Early life and adolescent arsenic exposure from drinking water and blood pressure in adolescence.

OBJECTIVES: Evidence of the association between inorganic arsenic (As) exposure, especially early-life exposure, and blood pressure (BP) in adolescence is limited. We examined the association of As exposure during early childhood, childhood, and adolescence with BP in adolescence. METHODS: We conducted a cross-sectional study of 726 adolescents aged 14-17 (mean 14.75) years whose mothers were participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS). Adolescents' BP was measured at the time of their recruitment between December 2012 and December 2016. We considered maternal urinary As (UAs), repeatedly measured during childhood, as proxy measures of early childhood (<5 years old, A1) and childhood (5-12 years old, A2) exposure. Adolescents' current UAs was collected at the time of recruitment (14-17 years of age, A3). RESULTS: Every doubling of UAs at A3 and maternal UAs at A1 was positively associated with a difference of 0.7-mmHg (95% confidence interval [CI]: 0.1, 1.3) and a 0.7-mmHg (95% CI: 0.05, 1.4) in SBP, respectively. These associations were stronger in adolescents with a BMI above the median (17.7 kg/m2) than those with a BMI below the median (P for interaction = 0.03 and 0.03, respectively). There was no significant association between any of the exposure measures and DBP. The Weighted Quantile Sum (WQS) regression confirmed that adolescents' UAs at A3 and maternal UAs at A1 contributed the most to the overall effect of As exposure at three life stages on SBP. Mixture analyses using Bayesian Kernel Machine Regression identified UAs at A3 as a significant contributor to SBP and DBP independent of other concurrent blood levels of cadmium, lead, manganese, and selenium. CONCLUSION: Our findings suggest an association of current exposure and early childhood exposure to As with higher BP in adolescents, which may be exacerbated by higher BMI at adolescence.

A cross-sectional study of water arsenic exposure and intellectual function in adolescence in Araihazar, Bangladesh.

BACKGROUND: Exposure to inorganic arsenic (As) from drinking water is associated with modest deficits in intellectual function in young children; it is unclear whether deficits occur during adolescence, when key brain functions are more fully developed. OBJECTIVES: We sought to determine the degree to which As exposure is associated with adolescent intelligence, and the contributory roles of lead, cadmium, manganese and selenium. METHODS: We recruited a cross-section of 726 14-16 year olds (mean age = 14.8 years) whose mothers are participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS), and whose household well water As levels, which varied widely, were well characterized. Using a culturally modified version of the WISC-IV, we examined raw Full Scale scores, and Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed Indices. Blood levels of As (BAs), Mn, Pb, Cd and Se were assessed at the time of the visit, as was creatinine-adjusted urinary As (UAs/Cr). RESULTS: Linear regression analyses revealed that BAs was significantly negatively associated with all WISC-IV scores except for Perceptual Reasoning. With UAs/Cr as the exposure variable, we observed significantly negative associations for all WISC-IV scores. Except for Se, blood levels of other metals, were also associated with lower WISC-IV scores. Controlling for covariates, doubling BAs, or UAs/Cr, was associated with a mean decrement (95% CI) of 3.3 (1.1, 5.5), or 3.0 (1.2, 4.5) points, respectively, in raw Full scale scores with a sample mean of 177.6 (SD = 36.8). Confirmatory analyses using Bayesian Kernel Machine Regression, which identifies important mixture members, supported these findings; the primary contributor of the mixture was BAs, followed by BCd. CONCLUSIONS: Our data indicate that the adverse consequences of As exposure on neurodevelopment observed in other cross-sectional studies of younger children are also apparent during adolescence. They also implicate Cd as a neurotoxic element that deserves more attention.

Serum homocysteine, arsenic methylation, and arsenic-induced skin lesion incidence in Bangladesh: A one-carbon metabolism candidate gene study.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Provision of well-water treatment units to 600 households in Bangladesh: A longitudinal analysis of urinary arsenic indicates fading utility.

