An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are ...unknown.
The objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh.
Maternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the 3H-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA.
In the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the 3H-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p = 0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N = 58) but negative among female newborns (N = 43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p = 0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p = 0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p<0.05).
These results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time.
Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary ...excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine.
This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine.
In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12–24, half of the participants receiving FA received placebo.
Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation.
The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.
In vitro and rodent studies have shown that arsenic (As) exposure can deplete glutathione (GSH) and induce oxidative stress. GSH is the primary intracellular antioxidant; it donates an electron to ...reactive oxygen species, thus producing glutathione disulfide (GSSG). Cysteine (Cys) and cystine (CySS) are the predominant thiol/disulfide redox couple found in human plasma. Arsenic, GSH, and Cys are linked in several ways: a) GSH is synthesized via the transsulfuration pathway, and Cys is the rate-limiting substrate; b) intermediates of the methionine cycle regulate both the transsulfuration pathway and As methylation; c) GSH serves as the electron donor for reduction of arsenate to arsenite; and d) As has a high affinity for sulfhydryl groups and therefore binds to GSH and Cys.
We tested the hypothesis that As exposure is associated with decreases in GSH and Cys and increases in GSSG and CySS (i.e., a more oxidized environment).
For this cross-sectional study, the Folate and Oxidative Stress Study, we recruited a total of 378 participants from each of five water As concentration categories: < 10 (n = 76), 10-100 (n = 104), 101-200 (n = 86), 201-300 (n = 67), and > 300 µg/L (n = 45). Concentrations of GSH, GSSG, Cys, and CySS were measured using HPLC.
An interquartile range (IQR) increase in water As was negatively associated with blood GSH (mean change, -25.4 µmol/L; 95% CI: -45.3, -5.31) and plasma CySS (mean change, -3.00 µmol/L; 95% CI: -4.61, -1.40). We observed similar associations with urine and blood As. There were no significant associations between As exposure and blood GSSG or plasma Cys.
The observed associations are consistent with the hypothesis that As may influence concentrations of GSH and other nonprotein sulfhydryls through binding and irreversible loss in bile and/or possibly in urine.
Several studies employing cell culture and animal models have suggested that arsenic (As) exposure induces global DNA hypomethylation. However, As has been associated with global DNA hypermethylation ...in human study populations. We hypothesized that this discrepancy may reflect a nonlinear relationship between As dose and DNA methylation.
The objective of this study was to examine the dose-response relationship between As and global methylation of peripheral blood mononuclear cell (PBMC) DNA in apparently healthy Bangladeshi adults chronically exposed to a wide range of As concentrations in drinking water.
Global PBMC DNA methylation, plasma folate, blood S-adenosylmethionine (SAM), and concentrations of As in drinking water, blood, and urine were measured in 320 adults. DNA methylation was measured using the 3H-methyl incorporation assay, which provides disintegration-per-minute (DPM) values that are negatively associated with global DNA methylation.
Water, blood, and urinary As were positively correlated with global PBMC DNA methylation (p < 0.05). In multivariable-adjusted models, 1-μg/L increases in water and urinary As were associated with 27.6-unit (95% CI: 6.3, 49.0) and 22.1-unit (95% CI: 0.5, 43.8) decreases in DPM per microgram DNA, respectively. Categorical models indicated that estimated mean levels of PBMC DNA methylation were highest in participants with the highest As exposures.
These results suggest that As is positively associated with global methylation of PBMC DNA over a wide range of drinking water As concentrations. Further research is necessary to elucidate underlying mechanisms and physiologic implications.
Exposure to inorganic arsenic is associated with numerous adverse health outcomes, with susceptibility differing by sex. Although evidence from in vitro studies suggests that arsenic alters ...post-translational histone modifications (PTHMs), evidence in humans is limited.
The objectives were to determine: a) if arsenic exposure is associated with global (percent) levels of PTHMs H3K36me2, H3K36me3, and H3K79me2 in a sex-dependent manner, and b) if %PTHMs are stable when arsenic exposure is reduced.
We examined associations between arsenic, measured in blood and urine, and %PTHMs in peripheral blood mononuclear cells from 317 participants enrolled in the Bangladesh Folic Acid and Creatine Trial (FACT). We also examined the stability of %PTHMs after the use of arsenic-removal water filters (n = 60).
