Gene-environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function
Open Access
- 21 August 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 17 (23), 3675-3685
- https://doi.org/10.1093/hmg/ddn262
Abstract
Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp2H) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp2H embryos, demonstrating a gene–environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation.Keywords
This publication has 49 references indexed in Scilit:
- Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell linesThe Journal of Nutritional Biochemistry, 2008
- Multiple B‐vitamin inadequacy amplifies alterations induced by folate depletion in p53 expression and its downstream effector MDM2International Journal of Cancer, 2008
- Global DNA methylation measured by liquid chromatography-tandem mass spectrometry: analytical technique, reference values and determinants in healthy subjectscclm, 2007
- Neural tube defects and folate: case far from closedNature Reviews Neuroscience, 2006
- Spontaneous neural tube defects in splotch mice supplemented with selected micronutrientsToxicology and Applied Pharmacology, 2006
- Failure of homocysteine to induce neural tube defects in a mouse modelBirth Defects Research Part B: Developmental and Reproductive Toxicology, 2006
- The genetic basis of mammalian neurulationNature Reviews Genetics, 2003
- Investigation of the effects of folate deficiency on embryonic development through the establishment of a folate deficient mouse modelTeratology, 2002
- Etiology and pathogenesis of human neural tube defectsCurrent Opinion in Pediatrics, 1994
- Neural tube defects and sex ratiosAmerican Journal of Medical Genetics, 1987