Gene-environment interactions, folate metabolism and the embryonic nervous system

Abstract

Formation of brain and spinal cord requires the successful closure of neural ectoderm into an embryonic neural tube. Defects in this process result in anencephaly or spina bifida, which together constitute a leading cause of mortality and morbidity in children, affecting all ethnic and socioeconomic groups. The subject of intensive research for decades, neural tube defects (NTDs), are understood to arise from complex interactions of genes and environmental conditions, though systems-level details are still elusive. Despite the variety of underlying causes, a single intervention, folic acid supplementation given in the first gestational month, can measurably reduce the occurrence of NTDs in a population. Evidence for and the scope of gene-environment interactions in the genesis of NTDs is discussed. A systems-based approach is now possible toward studies of genetic and environmental influences underlying NTDs that will enable the assessment of individual risk and personalized optimization of prevention.

Figure 1

Folate metabolism and its contributions to physiological processes. One carbon metabolism in the cytoplasm is depicted. Colors: Blue=enzymes catalyzing folate metabolic steps; Red=important products of the pathway; Magenta=physiological processes which pathway products support. THF=tetrahydrofolate; DHF=dihydrofolate; dUMP=deoxyuridine-monophosphate; Ado-Met=S-adenosylmethionine; Ado-Hcy=S-adenosylhomocysteine; BH4=tetrahydrobiopterin; qBH2=quinonoid dihydrobiopterin; PtdMME=phosphatidylethanolamine (monomethyl); PtdDME=phosphatidylethanolamine (dimethyl); PEMT=phosphatidylethanolamine methyltransferase. FTHFS=10-formyltetrahydrofolate synthase; MTHFC=methyltetrahydrofolate cyclohydrolase; MTHFD=methyltetrahydrofolate dehydrogenase; MTHFR=methyltetrahydrofolate reductase; MS=methionine synthase; cSHMT=cytoplasmic serine hydroxymethyltransferase; DHFR=dihydrofolate reductase; TS=thymidylate synthase