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Find video protocols related to scientific articles indexed in Pubmed.
Associations between cadmium exposure and circulating levels of sex hormones in postmenopausal women.
Environ. Res.
PUBLISHED: 08-28-2014
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Recent epidemiological as well as in vivo and in vitro studies collectively suggest that the metalloestrogen cadmium (Cd) could be a potential risk factor for hormone-related cancers in particularly breast cancer. Assessment of the association between Cd exposure and levels of endogenous sex hormones is of pivotal importance, as increased levels of such have been associated with a higher risk of breast cancer in postmenopausal women. The present study investigated the perceived relationship (multivariable-adjusted linear regression analyses) between Cd exposure [blood Cd (B-Cd) and urinary Cd (U-Cd)], and serum levels of androstenedione, testosterone, estradiol, and sex-hormone binding globulin (SHBG), in 438 postmenopausal Swedish women without hormone replacement therapy (HRT). A significant positive association between B-Cd (median 3.4nmol/L) and serum testosterone levels, as well as a significant inverse association between B-Cd and serum estradiol levels and with the estradiol/testosterone ratio were encountered. However, U-Cd (median 0.69nmol/mmol creatinine) was inversely associated with serum estradiol levels only. Our data may suggest that Cd interferes with the levels of testosterone and estradiol in postmenopausal women, which might have implications for breast cancer risk.
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Genetic variation in arsenic (+3 oxidation state) methyltransferase (AS3MT), arsenic metabolism and risk of basal cell carcinoma in a European population.
Environ. Mol. Mutagen.
PUBLISHED: 08-25-2014
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Exposure to inorganic arsenic increases the risk of basal cell carcinoma (BCC). Arsenic metabolism is a susceptibility factor for arsenic toxicity, and specific haplotypes in arsenic (+3 oxidation state) methyltransferase (AS3MT) have been associated with increased urinary fractions of the most toxic arsenic metabolite, methylarsonic acid (MMA). The aim of this study is to elucidate the association of AS3MT haplotypes with arsenic metabolism and the risk of BCC. Four AS3MT polymorphisms were genotyped in BCC cases (N?=?529) and controls (N?=?533) from Eastern Europe with low to moderate arsenic exposure (lifetime average drinking water concentration: 1.3 µg/L, range 0.01-167 µg/L). Urinary metabolites [inorganic arsenic (iAs), MMA, dimethylarsinic acid (DMA)] were analyzed by HPLC-ICPMS. Five AS3MT haplotypes (based on rs3740400 A/C, rs3740393 G/C, rs11191439 T/C and rs1046778 T/C) had frequencies >5%. Individuals with the CCTC haplotype had lower %iAs (P?=?0.032) and %MMA (P?=?0.020) in urine, and higher %DMA (P?=?0.033); individuals with the CGCT haplotype had higher %MMA (P?
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Maternal urinary iodine concentration up to 1.0 mg/L is positively associated with birth weight, length, and head circumference of male offspring.
J. Nutr.
PUBLISHED: 07-16-2014
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Adequate iodine status in early life is crucial for neurodevelopment. However, little is known about the effects of maternal iodine status during pregnancy on fetal growth. The present study investigated the potential impact of maternal iodine status during pregnancy on offspring birth size. This large prospective cohort study was nested in a Bangladeshi population-based randomized supplementation trial in pregnant women [MINIMat (Maternal and Infant Nutrition Interventions in Matlab)]. Urine samples obtained at 8 wk of gestation from 1617 women were analyzed for iodine and other elements, such as arsenic and cadmium, using inductively coupled plasma mass spectrometry. Anthropometric measurements at birth included weight, length, and head and chest circumference. Maternal urinary iodine concentrations (UICs) ranged from 0.020 to 10 mg/L, with a median of 0.30 mg/L. Below ?1.0 mg/L, UIC was significantly positively associated with birth weight and length. Birth weight and length increased by 9.3 g (95% CI: 2.9, 16) and 0.042 cm (95% CI: 0.0066, 0.076), respectively, for each 0.1-mg/L increase in maternal UIC. No associations were observed between UIC and head or chest circumference. When we stratified the analyses by newborn sex, the positive associations between maternal UIC (<1 mg/L) and measurements of size at birth were restricted to boys, with no evidence in girls. Among boys, the mean weight, length, and head circumference increased by 70 g (P = 0.019), 0.41 cm (P = 0.013), and 0.28 cm (P = 0.031) for every 0.5-mg/L increase in maternal UIC. Maternal iodine status was positively associated with weight, length, and head circumference in boys up to ?1 mg/L, which is well above the recommended maximum concentration of 0.5 mg/L. The associations leveled off at UIC ? 1 mg/L. Our findings support previous conclusions that the advantages of correcting potential iodine deficiency outweigh the risks of excess exposure.
