Faculty Bibliography

Epidermal growth factor receptor-dependent mechanisms have been implicated in growth signal transduction pathways that contribute to cancer development, including dermal carcinogenesis. Detection of the extracellular domain of the epidermal growth factor receptor (EGFR ECD) in serum has been suggested as a potential biomarker for monitoring this effect in vivo. Arsenic is a known human carcinogen, producing skin and other malignancies in populations exposed through their drinking water. One such exposed population, which we have been studying for a number of years, is in Bangladesh. The purpose of this study was to examine the EGFR ECD as a potential biomarker of arsenic exposure and/or effect in this population. Levels of the EGFR ECD were determined by enzyme-linked immunosorbent assay in the serum samples from 574 individuals with a range of arsenic exposures from drinking water in the Araihazar area of Bangladesh. In multiple regression analysis, serum EGFR ECD was found to be positively associated with three different measures of arsenic exposure (well water arsenic, urinary arsenic and a cumulative arsenic index) at statistically significant levels (p</=0.034), and this association was strongest among the individuals with arsenic-induced skin lesions (p </= 0.002). When the study subjects were stratified in tertiles of serum EGFR ECD levels, the risk of skin lesions increased progressively for each increase in all three arsenic measures (also stratified in tertiles) and this increasing risk became more pronounced among subjects within the highest tertile of EGFR ECD levels. These results suggest that serum EGFR ECD levels may be a potential biomarker of effect of arsenic exposure and may indicate those exposed individuals at greatest risk for the development of arsenic-induced skin lesions

OBJECTIVES: Arsenic contamination of groundwater is a severe public health crisis in Bangladesh, where the population is exposed to arsenic in drinking water through tube wells used for groundwater collection. In this study, we explored the association between socioeconomic status and arsenic toxicity. METHODS: We used baseline data from 11438 men and women who were recruited into the Health Effects of Arsenic Longitudinal Study (HEALS), a prospective cohort study on the health effects of arsenic exposure in Bangladesh. We conducted analyses with logistic regression and generalized estimating equations. RESULTS: We found a strong dose-response association with all measures of arsenic exposure and skin lesions. We also found that the effect of arsenic was modified by land ownership on a multiplicative scale, with an increased risk among non-land owners associated with well water arsenic (P=.04) and urinary total arsenic concentrations (P=.03). CONCLUSIONS: Our study provides insight into potentially modifiable host characteristics and identifies factors that may effectively target susceptible population subgroups for appropriate interventions

BACKGROUND: Inorganic arsenic (InAs) is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and this methylation facilitates urinary arsenic excretion. Previous studies suggest that persons with more complete methylation, characterized as greater proportions of DMA and lesser proportions of MMA and InAs in urine, have a lower risk of adverse arsenic-related health outcomes. OBJECTIVE: The purpose of this study was to examine whether the capacity to methylate arsenic differs by nutrient intake. DESIGN: Participants were 1016 Bangladeshi adults exposed to arsenic in drinking water. Nutrient intake was assessed with a validated food-frequency questionnaire. Multivariate regression analyses were used to examine associations of nutrients with urinary arsenic metabolite profiles. RESULTS: In multivariate analyses, higher intakes of cysteine, methionine, calcium, protein, and vitamin B-12 were associated with lower percentages of InAs and higher ratios of MMA to InAs in urine. Higher intakes of niacin (beta=0.22, P=0.02) and choline (beta=0.10, P=0.02) were associated with higher DMA-to-MMA ratios, after adjustment for age, sex, smoking, total urinary arsenic, and total energy intake. CONCLUSIONS: Findings from the current study show the influence of multiple nutrients on arsenic methylation. In particular, this study highlights the potential importance of dietary intakes of cysteine, methionine, niacin, vitamin B-12, and choline on health effects of arsenic by modulating its metabolism.

BACKGROUND: Acquisition of Helicobacter pylori, which predominantly occurs before age 10 years, may reduce risks of asthma and allergy. METHODS: We evaluated the associations of H pylori status with history of asthma and allergy and with skin sensitization using data from 7663 adults in the Third National Health and Nutrition Examination Survey. Adjusted odds ratios (ORs) for currently and ever having asthma, allergic rhinitis, allergy symptoms in the previous year, and allergen-specific skin sensitization were computed comparing participants seropositive for cagA(-) or cagA(+) strains of H pylori with those without H pylori. RESULTS: The presence of cagA(+) H pylori strains was inversely related to ever having asthma (OR, 0.79; 95% confidence interval [CI], 0.63-0.99), and the inverse association of cagA positivity with childhood-onset (age </=15 years) asthma was stronger (OR, 0.63; 95% CI, 0.43-0.93) than that with adult-onset asthma (OR, 0.97; 95% CI, 0.72-1.32). Colonization with H pylori, especially with a cagA(+) strain, was inversely associated with currently (OR, 0.77; 95% CI, 0.62-0.96) or ever (OR, 0.77; 95% CI, 0.62-0.94) having a diagnosis of allergic rhinitis, especially for childhood onset (OR, 0.55; 95% CI, 0.37-0.82). Consistent inverse associations were found between H pylori colonization and the presence of allergy symptoms in the previous year and sensitization to pollens and molds. CONCLUSION: These observations support the hypothesis that childhood acquisition of H pylori is associated with reduced risks of asthma and allergy

