Prenatal arsenic exposure, folic acid use and spina bifida in Bangladesh

Abstract

Spina bifida, a severe neural tube defect, constitutes a substantial population health burden globally. It increases the risk of stillbirth, infant and child mortality, and multiple neurological conditions, including lower limb paralysis and urinary and fecal incontinence. The etiology of spina bifida is multifactorial, and the prevalence varies greatly across different populations. Prenatal folic acid supplementation is an effective strategy for prevention of spina bifida; folic acid corrects folate deficiency and supports multiple essential reactions during neural tube development. However, folic acid alone does not lead to complete prevention of spina bifida, and the interactions of folic acid and naturally occurring folate with genetic and environmental factors are not fully understood. Arsenic exposure is a risk factor for spina bifida, and arsenic toxicity is closely linked to folate metabolism. Animal studies have shown that arsenic exposure increases the risk of neural tube defects by influencing folate metabolism and reducing available methyl groups. The risk of neural tube defects was particularly high in animals with folate deficiencies and those with genetic mutations related to folate metabolism. Epidemiologic studies also showed varying risks of spina bifida by arsenic exposure and mothers’ folic acid use. The association between arsenic exposure and spina bifida and its interactions with folic acid is particularly important for the population in Bangladesh. The country experiences widespread groundwater arsenic pollution, prevalent folate deficiency, and a higher prevalence of spina bifida and other neural tube defects. Therefore, this dissertation aims to understand the interactions between prenatal arsenic exposure, folic acid, and genetic factors on spina bifida risk in Bangladesh. Overview of Dissertation The first two studies utilized data from a case-control study at the National Institute of Neurosciences & Hospital, Dhaka, Bangladesh. The first study examined the associations between mothers' arsenic exposure and spina bifida risk. This study showed evidence of effect modification—the association between mothers' folic acid use and spina bifida risk differed by mothers’ toenail arsenic concentrations. Folic acid use reduced the risk of spina bifida among mothers with lower arsenic exposure, but this association was not observed among mothers with higher arsenic exposure. The second study explored the potential interactions between mothers' toenail arsenic concentrations and polymorphisms in both mothers' and infants' arsenic and folate metabolism genes. In this paper, we found that infants' AS3MT, MTR, and mothers' CBS and DNMT1 variants interacted with mothers' arsenic exposure to alter the risk of spina bifida. In the third study, we reviewed existing literature to estimate spina bifida prevalence in Bangladesh. Additionally, we assessed the prevention of neural tube defects under different folic acid provisions and arsenic reduction strategies in a hypothetical cohort with high arsenic exposure in Bangladesh. This study quantified the reduction in the prevalence and number of cases with neural tube defects when combining folic acid provision and arsenic reduction strategies. These studies expand the current understanding of the interaction between arsenic and folic acid, which influences the risk of spina bifida in Bangladesh. The dissertation advocates the approach of integrating environmental health interventions and nutritional strategies to optimize the prevention of spina bifida and neural tube defects. Specifically, the dissertation highlights the importance of addressing environmental arsenic exposure to enhance spina bifida prevention, especially in Bangladesh, where arsenic exposure remains prevalent.