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Exposure to arsenic and intra-chromosomal instability in blood.
Metallomics
PUBLISHED: 07-16-2014
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The 450k Chip Analysis Methylation Pipeline (ChAMP) is a novel Illumina Infinium HumanMethylation450 BeadChip data processing algorithm that allows the analysis of copy number alterations (CNAs). With this pipeline we evaluated the prevalence of CNAs in peripheral blood leukocyte samples from healthy Argentinean Andean women with varying exposure to inorganic arsenic in drinking water. Arsenic exposure was assessed based on the sum concentrations of metabolites of inorganic arsenic in urine (U-As), which ranged from 10-663 ?g L(-1) with a median of 185 ?g L(-1). We used linear regression analysis to elucidate the association between U-As and the prevalence of CNAs. We found that increasing arsenic exposure was positively associated with the frequency of CNAs (p = 0.002), possibly in a dose-response relationship. Adjustment of the regression model for age and BMI of the subjects did not significantly change the effect estimate, although both covariates were significant predictors. Our results suggest that exposure to arsenic increases genomic instability in the form of CNAs.
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Polymorphisms in DNA repair genes XRCC1 and XRCC3, occupational exposure to arsenic and sunlight, and the risk of non-melanoma skin cancer in a European case-control study.
Environ. Res.
PUBLISHED: 06-23-2014
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X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3) polymorphisms are relatively frequent in Caucasian populations and may have implications in skin cancer modulation. A few studies have evaluated their association with non-melanoma skin cancer (NMSC), but the results are inconsistent. In the current study, we aim to assess the impact of XRCC1 R399Q and XRCC3 T241M polymorphisms on the risk of NMSC associated with sunlight and arsenic exposure. Study participants consist of 618 new cases of NMSC and 527 hospital-based controls frequency matched on age, sex, and county of residence from Hungary, Romania, and Slovakia. Adjusted effects are estimated using multivariable logistic regression. The results indicate an increased risk of squamous cell carcinoma (SCC) for the homozygous variant genotype of XRCC1 R399Q (OR 2.53, 95% CI 1.14-5.65) and a protective effect against basal cell carcinoma (BCC) for the homozygous variant genotype of XRCC3 T241M (OR 0.61, 95% CI 0.41-0.92), compared with the respective homozygous common genotypes. Significant interactions are detected between XRCC3 T241M and sunlight exposure at work, and between XRCC3 T241M and exposure to arsenic in drinking water (p-value for interaction <0.10). In conclusion, the current study demonstrates that polymorphisms in XRCC genes may modify the associations between skin cancer risk and exposure to sunlight or arsenic. Given the high prevalence of genetic polymorphisms modifying the association between exposure to environmental carcinogens and NMSC, these results are of substantial relevance to public health.
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Arsenic exposure and cell-mediated immunity in pre-school children in rural bangladesh.
Toxicol. Sci.
