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Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis.

ABSTRACT: The Indian subcontinent is the only region where arsenic contamination of drinking water coexists with widespread resistance to antimonial drugs that are used to treat the parasitic disease visceral leishmaniasis. We have previously proposed that selection for parasite resistance within visceral leishmaniasis patients who have been exposed to trivalent arsenic results in cross-resistance to the related metalloid antimony, present in the pentavalent state as a complex in drugs such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). To test this hypothesis, Leishmania donovani was serially passaged in mice exposed to arsenic in drinking water at environmentally relevant levels (10 or 100 ppm). Arsenic accumulation in organs and other tissues was proportional to the level of exposure and similar to that previously reported in human liver biopsies. After five monthly passages in mice exposed to arsenic, isolated parasites were found to be completely refractory to 500 μg · mL(-1) Pentostam compared with the control passage group (38.5 μg · mL(-1)) cultured in vitro in mouse peritoneal macrophages. Reassessment of resistant parasites following further passage for 4 mo in mice without arsenic exposure showed that resistance was stable. Treatment of infected mice with Pentostam confirmed that resistance observed in vitro also occurred in vivo. We conclude that arsenic contamination may have played a significant role in the development of Leishmania antimonial resistance in Bihar because inadequate treatment with antimonial drugs is not exclusive to India, whereas widespread antimonial resistance is.

SUBMITTER: Perry MR

PROVIDER: S-EPMC3856816 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Investigational drugs for visceral leishmaniasis.

Project description:Introduction: The armamentarium of antileishmanial drugs is small. It is further being threatened by the development of resistance and decreasing sensitivity to the available drugs. The development of newer drugs is sorely needed. Areas covered: The authors have based their review on a literature search performed using PubMed. The article specifically looks at investigational drugs, which have demonstrated, at the very least, in vitro and in vivo activities against the leishmania species that cause visceral leishmaniasis. Specifically, the authors review the nitroimidazole compound fexinidazole, which is one of the few drugs which have reached Phase II trials. The article also discusses the R enantiomer of (S)-PA-824, which has shown good antileishmanial activity. Finally, the article also highlights the many novel delivery systems and oral formulations of amphotericin B, which are both cheap and less toxic and are currently under investigation. Expert opinion: Very few new drugs have reached the clinic for this neglected tropical disease and there is an urgent need for new efficacious therapeutics. The authors believe that support from public-private partnerships would help in enabling the prompt development of drug candidates that could potentially make the clinic.

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Estimated Childhood Lead Exposure From Drinking Water in Chicago.

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In utero exposure to arsenic via drinking water impairs lung development and mucociliary clearance genes.

Project description:In utero exposure to arsenic via drinking water increases the risk of lower respiratory tract infections during infancy and mortality from bronchiectasis in adulthood. Pregnant mice were exposed to arsenic, and gene expression patterns were profiled in peripheral lung tissue obtained from the offspring at 2 weeks of age.

2013-06-04 | GSE37831 | GEO

Arsenic exposure through drinking water is associated with longer telomeres in peripheral blood.

Project description:Inorganic arsenic is a strong carcinogen, possibly by interaction with the telomere length. The aim of the study was to evaluate how chronic arsenic exposure from drinking water as well as the arsenic metabolism efficiency affect the individual telomere length and the expression of telomere-related genes. Two hundred two women with a wide range in exposure to arsenic via drinking water (3.5-200 ?g/L) were recruited. Concentrations of arsenic metabolites in urine [inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were measured. The relative telomere length in blood was measured by quantitative real-time polymerase chain reaction. Genotyping (N = 172) for eight SNPs in AS3MT and gene expression of telomere-related genes (in blood; N = 90) were performed. Urinary arsenic (sum of metabolites) was positively associated with telomere length (? = 0.65 × 10(-4), 95% CI = 0.031 × 10(-4)-1.3 × 10(-4), adjusted for age and BMI). Individuals with above median fractions of iAs and MMA showed significantly longer telomeres by increasing urinary arsenic (? = 1.0 × 10(-4), 95% CI = 0.21 × 10(-4)-1.8 × 10(-4) at high % iAs; ? = 0.88 × 10(-4) 95% CI = 0.12 × 10(-4)-1.6 × 10(-4) at high % MMA) than those below the median (p = 0.80 and 0.44, respectively). Similarly, carriers of the slow and more toxic metabolizing AS3MT haplotype showed stronger positive associations between arsenic exposure and telomere length, as compared to noncarriers (interaction urinary arsenic and haplotype p = 0.025). Urinary arsenic was positively correlated with the expression of telomerase reverse transcriptase (TERT, Spearman r = 0.22, p = 0.037), but no association was found between TERT expression and telomere length. Arsenic in drinking water influences the telomere length, and this may be a mechanism for its carcinogenicity. A faster and less toxic arsenic metabolism diminishes arsenic-related telomere elongation.

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Association between arsenic exposure from drinking water and plasma levels of cardiovascular markers.

