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Spina bifida is a type of neural tube defect (NTD); NTDs are developmental malformations of the spinal cord that result from failure of neural tube closure during embryogenesis and are likely caused by interactions between genetic and environmental factors. Arsenic induces NTDs in animal models, and studies demonstrate that mice with genetic defects related to folate metabolism are more susceptible to arsenic's effects. We sought to determine whether 25 single-nucleotide polymorphisms (SNPs) in genes involved in folate and arsenic metabolism modified the associations between maternal arsenic exposure and risk of spina bifida (a common NTD) among a hospital-based case-control study population in Bangladesh. We used data from 262 mothers and 220 infants who participated in a case‒control study at the National Institutes of Neurosciences & Hospital and Dhaka Shishu Hospital in Dhaka, Bangladesh. Neurosurgeons assessed infants using physical examinations, review of imaging, and we collected histories using questionnaires. We assessed arsenic from mothers' toenails using inductively coupled plasma mass spectrometry (ICP-MS), and we genotyped participants using the Illumina Global Screening Array v1.0. We chose candidate genes and SNPs through a review of the literature. We assessed SNP-environment interactions using interaction terms and stratified models, and we assessed gene-environment interactions using interaction sequence/SNP-set kernel association tests (iSKAT). The median toenail arsenic concentration was 0.42 μg/g (interquartile range [IQR]: 0.27–0.86) among mothers of cases and 0.47 μg/g (IQR: 0.30–0.97) among mothers of controls. We found an two SNPs in the infants' AS3MT gene (rs11191454 and rs7085104) and one SNP in mothers' DNMT1 gene (rs2228611) were associated with increased odds of spina bifida in the setting of high arsenic exposure (rs11191454, OR 3.01, 95% CI: 1.28–7.09; rs7085104, OR 2.33, 95% CI: 1.20–4.and rs2228611, OR 2.11, 95% CI: 1.11–4.01), along with significant SNP-arsenic interactions. iSKAT analyses revealed significant interactions between mothers' toenail concentrations and infants' AS3MT and MTR genes (p = 0.02), and mothers' CBS gene (p = 0.05). Our results support the hypothesis that arsenic increases spina bifida risk via interactions with folate and arsenic metabolic pathways and suggests that individuals in the population who have certain genetic polymorphisms in genes involved with arsenic and folate metabolism may be more susceptible than others to the arsenic teratogenicity. • Our study takes place in Bangladesh, a country with exposure to arsenic. • Genetic susceptibility may affect the association between arsenic and NTDs. • Variants in AS3MT , MTR , and DNMT1 were associated with higher risk with arsenic. [ABSTRACT FROM AUTHOR]

• Limited human research explores parental metal levels and neural tube defect risk. • Our novel study examined the relationship using 18 metals measured in both parents. • Maternal toenail Se and Zn were associated with spina bifida in adjusted models. • Elevated paternal metals (i.e. As, Fe, and Se) were linked to spina bifida in infants. • Research that examines interventions that target paternal exposure is needed. Neural tube defects are a pressing public health concern despite advances in prevention from folic acid-based strategies. Numerous chemicals, in particular arsenic, have been associated with neural tube defects in animal models and could influence risk in humans. We investigated the relationship between parental exposure to arsenic and 17 metals and risk of neural tube defects (myelomeningocele and meningocele) in a case control study in Bangladesh. Exposure assessment included analysis of maternal and paternal toenail samples using inductively coupled plasma mass spectrometry (ICP-MS). A total of 278 participants (155 cases and 123 controls) with data collected from 2016 to 2020 were included in the analysis. In the paternal models, a one-unit increase in the natural logarithm of paternal toenail arsenic was associated with a 74% (odds ratio: 1.74, 95% confidence interval: 1.26–2.42) greater odds of having a child with spina bifida, after adjusting for relevant covariates. Additionally, paternal exposure to aluminum, cobalt, chromium, iron, selenium, and vanadium was associated with increased odds of having a child with spina bifida in the adjusted models. In the maternal models, a one-unit increase in the natural logarithm of maternal toenail selenium and zinc levels was related to a 382% greater (odds ratio: 4.82, 95% confidence interval: 1.32–17.60) and 89% lower (odds ratio: 0.11, 95% confidence interval: 0.03–0.42) odds of having a child with spina bifida in the adjusted models, respectively. Results did not suggest an interaction between parental toenail metals and maternal serum folate. Parental toenail levels of numerous metals were associated with increased risk of spina bifida in Bangladeshi infants. Paternal arsenic exposure was positively associated with neural tube defects in children and is of particular concern given the widespread arsenic poisoning of groundwater resources in Bangladesh and the lack of nutritional interventions aimed to mitigate paternal arsenic exposure. The findings add to the growing body of literature of the impact of metals, especially paternal environmental factors, on child health. [ABSTRACT FROM AUTHOR]