The authors performed a cross-sectional analysis to evaluate the association between arsenic exposure from drinking water and blood pressure using baseline data of 10,910 participants in the Health Effects of Arsenic Longitudinal Study in Bangladesh (October 2000-May 2002). A time-weighted well arsenic concentration (TWA) based on current and past use of drinking wells was derived. Odds ratios for high pulse pressure (> or = 55 mmHg) by increasing TWA quintiles (< or = 8, 8.1-40.8, 40.9-91.0, 91.1-176.0, and 176.1-864.0 microg/liter) were 1.00 (referent), 1.39 (95% confidence interval (CI): 1.14, 1.71), 1.21 (95% CI: 0.99, 1.49), 1.19 (95% CI: 0.97, 1.45), and 1.19 (95% CI: 0.97, 1.46). Among participants with a lower than average dietary intake level of B vitamins and folate, the odds ratios for high pulse pressure by increasing TWA quintiles were 1.00 (referent), 1.84 (95% CI: 1.07, 3.16), 1.89 (95% CI: 1.11, 3.20), 1.83 (95% CI: 1.09, 3.07), and 1.89 (95% CI: 1.12, 3.20). The odds ratios for systolic hypertension suggest a similar but weaker association. No apparent associations were observed between TWA and general or diastolic hypertension. These findings indicate that the effect of low-level arsenic exposure on blood pressure is nonlinear and may be more pronounced in persons with lower intake of nutrients related to arsenic metabolism and cardiovascular health. Future research is needed to evaluate the effect of low-level arsenic exposure on specific cardiovascular outcomes

We examined associations between polymorphisms in genes related to estrogen metabolism (CYP1B1 codon 432G --> C rs#1056836, CYP1B1 codon 453A --> G rs#1800440, COMT codon 158G --> A rs#4680) and biosynthesis (CYP17 T --> C promoter rs#743572, CYP19 exon 4 TTTA repeat) and urinary estrogen metabolites (2-hydroxyestrogens (2-OHE), 16alpha-hydroxyestrone (16alpha-OHE1), and their ratio) in a pilot study of 64 pre- and post-menopausal women with a family history of breast cancer. Women were participants in the Metropolitan New York Registry of Breast Cancer Families, one of six international sites of the National Cancer Institute's Breast Cancer Family Registry. We used linear regression to examine the effects of genetic variants on log-transformed urinary estrogen metabolites. After adjusting for menopausal status, BMI, and age, carriers of the CYP1B1 codon 453G variant allele had 31.0% lower levels of 2-OHE (P-value = 0.05) and 40.2% lower levels of 16alpha-OHE1 (P = 0.01). Results were similar after restricting the analyses to pre-menopausal women (n = 41). Consistent with other studies, among pre-menopausal women, carriers of the COMT codon 158A variant allele had increased 2-OHE levels (P = 0.03) and an increased 2-OHE/16alpha-OHE1 ratio (P = 0.04); carriers of the CYP17 C promoter variant allele had increased 2-OHE levels (P = 0.08). To our knowledge this is the first report showing associations between the CYP1B1 codon 453G variant allele and urinary 2-OHE and 16alpha-OHE1 metabolites. Further larger studies should be conducted to confirm these results. Future identification of individuals with genetic polymorphisms that affect estrogen metabolism and biosynthesis may help characterize women at higher breast cancer risk and could guide breast cancer prevention strategies for those individuals

Arsenic exposure from drinking water is considered to be a risk factor for skin and internal cancers. Animal studies suggest a potential antagonism between arsenic and selenium in the body. We did a case-cohort analysis to prospectively evaluate the association between arsenic-related premalignant skin lesions and prediagnostic blood selenium levels in 303 cases of skin lesions newly diagnosed from November 2002 to April 2004 and 849 subcohort members randomly selected from the 8,092 participants in the Health Effects of Arsenic Longitudinal Study with available baseline blood and urine samples collected in 2000. Incidence rate ratios for skin lesions in increasing blood selenium quintiles were 1.00 (reference), 0.68 [95% confidence interval (95% CI), 0.39-1.18], 0.51 (95% CI, 0.29-0.87), 0.52 (95% CI, 0.30-0.91), and 0.53 (95% CI, 0.31-0.90). Effect estimates remained similar with adjustments for age, sex, body mass index, smoking status, excessive sunlight exposure (in men), well water arsenic concentration at baseline, and nutritional intakes of folate, iron, protein, vitamin E, and B vitamins. At any given arsenic exposure level, the risk of premalignant skin lesions was consistently greater among participants with blood selenium lower than the average level. The findings support the hypothesis that dietary selenium intake may reduce the incidence of arsenic-related premalignant skin lesions among populations exposed to arsenic exposure from drinking water. (Cancer Epidemiol Biomarkers Prev 2007;16(2):207-13)