Associations between natural log-transformed (ln) urinary arsenic, adjusted for creatinine (uAsCr), and %H3K36me2 differed significantly between men and women (p = 0.01). ln(uAsCr) was positively associated with %H3K36me2 in men β = 0.12; 95% confidence interval (CI): 0.01, 0.23, p = 0.03 but was negatively associated with %H3K36me2 in women (β = -0.05; 95% CI: -0.12, 0.02, p = 0.19). The patterns of associations with blood arsenic were similar. On average, water filter use was also associated with reductions in %H3K36me2 (p < 0.01), but this did not differ significantly by sex. Arsenic was not significantly associated with %H3K36me3 or %H3K79me2 in men or women.
Arsenic exposure was associated with %H3K36me2 in a sex-specific manner but was not associated with %H3K36me3 or %H3K79me2. Additional studies are needed to assess changes in %H3K36me2 after arsenic removal.
Howe CG, Liu X, Hall MN, Slavkovich V, Ilievski V, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Graziano JH, Costa M, Gamble MV. 2016. Associations between blood and urine arsenic concentrations and global levels of post-translational histone modifications in Bangladeshi men and women. Environ Health Perspect 124:1234-1240; http://dx.doi.org/10.1289/ehp.1510412.
Fish is the main dietary source of long-chain n-3 fatty acids, which have been suggested to play a protective role in colorectal cancer development in laboratory and animal studies. Human studies ...have not shown consistent results. We examined the association between intakes of fish and n-3 fatty acids from fish and colorectal cancer risk in men enrolled in the Physicians' Health Study.
The Physicians' Health Study began as a randomized trial to examine the effect of aspirin and beta-carotene supplementation on cancer and cardiovascular disease. Fish intake was assessed at the 12-month follow-up with an abbreviated food-frequency questionnaire. Cox proportional hazards models were used to estimate multivariate relative risks for colorectal cancer for the categories of fish intake and quartiles of n-3 fatty acid intake.
During 22 years of follow-up, 500 men had a confirmed diagnosis of colorectal cancer. Fish intake was inversely associated with colorectal cancer risk multivariate relative risk (95% confidence interval) for highest versus lowest category, 0.63 (0.42-0.95); P trend = 0.02 corrected The inverse association was observed for both colon and rectal cancers. Our findings for n-3 fatty acids were similar to those for fish; the multivariate relative risk (95% confidence interval) of total colorectal cancer for the highest versus lowest quartile of n-3 fatty acids was 0.74 (0.57-0.95; P trend = 0.01).
Our results from this long-term prospective study suggest that intakes of fish and long-chain n-3 fatty acids from fish may decrease the risk for colorectal cancer.
Epidemiological transitions are occurring throughout Africa. To inform public health programs and policies, longitudinal cohorts investigating non-communicable diseases are needed. However, ...loss-to-follow up is a major problem. In preparation for a longitudinal study, we conducted a randomized controlled trial to test communication-based retention strategies (message content and delivery methods) among a pilot cohort of South African healthcare workers (n = 1536; median age = 36; women = 1270). Two messaging formats across three delivery modes were tested. Response rates were analyzed by intervention, survey return date and method using chi-square tests and univariate logistic regression. Sixty-seven of 238 (17.4%) control group participants and 238 of 1152 (24.6%) intervention group participants were retained (OR 1.54: CI 1.15-2.07; P = 0.004). Odds of being retained were 1.68 times greater for participants who received regular contact and themed messages compared to control (CI 1.22-2.32; P = 0.001). Neither health status nor clinical condition affected response rates (P>0.05). Time-to-first contact did not impact response rates (P>0.05). Message content and delivery method influenced response rates compared to the control, however no difference was found between intervention groups. Although greater retention is required for valid cohort studies, these findings are the first to quantitatively assess retention factors in Africa.
Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs ...facilitates urinary excretion and is associated with reduced risk for As-related health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation.
Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI: MMAs/InAs) and secondary methylation index (SMI: DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status.
In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms:
) PBO (
),
)
FA/d (400FA;
),
)
FA/d (800FA;
),
)
creatine/d (creatine;
), or
)
(
;
) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24.
At baseline, 80.3% (
) of participants were folate sufficient (
in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (
) decreased from
at baseline to
at week 1. After 1 wk, the mean within-person increase in SMI for the
group was greater than that of the PBO group (
). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group 400FA:
(95% CI:
,
), 800FA:
(95% CI:
,
), creatine:
(95% CI:
,
),
:
(95% CI:
,
), PBO:
(95% CI:
, 0.04), and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO 400FA: 12.8 (95% CI: 10.5, 15.2), 800FA: 11.3 (95% CI: 8.95, 13.8),
: 7.45 (95% CI: 5.23, 9.71), PBO:
(95% CI:
, 2.63). The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO (
). Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI
(95% CI:
,
) and bDMAs
(95% CI:
,
), whereas PMI and bMMAs concentrations continued to decline
(95% CI:
,
) and
(95% CI:
,
), respectively for those who remained on 800FA supplementation.
FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. https://doi.org/10.1289/EHP11270.
Kidney disease is emerging as an arsenic (As)-linked disease outcome, however further evidence of this association is warranted. Our first objective for this paper was to examine the potential renal ...toxicity of As exposure in Bangladesh. Our second objective relates to examining whether the previously reported positive association between urinary creatinine (uCrn) and As methylation may be explained by renal function. We had hypothesized that these associations relate to supply and demand for s-adenosylmethionine, the methyl donor for both creatine synthesis and As methylation. Alternatively, renal function could influence both As and creatinine excretion, or the As metabolites may influence renal function, which in turn influences uCrn. We conducted a cross-sectional study (N = 478) of adults, composed of a sample recruited in 2001 and a sample recruited in 2003. We assessed renal function using plasma cystatin C, and calculated the estimated glomerular filtration rate (eGFR). Consistent with renal toxicity of As, log-uAs had a marginal inverse association with eGFR in the 2003 sample (b = -5.6, p = 0.07), however this association was not significant in the 2001 sample (b = -1.9, p = 0.24). Adjustment for eGFR did not alter the associations between uCrn and the %uAs metabolites, indicating that GFR does not explain these associations. Increased eGFR was associated with increased odds of having %uInAs >12.2% (2001: OR = 1.01, 95%CI (1.00,1.03); 2003: OR = 1.04, 95%CI (1.01,1.07)). In the 2003 sample only, there was a negative association between eGFR and %uDMA (b = -0.08, p = 0.02). These results may indicate differential effects of renal function on excretion of InAs and DMA. Alternatively, a certain methylation pattern, involving decreased %InAs and increased %DMA, may reduce renal function. Given that these studies were cross-sectional, we cannot distinguish between these two possibilities. Discrepancies between the samples may be due to the higher As exposure, poorer nutrition, and lower As methylation capacity in the 2003 sample.
Inorganic arsenic (As) is methylated via one carbon metabolism (OCM) to mono- and dimethylated arsenicals (MMA and DMA), facilitating urinary excretion. Hyperhomocysteinemia (HHcys), a marker of ...impaired OCM, is a risk factor for As-induced skin lesions, but the influences of single nucleotide polymorphisms (SNPs) in OCM genes on Hcys, As metabolism and skin lesion risk is unclear.
To (i) explore genetic sources of Hcys and the causal role of HHcys in As-induced skin lesion development using OCM genetic proxies for HHcys and (ii) identify OCM SNPs associated with urinary As metabolite proportions and/or skin lesion incidence.
We conducted a case-control study nested in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh which 876 incident skin lesion cases were matched to controls on sex, age, and follow-up time. We measured serum Hcys, urinary As metabolites, and 26 SNPs in 13 OCM genes.
Serum Hcys and urinary %DMA were independently associated with increased and decreased odds of skin lesions, respectively. The T allele of MTHFR 677 C ➔ T (rs1801133) was associated with HHcys, higher %MMA, and lower %DMA, but not with skin lesions. Interactions between SNPs and water As on skin lesion risk were suggestive for three variants: the G allele of MTRR rs1801394 and T allele of FOLR1 rs1540087 were associated with lower odds of skin lesions with lower As (≤50 μg/L), and the T allele of TYMS rs1001761 was associated with higher odds of skin lesions with higher As.
While HHcys and decreased %DMA were associated with increased risk for skin lesions, and MTHFR 677 C ➔ T was a strong predictor of HHcys, MTHFR 677 C ➔ T was not associated with skin lesion risk. Future studies should explore (i) non-OCM and non-genetic determinants of Hcys and (ii) if genetic findings are replicated in other As-exposed populations, mechanisms by which OCM SNPs may influence the dose-dependent effects of As on skin lesion risk.
•Arsenic (As) is methylated to MMA and DMA via one-carbon metabolism (OCM).•Elevated homocysteine (HHcys) is a marker of dysregulated OCM.•HHcys and lower %DMA were independent risk factors for As-induced skin lesions.•MTHFR C677T was associated with HHcys, %MMA, and %DMA, but not with skin lesions.•Dysregulated OCM may influence susceptibility to As toxicity.
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