BACKGROUND: Millions of villagers in Bangladesh remain exposed to high levels of arsenic (As) from drinking untreated well-water even though the scale of the problem was recognized 15years ago. Water treatment at the household-level has been promoted as a viable complement but few longitudinal studies of their efficacy using an objective measure of exposure have been conducted. Participants (N=622) of a nutrition trial in Araihazar, Bangladesh were each provided with READ-F filters at the beginning of the study and encouraged to use them over the 6month duration of the intervention. Well-water As, treated water As, and urinary As were monitored periodically during the trial and measured again one year after the trial ended. RESULTS: The READ-F filters were initially well received and median urinary As levels for participants declined from 117µg/L to 51µg/L within a single week. However, median urinary As levels gradually rose back to 126µg/L by the end of the trial. Fifty filters were replaced over the course of the trial because of insufficient As removal or reduced flow. With these exceptions, most of the treated water met the WHO guideline for As in drinking water of 10µg/L. One year after the nutritional trial ended, 95% of participants had abandoned their filter citing inconvenience as the primary reason. At that time, median urinary As levels for 10 participants who had switched to a nearby low-As well had declined to 63µg/L. CONCLUSIONS: Participants were probably no longer using the READ-F filter long before the 6month nutritional intervention ended despite claiming that they were using them. Household-level treatment is likely to continue to play a minor role in the effort to reduce As exposure in Bangladesh. Understanding the limitations of such expensive interventions is important for future policy regarding As mitigation.

Betel quid use and mortality in Bangladesh: a cohort study.

OBJECTIVE: To evaluate the potential effects of betel quid chewing on mortality. (A quid consists of betel nut, wrapped in betel leaves; tobacco is added to the quid by some users). METHODS: Prospective data were available on 20 033 individuals aged 18-75 years, living in Araihazar, Bangladesh. Demographic and exposure data were collected at baseline using a standardized questionnaire. Cause of death was defined by verbal autopsy questionnaires administered to next of kin. We estimated hazard ratios (HR) and their 95% confidence intervals (CI) for associations between betel use and mortality from all causes and from specific causes, using Cox proportional hazards models. We adjusted for age, sex, body mass index, educational attainment and tobacco smoking history. FINDINGS: There were 1072 deaths during an average of 10 years of follow-up. Participants who had ever used betel were significantly more likely to die from all causes (HR: 1.26; 95% CI: 1.09-1.44) and cancer (HR: 1.55; 95% CI: 1.09-2.22); but not cardiovascular disease (HR: 1.16; 95% CI: 0.93-1.43). These findings were robust to adjustment for potential confounders. There was a dose-response relationship between mortality from all causes and both the duration and the intensity of betel use. The population attributable fraction for betel use was 14.1% for deaths from all causes and 24.2% for cancer. CONCLUSION: Betel quid use was associated with mortality from all causes and from cancer in this cohort.

Sex-specific associations of arsenic exposure with global DNA methylation and hydroxymethylation in leukocytes: results from two studies in Bangladesh.

BACKGROUND: Depletion of global 5-hydroxymethylcytosine (5-hmC) is observed in human cancers and is strongly implicated in skin cancer development. Although arsenic (As)-a class I human carcinogen linked to skin lesion and cancer risk-is known to be associated with changes in global %5-methylcytosine (%5-mC), its influence on 5-hmC has not been widely studied. METHODS: We evaluated associations of As in drinking water, urine, and blood with global %5-mC and %5-hmC in two studies of Bangladeshi adults: (i) leukocyte DNA in the Nutritional Influences on Arsenic Toxicity study (n = 196; 49% male, 19-66 years); and (ii) peripheral blood mononuclear cell DNA in the Folate and Oxidative Stress study (n = 375; 49% male, 30-63 years). RESULTS: Overall, As was not associated with global %5-mC or %5-hmC. Sex-specific analyses showed that associations of As exposure with global %5-hmC were positive in males and negative in females (P for interaction < 0.01). Analyses examining interactions by elevated plasma total homocysteine (tHcys), an indicator of B-vitamin deficiency, found that tHcys also modified the association between As and global %5-hmC (P for interaction < 0.10). CONCLUSION: In two samples, we observed associations between As exposure and global %5-hmC in blood DNA that were modified by sex and tHcys. IMPACT: Our findings suggest that As induces sex-specific changes in 5-hmC, an epigenetic mark that has been associated with cancer. Future research should explore whether altered %5-hmC is a mechanism underlying the sex-specific influences of As on skin lesion and cancer outcomes.