Background: In human pedigree data age at disease occurrence frequently is missing and is imputed using various methods. However, little is known about the performance of these methods when applied to families. In particular, there is little information about the level of agreement between imputed and actual values of temporal data and their effects on inferences. Methods: We performed two evaluations of five imputation methods used to generate complete data for repositories to be shared by many investigators. Two of the methods are mean substitution methods, two are regression methods and one is a multiple imputation method based on one of the regression methods. To evaluate the methods, we randomly deleted the years of disease diagnosis of some men in a sample of pedigrees ascertained as part of a prostate cancer study. In the first evaluation, we used the five methods to impute the missing diagnosis years and evaluated agreement between imputed and actual values. In the second evaluation, we compared agreement between regression coefficients estimated using imputed diagnosis years with those estimated using the actual years. Results/Conclusions: For both evaluations, we found optimal or near-optimal performance from a regression method that imputes a man's diagnosis year based on the year of birth and year of last observation of all affected men with complete data. The multiple imputation analogue of this method also performed well.

BACKGROUND: Populations in South and East Asia and many other regions of the world are chronically exposed to arsenic-contaminated drinking water. To various degrees, ingested inorganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one-carbon metabolism; impaired methylation is associated with adverse health outcomes. Consequently, folate nutritional status may influence arsenic methylation and toxicity. OBJECTIVE: The objective of this study was to test the hypothesis that folic acid supplementation of arsenic-exposed adults would increase arsenic methylation. DESIGN: Two hundred adults in a rural region of Bangladesh, previously found to have low plasma concentrations of folate (</=9 nmol/L) were enrolled in a randomized, double-blind, placebo-controlled folic acid-supplementation trial. Plasma concentrations of folate and homocysteine and urinary concentrations of arsenic metabolites were analyzed at baseline and after 12 wk of supplementation with folic acid at a dose of 400 microg/d or placebo. RESULTS: The increase in the proportion of total urinary arsenic excreted as DMA in the folic acid group (72% before and 79% after supplementation) was significantly (P < 0.0001) greater than that in the placebo group, as was the reduction in the proportions of total urinary arsenic excreted as MMA (13% and 10%, respectively; P < 0.0001) and as InAs (15% and 11%, respectively; P < 0.001). CONCLUSIONS: These data indicate that folic acid supplementation to participants with low plasma folate enhances arsenic methylation. Because persons whose urine contains low proportions of DMA and high proportions of MMA and InAs have been reported to be at greater risk of skin and bladder cancers and peripheral vascular disease, these results suggest that folic acid supplementation may reduce the risk of arsenic-related health outcomes

BACKGROUND: The nutritional determinants of hypertension in Bangladesh and other low-income countries are largely unknown. OBJECTIVE: We assessed the associations of general hypertension with nutrient intakes and diet patterns in Bangladesh. DESIGN: This was a cross-sectional analysis of 11 116 participants enrolled in the Health Effects of Arsenic Longitudinal Study in Bangladesh. Dietary intakes were measured by use of a validated food-frequency questionnaire. RESULTS: Three major dietary patterns were identified by using principal component analysis: 1) the 'balanced' pattern, which was characterized by rice, some meat, small fish, fruit, and vegetables; 2) the 'animal protein' pattern, which was more heavily weighted on meat, milk, poultry, eggs, bread, large fish, and fruit; and 3) the 'gourd and root vegetable' pattern, which consisted largely of squashes and root and leafy vegetables. Adjusted prevalence odds ratios for general hypertension in increasing quintiles of balanced pattern scores were 1.00 (reference), 0.81 (95% CI: 0.79, 0.97), 0.82 (0.68, 0.97), 0.79 (0.66, 0.94), and 0.71 (0.59, 0.85) (P for trend < 0.01). Prevalence odds ratios for general hypertension in increasing quintiles of animal protein pattern scores were 1.00 (reference), 1.30 (1.01, 1.52), 1.20 (1.01, 1.47), 1.22 (1.00, 1.44), and 1.21 (1.03, 1.49) (P for trend = 0.23). Markers of high socioeconomic status were positively associated with the animal protein pattern. CONCLUSION: Our findings suggest the importance of dietary patterns in general hypertension in a low-income population undergoing the early stage of the epidemiologic transition