Neural tube defects are debilitating birth defects that occur when the developing neural plate fails to close in early gestation. In humans, neural tube defects are characterized by high rates of mortality and lifelong disabilities including paralysis, hydrocephalus and epilepsy. Arsenic induces neural tube defects in animal models, but whether environmental arsenic exposure increases risk of neural tube defects in humans is unknown. Studies investigating arsenic's role in human neural tube defects have been hampered by the relative rarity of these birth defects in the United States and the lack of individual measures of exposure. Though difficult to study, it is critical to understand the role of arsenic exposure in neural tube defects, as exposure to arsenic is common in the United States and throughout the world, and reduction of arsenic exposure and mitigation of arsenic toxicity may present new opportunities for prevention. Our long-range goals are to develop novel screening strategies to identify populations at high risk of neural tube defects and to direct the development of more effective preventive interventions. In this application, we present preliminary data that suggest that folic acid supplementation, currently the primary strategy for neural tube defect prevention, may be less effective in preventing neural tube defects in areas with high arsenic exposure. We now propose a comprehensive set of studies that leverage a unique case ascertainment program in rural Bangladesh, a country that is currently experiencing an epidemic of arsenic poisoning through contaminated drinking water. We plan to understand how arsenic influences risk of neural tube defects in humans through mechanisms that include disruption of maternal glucose and folate metabolism, as well as epigenetic effects. We will also test whether sweat chloride concentration, a potential new biomarker for arsenic toxicity, can be used to identify women at higher risk for having a child affected by neural tube defect. Finally, in an exploratory aim, we propose to collect and study dural tissue, obtained at the time of surgical closure of the defect, to provide insight into the epigenetic mechanisms by which prenatal arsenic exposure affects the developing nervous system. These studies explore mechanisms by which arsenic may increase risk of neural tube defects in humans, and use a unique population with high arsenic exposure in order to test hypotheses. We expect these studies to identify populations at high risk of neural tube defects due to environmental exposures as well as direct development of novel screening strategies for maternal risk. In addition, results from these studies will provie fundamental new knowledge regarding the effect of arsenic on the developing nervous system and the mechanisms that affect developmental neurotoxicity.

Public Health Relevance

This research project builds on strong preliminary data that suggests arsenic exposure is an important risk factor for neural tube defects. This project will utilize a case-control study design to enroll infants with myelomeningocele, a common subtype of neural tube defect, to investigate how maternal arsenic exposure may contribute to increased risk. Specifically, this study will investigate the arsenic's known effects on maternal glucose regulation and folate status as possible mechanisms of arsenic's toxicity in this disorder. In an exploratory aim, discarded neural tube tissue will be evaluated for epigenetic markers associated with arsenic exposure. These studies will take place in Bangladesh, a country experiencing an unprecedented epidemic of arsenic poisoning through contaminated drinking water.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-JAB-J (R0))
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Gray, Kimberly A
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Children's Hospital Boston
United States
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Lee, Jane J; Valeri, Linda; Kapur, Kush et al. (2018) Growth parameters at birth mediate the relationship between prenatal manganese exposure and cognitive test scores among a cohort of 2- to 3-year-old Bangladeshi children. Int J Epidemiol 47:1169-1179
Tauheed, Jannah; Sanchez-Guerra, Marco; Lee, Jane J et al. (2017) Associations between post translational histone modifications, myelomeningocele risk, environmental arsenic exposure, and folate deficiency among participants in a case control study in Bangladesh. Epigenetics 12:484-491
Mazumdar, Maitreyi (2017) Does arsenic increase the risk of neural tube defects among a highly exposed population? A new case-control study in Bangladesh. Birth Defects Res 109:92-98
Lee, Jane J; Kapur, Kush; Rodrigues, Ema G et al. (2017) Anthropometric measures at birth and early childhood are associated with neurodevelopmental outcomes among Bangladeshi children aged 2-3years. Sci Total Environ 607-608:475-482
Rahman, Mohammad L; Valeri, Linda; Kile, Molly L et al. (2017) Investigating causal relation between prenatal arsenic exposure and birthweight: Are smaller infants more susceptible? Environ Int 108:32-40
Kancherla, Vijaya; Ibne Hasan, Md Omar Sharif; Hamid, Rezina et al. (2017) Prenatal folic acid use associated with decreased risk of myelomeningocele: A case-control study offers further support for folic acid fortification in Bangladesh. PLoS One 12:e0188726
Wang, Zhaoxi; Claus Henn, Birgit; Wang, Chaolong et al. (2017) Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment. Environ Health 16:81
Gleason, Kelsey M; Valeri, Linda; Shankar, A H et al. (2016) Stunting is associated with blood lead concentration among Bangladeshi children aged 2-3 years. Environ Health 15:103