Evaluation of an Elementary School-based Educational Intervention for Reducing Arsenic Exposure in Bangladesh.

BACKGROUND: Chronic exposure to well water arsenic (As) remains a major rural health challenge in Bangladesh and some other developing countries. Many mitigation programs have been implemented to reduce As exposure, although evaluation studies for these efforts are rare in the literature. OBJECTIVES: In this study we estimated associations between a school-based intervention and various outcome measures of As mitigation. METHODS: We recruited 840 children from 14 elementary schools in Araihazar, Bangladesh. Teachers from 7 schools were trained on an As education curriculum, whereas the remaining 7 schools without any training formed the control group. Surveys, knowledge tests, and well-water testing were conducted on 773 children both at baseline and postintervention follow-up. Urine samples were collected from 210 children from 4 intervention schools and the same number of children from 4 control schools. One low-As (< 10 µg/L) community well in each study village was ensured during an 18-month intervention period. RESULTS: After adjustment for the availability of low-As wells and other sociodemographic confounders, children receiving the intervention were five times more likely to switch from high- to low-As wells (p < 0.001). We also observed a significant decline of urinary arsenic (UAs) (p = < 0.001) (estimated ß = -214.9; 95% CI: -301.1, -128.7 µg/g creatinine) among the children who were initially drinking from high-As wells (> Bangladesh standard of 50 µg/L) and significantly improved As knowledge attributable to the intervention after controlling for potential confounders. CONCLUSIONS: These findings offer strong evidence that school-based intervention can effectively reduce As exposure in Bangladesh by motivating teachers, children, and parents.

Association between Arsenic Exposure from Drinking Water and Longitudinal Change in Blood Pressure among HEALS Cohort Participants.

BACKGROUND: Cross-sectional studies have shown associations between arsenic exposure and prevalence of high blood pressure; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking. METHOD: We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every 2 years after baseline. Mixed-effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with annual change in blood pressure during follow-up (median, 6.7 years). RESULT: In the HEALS population, the median water arsenic concentration at baseline was 62 µg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in systolic blood pressure compared with those in the reference group (ß = 0.48 mmHg/year; 95% CI: 0.35, 0.61, and ß = 0.43 mmHg/year; 95% CI: 0.29, 0.56 for water arsenic and urinary creatinine-adjusted arsenic, respectively) in fully adjusted models. Likewise, individuals in the highest quartile of baseline arsenic exposure had a greater annual increase in diastolic blood pressure for water arsenic and urinary creatinine-adjusted arsenic, (ß = 0.39 mmHg/year; 95% CI: 0.30, 0.49, and ß = 0.45 mmHg/year; 95% CI: 0.36, 0.55, respectively) compared with those in the lowest quartile. CONCLUSION: Our findings suggest that long-term arsenic exposure may accelerate age-related increases in blood pressure. These findings may help explain associations between arsenic exposure and cardiovascular disease.

Association of major dietary patterns and blood pressure longitudinal change in Bangladesh.

BACKGROUND: Observational studies and clinical trials have shown associations of diet and high blood pressure (BP). However, prospective studies on the association between dietary patterns and longitudinal BP change are lacking, especially in low-income populations. METHOD: We evaluated the association of dietary patterns and food groups with longitudinal change of BP in 10 389 participants in the Health Effects of Arsenic Longitudinal Study, with a median of 6.7 years of follow-up. Dietary information was obtained through a previously validated food-frequency questionnaire. BP was measured at baseline and at each biennial follow-up using the same method. RESULT: Each standard deviation (SD) increase for the 'gourd vegetable' dietary pattern score was related to a slower annual change of 0.08, 0.04, and 0.05 mmHg in SBP, DBP, or pulse pressure, respectively. Each SD increase in the 'balanced' dietary pattern score was related to a decreasing annual change of 0.06 mmHg (P = 0.012) and 0.08 mmHg in SBP and pulse pressure (P < 0.001). On the contrary, one SD increase in 'western' dietary pattern score was related to a greater annual increase of 0.07 (P = 0.005) and 0.05 mmHg in SBP and pulse pressure (P = 0.013). Higher intake of fruits and vegetables was associated with a slower rate of change in annual SBP and pulse pressure, whereas higher meat intake was related to a more rapid increase in annual pulse pressure. CONCLUSION: The findings suggest that dietary patterns play a significant role in the rate of BP change over time in a low-income population.

