . Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biol Reprod. 2010; 83(6):909-18. DOI: 10.1095/biolreprod.110.084145. View