Project description:The authors conducted a cross-sectional study to assess the relation between arsenic exposure from drinking water and plasma levels of markers of systemic inflammation and endothelial dysfunction (matrix metalloproteinase-9, myeloperoxidase, plasminogen activator inhibitor-1, soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble vascular adhesion molecule-1 (VCAM-1)) using baseline data from 668 participants (age, >30 years) in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2007-2008). Both well water arsenic and urinary arsenic were positively associated with plasma levels of soluble VCAM-1. For every 1-unit increase in log-transformed well water arsenic (ln μg/L) and urinary arsenic (ln μg/g creatinine), plasma soluble VCAM-1 was 1.02 (95% confidence interval: 1.01, 1.03) and 1.04 (95% confidence interval: 1.01, 1.07) times greater, respectively. There was a significant interaction between arsenic exposure and higher body mass index, such that the increased levels of plasminogen activator inhibitor-1 and soluble VCAM-1 associated with arsenic exposure were stronger among people with higher body mass index. The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation and endothelial dysfunction that could be modified by body mass index and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease.

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Arsenate Sub-chronic Drinking Water Study

Project description:Concentration- and time-dependent genomic changes in the mouse urinary bladder following exposure to arsenate in drinking water for up to twelve weeks. Inorganic arsenic (Asi) is a known human bladder carcinogen. The objective of this study was to examine the concentration dependence of the genomic response to Asi in the urinary bladders of mice. C57BL/6J mice were exposed for 1 or 12 weeks to arsenate in drinking water at concentrations of 0.5, 2, 10, and 50 mg As/L. Urinary bladders were analyzed using gene expression microarrays. A consistent reversal was observed in the direction of gene expression change: from predominantly decreased expression at 1 week to predominantly increased expression at 12 weeks. These results are consistent with evidence from in vitro studies of an acute adaptive response that is suppressed on longer exposure due to down-regulation of Fos. Pathways with the highest enrichment in gene expression changes were associated with epithelial-to-mesenchymal transition, inflammation, and proliferation. Benchmark dose (BMD) analysis determined that the lowest median BMD values for pathways were above 5 mg As/L, despite the fact that pathway enrichment was observed at the 0.5 mg As/L exposure concentration. This disparity may result from the non-monotonic nature of the concentration-responses for the expression changes of a number of genes, as evidenced by the much fewer gene expression changes at 2 mg As/L compared to lower or higher concentrations. Pathway categories with concentration-related gene expression changes included cellular morphogenesis, inflammation, apoptosis/survival, cell cycle control, and DNA damage response. The results of this study provide evidence of a concentration-dependent transition in the mode of action for the subchronic effects of Asi in mouse bladder cells in the vicinity of 2 mg Asi/L.

2011-09-15 | GSE32102 | GEO

Arsenic exposure from drinking water and QT-interval prolongation: results from the Health Effects of Arsenic Longitudinal Study.

Project description:BackgroundArsenic exposure from drinking water has been associated with heart disease; however, underlying mechanisms are uncertain.ObjectiveWe evaluated the association between a history of arsenic exposure from drinking water and the prolongation of heart rate-corrected QT (QTc), PR, and QRS intervals.MethodWe conducted a study of 1,715 participants enrolled at baseline from the Health Effects of Arsenic Longitudinal Study. We assessed the relationship of arsenic exposure in well water and urine samples at baseline with parameters of electrocardiogram (ECG) performed during 2005-2010, 5.9 years on average since baseline.ResultsThe adjusted odds ratio (OR) for QTc prolongation, defined as a QTc ? 450 msec in men and ? 460 msec in women, was 1.17 (95% CI: 1.01, 1.35) for a 1-SD increase in well-water arsenic (108.7 µg/L). The positive association appeared to be limited to women, with adjusted ORs of 1.24 (95% CI: 1.05, 1.47) and 1.24 (95% CI: 1.01, 1.53) for a 1-SD increase in baseline well-water and urinary arsenic, respectively, compared with 0.99 (95% CI: 0.73, 1.33) and 0.86 (95% CI: 0.49, 1.51) in men. There were no apparent associations of baseline well-water arsenic or urinary arsenic with PR or QRS prolongation in women or men.ConclusionsLong-term arsenic exposure from drinking water (average 95 µg/L; range, 0.1-790 µg/L) was associated with subsequent QT-interval prolongation in women. Future longitudinal studies with repeated ECG measurements would be valuable in assessing the influence of changes in exposure.

| S-EPMC3620737 | biostudies-literature

Arsenic in Drinking Water, Transition Cell Cancer and Chronic Cystitis in Rural Bangladesh.

Project description:In earlier analyses, we demonstrated dose-response relationships between renal and lung cancer and local arsenic concentrations in wells used by Bangladeshi villagers. We used the same case-referent approach to examine the relation of arsenic to biopsy confirmed transition cell cancer (TCC) of the ureter, bladder or urethra in these villagers. As the International Agency for Research on Cancer (IARC) has conclude that arsenic in drinking water causes bladder cancer, we expected to find higher risk with increasing arsenic concentration. We used histology/cytology results from biopsies carried out at a single clinic in Dhaka, Bangladesh from January 2008 to October 2011. We classified these into four groups, TCC (n = 1466), other malignancies (n = 145), chronic cystitis (CC) (n = 844) and other benign (n = 194). Arsenic concentration was estimated from British Geological Survey reports. Odds ratios were calculated by multilevel logistic regression adjusted for confounding and allowing for geographic clustering. We found no consistent trend for TCC with increasing arsenic concentration but the likelihood of a patient with benign disease having CC was significantly increased at arsenic concentrations >100 µg/L. We conclude that the expected relationship of TCC to arsenic was masked by over-matching that resulted from the previously unreported relationship between arsenic and CC. We hypothesize that CC may be a precursor of TCC in high arsenic areas.

| S-EPMC4661611 | biostudies-literature

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