Too Much of a Good Thing? Considering Gene-Environment Interactions in Health and Disease

Neural tube defects (NTDs), like spina bifida, are a devastating and common birth defect, with current rates ranging from less than 1 to 10 per 1,000 births worldwide. Environmental factors influence the risk for NTDs. Certain medications, diabetes, obesity, and nutrient deficiencies are associated with a greater risk for NTDs. A key public health breakthrough was the recognition that low folate levels can increase the risk for NTDs and that taking synthetic folic acid (FA) could help prevent NTDs. Currently, more than 80 countries have implemented mandatory FA fortification campaigns. Key questions remain as to what role FA plays in affecting neural tube closure rates, and how FA may modify the underlying genetic risks for NTD. Moreover, the combination of FA fortification and multiple supplements has significantly increased FA intake, yet the consequences for human health are debated and it is unknown whether particular genetic backgrounds may be sensitive to FA levels.

We have been exploring these questions starting with mouse models of NTDs and multi-generational diets that differ only in FA levels to better mimic the multi-generational exposure of the human population to FA since mandatory fortification in the early 1990s. Our results show predicted beneficial effects, as well as some surprising effects including unexpected loss of mutant embryos early in development as well as an adverse effect of increased NTD risk with FA supplementation. We have honed in on a biological process that appears particularly susceptible to increased FA intake. Mutations in cilia genes in both mouse and human result in ciliopathies and NTDs. We find that mice carrying mutations that affect cilia form and function respond detrimentally to enriched FA diets. On the positive side, moderate FA diets can prevent NTD and other ciliopathies. We have extended these findings using cells from ciliopathy patients. Mechanistically we suggest that FA through its role in methylation may lead to epigenetic changes and transcriptional variability. While it is clear at a population level that FA fortification is beneficial for preventing NTDs in humans, our studies raise the possibility of unintended consequences of increasing FA levels, and that perhaps some cilia-related deficits could be ameliorated by the moderation of FA levels.