Micronutrient imbalance and common phenotypes in neural tube defects

Abstract

Neural tube defects (NTDs) are among the most common birth defects, with a prevalence of close to 19 per 10,000 births worldwide. The etiology of NTDs is complex involving the interplay of genetic and environmental factors. Since nutrient deficiency is a risk factor and dietary changes are the major preventative measure to reduce the risk of NTDs, a more detailed understanding of how common micronutrient imbalances contribute to NTDs is crucial. While folic acid has been the most discussed environmental factor due to the success that population-wide fortification has had on prevention of NTDs, folic acid supplementation does not prevent all NTDs. The imbalance of several other micronutrients has been implicated as risks for NTDs by epidemiological studies and in vivo studies in animal models. In this review, we highlight recent literature deciphering the multifactorial mechanisms underlying NTDs with an emphasis on mouse and human data. Specifically, we focus on advances in our understanding of how too much or too little retinoic acid, zinc, and iron alter gene expression and cellular processes contributing to the pathobiology of NTDs. Synthesis of the discussed literature reveals common cellular phenotypes found in embryos with NTDs resulting from several micronutrient imbalances. The goal is to combine knowledge of these common cellular phenotypes with mechanisms underlying micronutrient imbalances to provide insights into possible new targets for preventative measures against NTDs.

Pathogenesis of neural tube defects: The regulation and disruption of cellular processes underlying neural tube closure

“…Animal models that show NTD phenotypes have been crucial for elucidating mechanism of NTC and gene action. Indeed, over 300 genes in mice play critical roles in NTC and over 80 genes in human are associated with NTDs to date (Kakebeen & Niswander, 2021; Wilde et al, 2014). However, most of the animal studies have investigated the effect of single gene, and often homozygous mutations, whereas the risk in humans of presenting with an NTD is multifactorial and often polygenic, rather than simple Mendelian inheritance due to single gene mutations (Lee & Gleeson, 2020; Neumann et al, 1994; Zohn, 2012).…”

“…Loss of apoptosis in mouse models has been observed to accompany disrupted neural fold bending and delayed NTC in the mid‐ and hind‐brain (Yamaguchi et al, 2011). Regardless of the necessity of apoptosis for NTC, there is evidence that abnormally increased apoptosis can underlie NTDs in animal models, and this can result from genetic insult, nutritional deficiencies, or pharmacological insults (Kakebeen & Niswander, 2021).…”

“…These experiments not only demonstrated a mechanism for zinc‐deficiency associated NTD risk, but also provide evidence that increased apoptosis can drive NTDs as opposed to simply accompanying them. Perhaps in a similar fashion, an excess of the drug all‐trans‐retinoic acid (RA) has also been demonstrated to induce caudal NTDs in mice and rats, which is accompanied by an increase in apoptosis (Kakebeen & Niswander, 2021; Wei et al, 2012). Notably, as discussed later, increased apoptosis is thought to be a driver of diabetes associated NTDs (Gao & Gao, 2007).…”

Identification of novel nutrient-sensitive gene regulatory networks in amniocytes from fetuses with spina bifida

“…Complex genetic and environmental contributions underly around 75% of NTDs, which have multifactorial causation 3,4 and can associate with multiple comorbidities, including placental maldevelopment and function 5 , fetal growth restriction 6 and preterm birth 7 . Nutritional factors have a well-recognised contribution to the etiology of isolated NTDs, namely folate and vitamin B12 8 , and to a lesser extent, inositol 9 , vitamin D 10 , choline 11 and essential trace elements 12,13 . Accordingly, widespread and targeted nutritional prevention strategies, such as fortification of food products with folic acid and periconceptional folic acid supplementation, have decreased NTD incidence 14 .…”

Model organisms and mechanisms of gene–environment interactions in structural birth defects

“…Thus, identifying these factors will be key toward prevention. As described in two of the reviews in this collection (Kakebeen & Niswander, 2021;Wolujewicz, Steele, Kaltschmidt, Finnell, & Ross, 2021), the success of this strategy is illustrated by the significant reduction in the incidence of neural tube defects with folic acid supplementation and fortification. However, in spite of this success, not all neural tube defects are prevented by folic acid supplementation.…”