Interdisciplinary approaches for understanding how arsenic and micronutrients affect the epigenome to influence spina bifida risk

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PROJECT SUMMARY/ABSTRACT Neural tube defects, including spina bifida and anencephaly, are common and severe birth defects that occur when the neural plate, the embryonic precursor to the brain and spinal cord, fails to close during early gestation. Folic acid fortification and supplementation have helped to reduce the global burden of neural tube defects; however, less than 50% of neural tube defects are estimated to be attributed to known risk factors. Arsenic contamination of drinking water continues to be a major public health threat worldwide and has been shown to induce neural tube defects in animal models. An emerging hypothesis is that arsenic acts via the epigenome, the multitude of compounds that affect the expression of genes without changing the underlying DNA sequence. In this ViCTER application, we have established a team of experts in child neurology, neurosurgery, epigenetics, developmental and molecular epidemiology, functional genomics and biostatistics to test the hypothesis that DNA methylation mediates the neurotoxicity of arsenic on the developing nervous system. Better understanding of the interplay of epigenetics, nutrition, and environmental arsenic exposure will inform strategies to prevent and treat neural tube defects. In this proposal, we establish a new basic science-clinical science consortium to assess whether arsenic induces recognizable DNA methylation changes at loci critical for normal neural tube closure. We will utilize in vitro methods and biological samples collected from an epidemiological study in Bangladesh to measure DNA methylation patterns using cutting-edge methodologies, including whole genome bisulfite sequencing and the Illumina EPIC/850K BeadChip technology. Additionally, we will investigate DNA methylation changes in genes associated with arsenic exposure and folate status following a short course of high-dose folic acid supplementation in women who previously conceived a child with a neural tube defect. This interdisciplinary and collaborative study, which includes research activities spanning basic to applied research, will seek to identify genes involved in neural tube closure that are differentially methylated in relation to arsenic exposure and folate status. This consortium effort will accelerate the translation of findings into folic acid-based preventive strategies to reduce the global burden of neural tube defects, particularly in areas with high arsenic exposure.