Arsenic exposure and early biomarkers of cardiovascular disease and cancer

AbstractInorganic arsenic exposure through drinking water is a serious public health concern because of its association to cancer and non-cancer diseases. More than one hundred million people world-wide are exposed to elevated levels of arsenic on a regular basis. Arsenic is classified as class I carcinogen by International Agency for Research on Cancer (IARC). Recent report shows that arsenic exposure via drinking water is associated with increased risk of cardiovascular disease and diabetes. Several mechanisms of arsenic-related toxicity have been suggested, among those are genotoxicity and epigenetic modifications affecting gene expression. The aim of this thesis was to identify early biomarkers for arsenic-related cancer and cardiovascular disease, as well as, to analyse changes in gene expression and DNA methylation related to chronic arsenic exposure. The study participants were from the Salta Province of northern Argentina, a region known to have areas with arsenic in drinking water. Two groups of study subjects, one residing in Puna area of Andes mountains (~4000 meters above the sea level) here called as Andes, and another residing in Salta plains (~300 meters above sea level) called Chaco, were studied. Arsenic exposure was assessed as the sum of inorganic arsenic and its metabolites, inorganic arsenic (iAs), methylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine, measured by high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry (HPLC-HG-ICPMS). The arsenic metabolism efficiency was assessed by the urinary fractions (%) of individual metabolites. To evaluate cardiovascular health, blood pressure was measured and homocysteine concentration and lipid profile were analysed in the plasma as early cardiovascular biomarkers in Andean women. To evaluate arenic realted DNA damage, telomere length and mitochondrial DNA copy number (mtDNAcn) were measured in peripheral blood in both Andes and Chaco study groups. Gene expression and DNA methylation were measured in peripheral blood in the Andes study group. The arsenic concentrations in water had large ranges in both Andes and Chaco, and the median urinary arsenic concentrations for Andes and Chaco were 196 µg/L and 80 µg/L, respectively. The urinary arsenic metabolites differed significantly between the study groups, the median %iAs and %MMA were higher and the median %DMA was lower in Chaco population compared to the Andes, reflecting a less efficient arsenic metabolism in the Chaco study group. In women from Andes, increased urinary arsenic concentration was associated with decreased diastolic blood pressure and apoB/A, but there were no associations between urinary arsenic and homocysteine, triglycerides or cytokines, suggesting no evident cardiovascular toxicity. In men and women in Andes and Chaco, urinary arsenic was associated with longer telomere length and in Chaco with increased mtDNAcn. When the study groups were stratified according to fraction of inorganic arsenic in urine (%iAs), the associations remained significant in the above %iAs group, i.e. with less efficient arsenic metabolism capacity, for both Andes and Chaco. This suggests that individuals with less efficient arsenic metabolism are more prone to arsenic-related DNA damage and may be at high risk for arsenic-related future diseases. In Andes women, urinary arsenic was associated with decreased gene expression and increased DNA methylation in peripheral blood, indicating that arsenic exposure may have silenced gene expression by increasing DNA methylation. This thesis showed genotoxic and epigenetic, but no adverse cardiovascular, effects of arsenic exposure via drinking water. Future studies are needed to follow-up the study groups for future arsenic-related disease

Arsenic-Associated Oxidative Stress, Inflammation, and Immune Disruption in Human Placenta and Cord Blood

BACKGROUND: Arsenic (As) exposure during pregnancy induces oxidative stress and increases the risk of fetal loss and low birth weight. OBJECTIVES: In this study we aimed to elucidate the effects of As exposure on immune markers in the placenta and cord blood, and the involvement of oxidative stress. METHODS: Pregnant women were enrolled around gestational week (GW) 8 in our longitudinal, population-based, mother-child cohort in Matlab, an area in rural Bangladesh with large variations in As concentrations in well water. Women (n = 130) delivering at local clinics were included in the present study. We collected maternal urine twice during pregnancy (GW8 and GW30) for measurements of As, and placenta and cord blood at delivery for assessment of immune and inflammatory markers. Placental markers were measured by immunohistochemistry, and cord blood cytokines by multiplex cytokine assay. RESULTS: In multivariable adjusted models, maternal urinary As (U-As) exposure both at GW8 and at GW30 was significantly positively associated with placental markers of 8-oxoguanine (8-oxoG) and interleukin-1β (IL-1β); U-As at GW8, with tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); and U-As at GW30, with leptin; U-As at GW8 was inversely associated with CD3+ T cells in the placenta. Cord blood cytokines (IL-1β, IL-8, IFNγ, TNFα) showed a U-shaped association with U-As at GW30. Placental 8-oxoG was significantly positively associated with placental proinflammatory cytokines. Multivariable adjusted analyses suggested that enhanced placental cytokine expression (TNFα and IFNγ) was primarily influenced by oxidative stress, whereas leptin expression appeared to be mostly mediated by As, and IL-1β appeared to be influenced by both oxidative stress and As. CONCLUSION: As exposure during pregnancy appeared to enhance placental inflammatory responses (in part by increasing oxidative stress), reduce placental T cells, and alter cord blood cytokines. These findings suggest that effects of As on immune function may contribute to impaired fetal and infant health

Influenza in Outpatient ILI Case-Patients in National Hospital-Based Surveillance, Bangladesh, 2007–2008

Recent population-based estimates in a Dhaka low-income community suggest that influenza was prevalent among children. To explore the epidemiology and seasonality of influenza throughout the country and among all age groups, we established nationally representative hospital-based surveillance necessary to guide influenza prevention and control efforts.We conducted influenza-like illness and severe acute respiratory illness sentinel surveillance in 12 hospitals across Bangladesh during May 2007–December 2008. We collected specimens from 3,699 patients, 385 (10%) which were influenza positive by real time RT-PCR. Among the sample-positive patients, 192 (51%) were type A and 188 (49%) were type B. Hemagglutinin subtyping of type A viruses detected 137 (71%) A/H1 and 55 (29%) A/H3, but no A/H5 or other novel influenza strains. The frequency of influenza cases was highest among children aged under 5 years (44%), while the proportions of laboratory confirmed cases was highest among participants aged 11–15 (18%). We applied kriging, a geo-statistical technique, to explore the spatial and temporal spread of influenza and found that, during 2008, influenza was first identified in large port cities and then gradually spread to other parts of the country. We identified a distinct influenza peak during the rainy season (May–September).Our surveillance data confirms that influenza is prevalent throughout Bangladesh, affecting a wide range of ages and causing considerable morbidity and hospital care. A unimodal influenza seasonality may allow Bangladesh to time annual influenza prevention messages and vaccination campaigns to reduce the national influenza burden. To scale-up such national interventions, we need to quantify the national rates of influenza and the economic burden associated with this disease through further studies

Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood

Background Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N = 80 women) and DNA methylation (N = 93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results U-As concentrations, ranging 10–1251 μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000 CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap

Global positioning system coordinated map of Bangladesh showing the surveillance sites and geographical distribution of influenza positive cases during May 2007–December 2008.

<p>Global positioning system coordinated map of Bangladesh showing the surveillance sites and geographical distribution of influenza positive cases during May 2007–December 2008.</p

Clinical presentations in influenza and non-influenza case-patients.

*<p>Fever was the essential criterion for enrolment.</p>**<p>Significant.</p

Non-coinciding seasonality of seasonal influenza in human and avian influenza in poultry in Bangladesh.

<p>Non-coinciding seasonality of seasonal influenza in human and avian influenza in poultry in Bangladesh.</p

Proportion of ILI and SARI case patients with influenza virus infection.

<p>Proportion of ILI and SARI case patients with influenza virus infection.</p