Interaction between arsenic exposure from drinking water and genetic polymorphisms on cardiovascular disease in Bangladesh: a prospective case-cohort study.

BACKGROUND: Epidemiologic data on genetic susceptibility to cardiovascular effects of arsenic exposure from drinking water are limited. OBJECTIVE: We investigated whether the association between well-water arsenic and cardiovascular disease (CVD) differed by 170 single nucleotide polymorphisms (SNPs) in 17 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. METHOD: We conducted a prospective case-cohort study nested in the Health Effects of Arsenic Longitudinal Study, with a random subcohort of 1,375 subjects and 447 incident fatal and nonfatal cases of CVD. Well-water arsenic was measured in 2000 at baseline. The CVD cases, 56 of which occurred in the subcohort, included 238 coronary heart disease cases, 165 stroke cases, and 44 deaths due to other CVD identified during follow-up from 2000 to 2012. RESULTS: Of the 170 SNPs tested, multiplicative interactions between well-water arsenic and two SNPs, rs281432 in ICAM1 (padj = 0.0002) and rs3176867 in VCAM1 (padj = 0.035), were significant for CVD after adjustment for multiple testing. Compared with those with GC or CC genotype in rs281432 and lower well-water arsenic, the adjusted hazard ratio (aHR) for CVD was 1.82 (95% CI: 1.31, 2.54) for a 1-SD increase in well-water arsenic combined with the GG genotype, which was greater than expected given aHRs of 1.08 and 0.96 for separate effects of arsenic and the genotype alone, respectively. Similarly, the joint aHR for arsenic and the rs3176867 CC genotype was 1.34 (95% CI: 0.95, 1.87), greater than expected given aHRs for their separate effects of 1.02 and 0.84, respectively. CONCLUSIONS: Associations between CVD and arsenic exposure may be modified by genetic variants related to endothelial dysfunction.

Creatinine, arsenic metabolism, and renal function in an arsenic-exposed population in Bangladesh.

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.

A dose-response study of arsenic exposure and markers of oxidative damage in Bangladesh.

OBJECTIVE: To evaluate the dose-response relationship between arsenic (As) exposure and markers of oxidative damage in Bangladeshi adults. METHODS: We recruited 378 participants drinking water from wells assigned to five water As exposure categories; the distribution of subjects was as follows: (1) less than 10 µg/L (n=76); (2) 10 to 100 µg/L (n=104); (3) 101 to 200 µg/L (n=86); (4) 201 to 300 µg/L (n=67); and (5) more than 300 µg/L (n=45). Arsenic concentrations were measured in well water, as well as in urine and blood. Urinary 8-oxo-2'-deoxyguanosine and plasma protein carbonyls were measured to assess oxidative damage. RESULTS: None of our measures of As exposure were significantly associated with protein carbonyl or 8-oxo-2'-deoxyguanosine levels. CONCLUSIONS: We found no evidence to support a significant relationship between long-term exposure to As-contaminated drinking water and biomarkers of oxidative damage among Bangladeshi adults.

A cross-sectional study of well water arsenic and child IQ in Maine schoolchildren.

BACKGROUND: In recent studies in Bangladesh and elsewhere, exposure to arsenic (As) via drinking water is negatively associated with performance-related aspects of child intelligence (e.g., Perceptual Reasoning, Working Memory) after adjustment for social factors. Because findings are not easily generalizable to the US, we examine this relation in a US population. METHODS: In 272 children in grades 3-5 from three Maine school districts, we examine associations between drinking water As (WAs) and intelligence (WISC-IV). RESULTS: On average, children had resided in their current home for 7.3 years (approximately 75% of their lives). In unadjusted analyses, household well WAs is associated with decreased scores on most WISC-IV Indices. With adjustment for maternal IQ and education, HOME environment, school district and number of siblings, WAs remains significantly negatively associated with Full Scale IQ and Perceptual Reasoning, Working Memory and Verbal Comprehension scores. Compared to those with WAs < 5 µg/L, exposure to WAs ≥ 5 µg/L was associated with reductions of approximately 5-6 points in both Full Scale IQ (p < 0.01) and most Index scores (Perceptual Reasoning, Working Memory, Verbal Comprehension, all p's < 0.05). Both maternal IQ and education were associated with lower levels of WAs, possibly reflecting behaviors (e.g., water filters, residential choice) limiting exposure. Both WAs and maternal measures were associated with school district. CONCLUSIONS: The magnitude of the association between WAs and child IQ raises the possibility that levels of WAs ≥ 5 µg/L, levels that are not uncommon in the United States, pose a threat to child development.

