Associations of arsenic exposure and folate

Overview

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Key numbers

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• the national standard (50 µg/l), while nearly half exceed the World Health Organization guideline (10 µg/l). Among
• 42% of tubewells tested in Bangladesh reported arse- aimed to characterize the independent associations of
• nic in excess of 10 µg/L, the World Health Organization arsenic exposure, folate status, and offspring spina bifida
• than a quarter of all wells tested exceeded 50 µg/L (27). tionally, we investigated two-way cross-product interac-
• & Hospital (NINS&H) (ERC-NINS number 2016/07/10, were imputed to the median of the overall study sample,
• except in the case of known technical replicates (n = 11), folate, as well as effect modification of arsenic by folate,
• the mean of the dataset, inter-array correlation < 0.90, main effects of spina bifida status (Model 1a), toenail
• SNP outlier log odds metric > −4, > 1% of probes failing arsenic (Model 1b), and plasma folate (Model 1c), from
• had > 1% failed probes; the third failed all of the follow- other. Cross-product interaction terms were then added
• logodds, > 1% failed probes, and average detection P spina bifida*arsenic), spina bifida status by folate (Model
• ciation studies against the KEGG and GO databases included in the analysis are presented in Table 1. All
• using default settings (59). a spina bifida-affected child (n = 246) or a control child
• To determine whether differentially methylated CpGs of education (94.7% less than university) than mothers of
• identified in the current study replicated previously pub- controls (87.5% less than university) (p = 0.023), and the
• ing CpGs at FDR and nominal (p < 0.05) significance in (49.2% female spina bifida-affected offspring versus 35.2%
• Table 1 Participant characteristics among 374 Bangladeshi lection also occurred sooner postnatally in the mothers
• The p value column reflects unadjusted comparison of women in the mothers of controls (187.23 ± 97.4 days). The mean
• N = 246 N = 128 case-control status; cell type proportions were included
• or count count (%) pants were evenly distributed across the six EPIC v2.0
• Maternal education 233 (94.7%) 112 (87.5%) 0.023
• Child sex (female) 121 (49.2%) 45 (35.2%) 0.013 (PCs 1–4), Supplementary Fig. 2. Plasma folate was asso-
• Child level of spinal defect and with PCs 8 and 9, which explained 0.7% and 0.6% of
• Pre/peri-natal folic acid 41 (16.7%) 33 (25.8%) n.s. (1–8) was associated with PCs 4, 5, and 7–9.
• Estimated cell type proportions studies (EWAS) is shown in Table 2. The differentially
• CD4T 0.14 (0.04) 0.15 (0.04) n.s. nificance in each EWAS are shown in Table 3, all CpGs
• Table 2 Summary of results from epigenome-wide association chr17:81,821,352 − 81,822,448); the other two overlapped
• 3 Spina 0.97 0 0 0 were inversely associated with arsenic, meaning that
• EWAS Model 1a investigated the main effect of spina body of UCN, Supplementary Table 2. Contrary to the
• and 22 reaching Bonferroni p < 0.05, Table 2. The con- this DMR was positively associated with arsenic concen-
• majority of FDR-significant CpGs (n = 58, 81.6%) were
• bifida-affected offspring had lower mean DNAme at the EWAS Model 1c evaluated DNAme associated with
• CpGs, 61%), two of which had Δβ > |0.05| (both in the Bonferroni significance showed inverse associations with
• tary Table 2. There were four additional DMRs associ- significant CpGs, but were located on chromo-
• Table 3 Top significant results of epigenome-wide association studies. For brevity this table indicates CpGs associated at Bonferroni
• expanded list of all CpGs meeting FDR significance see Supplementary table 1. Gene and genomic region annotations were sourced
• Table 3 (continued)
• OCM. Acknowledging the size of the study sample, these mL) or high (≥ 4 ng/mL) plasma folate, Table 5. The 4 ng/
• 11 CpGs (FDR < 0.05), six of which met Bonferroni sig- one or both folate strata (n = 26). Half of the CpGs (n =
• of arsenic on DNAme at the 11 CpGs that met FDR sig- showed increasing mean DNAme with increasing arse-
• arsenic in the spina bifida cases (n = 246) and controls ated with the interaction of arsenic and folate half (n =
• (n = 128); all 11 CpGs reached nominal significance in 6) were associated with arsenic only in the high-folate
• one or both strata, Table 4. Among these 11 CpGs, three group and showed decreasing DNAme with increas-

Methods (brief)

• maternal health and exposures to spina bifida risk, pro- 381 individuals provided leukocyte samples at the study
• Methods fewer control mothers enrolled as biological sample col-
• gladesh Medical Research Council (BMRC IRB registra- ously described (47). In brief, nail samples from all ten
• tion number 006 23 08 2016; reference number BMRC/ toes were collected at the enrollment visit; arsenic con-
• the Human Research Committees at Boston Children’s mass spectrometry (ICP-MS) at the Dartmouth College
• & Hospital (NINS&H) (ERC-NINS number 2016/07/10, were imputed to the median of the overall study sample,
• ton Children’s Hospital. Clinical trial number: not appli- For folate assessment, blood samples (minimum 8 h
• cable. Written informed consent was obtained from all fasting for glucose assessment) were collected at the
• sant medication use, chromosomal abnormality (Tri- samples at NINS&H, after which the buffy coat layer
• converted samples across six array batches according to and reference set prior to estimation.
• minfi packages were used to assess sample quality (48, identify differentially methylated CpGs associated with
• and in-built genotyping “rs” probes. Sample genetic iden- scales without transformation. We additionally tested for
• SNP genotypes. Sample sex was assessed from the data R (55), effect sizes in Δβ units were computed using the
• for all leukocyte samples, data-derived sex corresponded and DNAme-estimated cell-type proportions (B cells,
• samples were removed for being flagged in two or more phils) and EPIC array row (8 levels). Multiple compari-
• samples, two failed the SNP outlier logodds check and tions with DNAme while mutually adjusting for each
• the lowest mean detection P value across all samples. Differentially methylated regions (DMRs) were evalu-
• count < 3 in > 1% of samples, (ii) CpGs mapping to the utilized for compatibility with the v2.0 array (58), repli-

Implications

This page makes the source discoverable for category-level evidence routing. Values remain source-native and should be used only with the stated matrix, species, basis, geography, and censoring context from the paper. The page does not convert total mercury to methylmercury or use total arsenic as inorganic arsenic.

Wiki pages this source may touch

• Fish — marine, non-predatory (sardines, anchovies, salmon, cod)
• Mercury
• Cadmium
• Arsenic

Verification notes

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Update history

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