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Background: 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., Methods: 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)., Results: 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)., Conclusions: 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An emerging hypothesis linking arsenic toxicity involves altered epigenetic mechanisms, such as DNA methylation. In this study, we examined the relationship between parents' arsenic exposure and DNA methylation in tissues obtained from 28 infants with spina bifida from Bangladesh. We analyzed arsenic in parents' toenails using inductively coupled plasma mass spectrometry (ICP-MS). DNA methylation was measured in infants' dural tissue, buccal swabs, and whole blood using the Illumina Infinium MethylationEPIC BeadChip. We performed epigenome-wide association analyses (EWAS) and tested differentially methylated regions (DMRs). In EWAS, DNA methylation at cg24039697 in dural tissue was positively associated (β = 0.59, p  = 7.6 × 10 -9 ) with father's toenail arsenic concentrations, adjusting for covariates. We did not identify any CpG sites related to father's arsenic exposure in the other tissues, or any CpG sites related to mother's arsenic exposure. Gene ontology analysis identified many biological pathways of interest, including the Wnt signaling pathways. We identified several DMRs across the tissues related to arsenic exposure that included probes mapping to genes that have previously been identified in studies of neural tube defects. This study emphasizes the potential impact of arsenic exposure in fathers, often understudied in epidemiological studies, on DNA methylation in a unique neurological tissue specific to spina bifida.

Background: Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. This study examines the relationships between mother's arsenic exposure, folic acid, and spina bifida risk in Bangladesh., Methods: We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified by a neurosurgeon and imaging. Controls were drawn from children seen at NINS&H and nearby Dhaka Shishu Hospital. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). We used logistic regression to examine the associations between arsenic and spina bifida. We used stratified models to examine the associations between folic acid and spina bifida at different levels of arsenic exposure., Results: We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median value of 0.46 µg/g, and no association was seen among mothers with toenail arsenic concentrations higher than 0.46 µg/g (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82)., Conclusions: Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure., (© 2024. The Author(s).)

Background: Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown., Methods: We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-β, a marker of beta cell function., Results: Median (IQR) arsenic concentration was 0.45 (0.67) μg/g in toenails and 2.0 (6.5) μg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (- 3.13, 3.37) higher and HOMA-β was 0.96% (- 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null., Conclusions: Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function., (© 2021. The Author(s).)

Background: 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., Objectives: 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., Methods: 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., Results: 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., Discussion: 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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The effects of bromocriptine (CB-154) on the proliferative capacities of prolactinoma and somatotropinoma were investigated by immunocytochemical staining indices of proliferating cell nuclear antigen (PCNA) and Ki-67 (with MIB-1 antibody), and silver staining of nucleolar organizer region (NOR) number in histological sections. Patients with prolactinoma and somatotropinoma were divided into two groups: no preoperative treatment (control group), and treated with CB-154 for 2 weeks before adenomectomy (CB-154 group). The prolactinoma CB-154 group showed a significantly lower PCNA staining index (n = 6, 13.1 +/- 2.0%) and Ki-67 staining index (n = 6, 0.2 +/- 0.03%) than the control group (n = 4, 27.1 +/- 2.1%; n = 8, 1.9 +/- 0.5%; respectively) (p < 0.01). The somatotropinoma CB-154 group showed a significantly lower Ki-67 staining index (n = 5, 0.7 +/- 0.07%) than the control group (n = 11, 1.2 +/- 0.2%) (p < 0.05), but there was no significant difference in PCNA staining index (control: n = 5, 19.1 +/- 2.8% vs. CB-154: n = 5, 20.2 +/- 1.4%). However, variable intensities of PCNA staining between the cells were observed, resulting in an extraordinarily high staining index. NOR numbers did not vary significantly between the two prolactinoma groups (control: n = 4, 2.0 +/- 0.3 vs. CB-154: n = 6, 1.7 +/- 0.1) and two somatotropinoma groups (control: n = 5, 1.3 +/- 0.1 vs. CB-154: n = 5, 1.4 +/- 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)