Interaction of plasma glutathione redox and folate deficiency on arsenic methylation capacity in Bangladeshi adults.

Inorganic arsenic(As) is metabolized through a series of methylation reactions catalyzed by arsenic(III)-methyltransferase (AS3MT), resulting in the generation of monomethylarsonic (MMAs) and dimethylarsinic acids (DMAs). AS3MT activity requires the presence of the methyl donor S-adenosylmethionine, a product of folate-dependent one-carbon metabolism, and a reductant. Although glutathione (GSH), the primary endogenous antioxidant, is not required for As methylation, GSH stimulates As methylation rates in vitro. However, the relationship between GSH redox and As methylation capacity in humans is unknown. We wished to test the hypothesis that a more oxidized plasma GSH redox status is associated with decreased As methylation capacity and examine whether these associations are modified by folate nutritional status. Concentrations of plasma GSH and GSSG, plasma folate, total blood As (bAs), total urinary As (uAs), and uAs metabolites were assessed in a cross-sectional study of n=376 Bangladeshi adults who were chronically exposed to As in drinking water. We observed that a decreased plasma GSH/GSSG ratio (reflecting a more oxidized redox state) was significantly associated with increased urinary %MMA, decreased urinary %DMA, and increased total bAs in folate-deficient individuals (plasma folate ≤ 9.0 nmol/L). Concentrations of plasma GSH and GSSG were independently associated with increased and decreased As methylation capacity, respectively. No significant associations were observed in folate-sufficient individuals, and interactions by folate status were statistically significant. Our findings suggest that GSH/GSSG redox regulation might contribute to the large interindividual variation in As methylation capacity observed in human populations.

A prospective study of arm circumference and risk of death in Bangladesh.

BACKGROUND: Epidemiological studies have observed protective effects of mid-upper arm circumference (MUAC) against all-cause mortality mostly in Western populations. However, evidence on cause-specific mortality is limited. METHODS: The sample included 19 575 adults from a population-based cohort study in rural Bangladesh, who were followed up for an average of 7.9 years for mortality. Cox proportional hazards regression was used to evaluate the effect of MUAC, as well as the joint effect of body mass index (BMI) and MUAC, on the risk of death from any cause, cancer and cardiovascular disease (CVD). RESULTS: During 154 664 person-years of follow-up, 744 deaths including 312 deaths due to CVD and 125 deaths due to cancer were observed. There was a linear inverse relationship of MUAC with total and CVD mortality. Each 1-cm increase in MUAC was associated a reduced risk of death from any cause [hazard ratio (HR) = 0.85; 95% confidence interval (C), 0.81-0.89) and CVD (HR = 0.87; 95% CI, 0.80-0.94), after controlling for potential confounders. No apparent relationship between MUAC and the risk of death from cancer was observed. Among individuals with a low BMI (<18.5 kg/m(2)), a MUAC less than 24 cm was associated with increased risk for all-cause (HR = 1.81; 95% CI, 1.52-2.17) and CVD mortality (HR = 1.45; 95% CI, 1.11-1.91). CONCLUSIONS: MUAC may play a critical role on all-cause and CVD mortality in lean Asians.

Effect of esomeprazole versus placebo on pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Gastro esophageal reflux (GER) is common in cystic fibrosis (CF) and may contribute to lung disease. Approximately 50% of patients with cystic fibrosis are being treated with proton pump inhibitors (PPIs). METHODS: In a randomized controlled study in adults, we compared treatment with esomeprazole 40 mg twice daily versus placebo in patients with CF and frequent respiratory exacerbations over a thirty-six week treatment period to determine effect on time to first exacerbation and other health related outcomes. RESULTS: 17 patients without symptoms of GER were randomized and 15 completed the study. 13 subjects underwent 24 hour ambulatory pH probe monitoring; 62% had pH probe evidence of GER. Forty one percent of subjects had a pulmonary exacerbation during the study. There was no significant difference in time to first pulmonary exacerbation (log rank test p = 0.3169). Five of nine subjects in the esomeprazole group compared with 2 of eight subjects in the placebo group experienced exacerbations (esomeprazole vs. placebo: odds ratio = 3.455, 95% CI = (0.337, 54.294), Fisher's exact test: p = 0.334). There was no change in Forced Expiratory Volume in one second, Gastroesophageal Symptom Assessment Score or CF Quality of Life score between the two treatment groups. CONCLUSIONS: There was a trend to earlier exacerbation and more frequent exacerbations in subjects randomized to esomeprazole compared with placebo. The effect of proton pump inhibitors on pulmonary exacerbations in CF warrants further investigation. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov, NCT01983774.

A dose-response study of arsenic exposure and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A cross-sectional study of the impact of blood selenium on blood and urinary arsenic concentrations in Bangladesh.

BACKGROUND: Arsenic can naturally occur in the groundwater without an anthropogenic source of contamination. In Bangladesh over 50 million people are exposed to naturally occurring arsenic concentrations exceeding the World Health Organization's guideline of 10 µg/L. Selenium and arsenic have been shown to facilitate the excretion of each other in bile. Recent evidence suggests that selenium may play a role in arsenic elimination by forming a selenium-arsenic conjugate in the liver before excretion into the bile. METHODS: A cross-sectional study of 1601 adults and 287 children was conducted to assess the relationship between blood selenium and urinary and blood arsenic in a study population residing in a moderately arsenic-contaminated rural area in Bangladesh. RESULTS: The results of this study indicate a statistically significant inverse relationship between blood selenium and urinary arsenic concentrations in both adult and pediatric populations in rural Bangladesh after adjustment for age, sex, Body Mass Index, plasma folate and B12 (in children), and ever smoking and current betel nut use (in adults). In addition, there appears to be a statistically significant inverse relationship between blood selenium and blood arsenic in children. CONCLUSIONS: Our results suggest that selenium is inversely associated with biomarkers of arsenic burden in both adults and children. These findings support the hypothesis that Se facilitates the biliary elimination of As, possibly via the putative formation of a Se-As conjugate using a glutathione complex. However, laboratory based studies are needed to provide further evidence to elucidate the presence of Se-As conjugate and its role in arsenic elimination in humans.

Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults.

Oxidative stress and DNA methylation are metabolically linked through the relationship between one-carbon metabolism and the transsulfuration pathway, but possible modulating effects of oxidative stress on DNA methylation have not been extensively studied in humans. Enzymes involved in DNA methylation, including DNA methyltransferases and histone deacetylases, may show altered activity under oxidized cellular conditions. Additionally, in vitro studies suggest that glutathione (GSH) depletion leads to global DNA hypomethylation, possibly through the depletion of S-adenosylmethionine (SAM). We tested the hypothesis that a more oxidized blood GSH redox status is associated with decreased global peripheral blood mononuclear cell (PBMC) DNA methylation in a sample of Bangladeshi adults. Global PBMC DNA methylation and whole blood GSH, glutathione disulfide (GSSG), and SAM concentrations were measured in 320 adults. DNA methylation was measured by using the [ (3)H]-methyl incorporation assay; values are inversely related to global DNA methylation. Whole blood GSH redox status (Eh) was calculated using the Nernst equation. We found that a more oxidized blood GSH Eh was associated with decreased global DNA methylation (B ± SE, 271 ± 103, p = 0.009). Blood SAM and blood GSH were associated with global DNA methylation, but these relationships did not achieve statistical significance. Our findings support the hypothesis that a more oxidized blood GSH redox status is associated with decreased global methylation of PBMC DNA. Furthermore, blood SAM does not appear to mediate this association. Future research should explore mechanisms through which cellular redox might influence global DNA methylation.