PUBLISHED: 06-12-2014
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Prenatal arsenic exposure has been associated with reduced thymic index and increased morbidity in infants, indicating arsenic-related impaired immune function. We aimed at elucidating potential effects of pre- and postnatal arsenic exposure on cell-mediated immune function in pre-school aged children. Children born in a prospective mother-child cohort in rural Bangladesh were followed up at 4.5 years of age (n = 577). Arsenic exposure was assessed by concentrations of arsenic metabolites (U-As) in child urine and maternal urine during pregnancy, using high-performance liquid chromatography online with inductively coupled plasma mass spectrometry. For assessment of delayed type hypersensitivity response, an intradermal injection of purified protein derivative (PPD) was given to Bacillus Calmette-Guerin vaccinated children. The diameter (mm) of induration was measured after 48-72 h. Plasma concentrations of 27 cytokines were analyzed by a multiplex cytokine assay. Children's concurrent, but not prenatal, arsenic exposure was associated with a weaker response to the injected PPD. The risk ratio (RR) of not responding to PPD (induration <5 mm) was 1.37 (95% confidence interval (CI): 1.07, 1.74) in children in the highest quartile of U-As (range 126-1228 ?g/l), compared with the lowest (range 12-34 ?g/l). The p for trend across the quartiles was 0.003. The association was stronger in undernourished children. Children's U-As in tertiles was inversely associated with two out of 27 cytokines only, i.e., IL-2 and TNF-?, both Th1 cytokines (in the highest tertile, regression coefficients (95% CI): -1.57 (-2.56, -0.57) and -4.53 (-8.62, -0.42), respectively), but not with Th2 cytokines. These associations were particularly strong in children with recent infections. In conclusion, elevated childhood arsenic exposure appeared to reduce cell-mediated immunity, possibly linked to reduced concentrations of Th1 cytokines.
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Impact of Ficoll density gradient centrifugation on major and trace element concentrations in erythrocytes and blood plasma.
J Trace Elem Med Biol
PUBLISHED: 05-23-2014
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Ficoll density gradient centrifugation is widely used to separate cellular components of human blood. We evaluated the suitability to use erythrocytes and blood plasma obtained from Ficoll centrifugation for assessment of elemental concentrations.
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Maternal-Child Transfer of Essential and Toxic Elements through Breast Milk in a Mine-Waste Polluted Area.
Am J Perinatol
PUBLISHED: 03-28-2014
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Objective?To determine the daily intake of essential micronutrients and toxic elements through breast milk in exclusive and nonexclusive breastfed infants living in an area with major mine tailing deposition (n?=?24), compared with a control area (n?=?11). Study Design?The milk volume ingested by 2 to 4 and 4 to 6?month infants was measured by a stable isotopic method. Elements in milk, maternal and infant urine, and drinking water were measured by inductively coupled plasma mass spectrometry (ICP-MS). Results?Similar breast milk volume and essential micronutrients intake in groups of exclusively breastfed infants, but more cadmium, boron, and lithium through breastfeeding in experimental area was found. This exposure was even higher in the nonexclusively breastfed infants, who also ingested more arsenic, boron, and lithium than exclusive breastfed infants. Conclusion?The use of the deuterium and the ICP-MS methods made it possible to evaluate the exact amount of essential and toxic elements ingested by infants through breast milk demonstrating that lower amount of toxic elements are transferred to exclusive breastfed infants compared with those who additionally received nonmaternal milk.
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Cadmium concentrations in human blood and urine are associated with polymorphisms in zinc transporter genes.
Metallomics
PUBLISHED: 02-12-2014
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Variation in susceptibility to cadmium (Cd) toxicity may partly be due to differences in Cd toxicokinetics. Experimental studies indicate that zinc (Zn) homeostasis proteins transport Cd.
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Formal recycling of e-waste leads to increased exposure to toxic metals: An occupational exposure study from Sweden.
Environ Int
PUBLISHED: 01-23-2014
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Electrical and electronic waste (e-waste) contains multiple toxic metals. However, there is currently a lack of exposure data for metals on workers in formal recycling plants. The objective of this study was to evaluate workers' exposure to metals, using biomarkers of exposure in combination with monitoring of personal air exposure. We assessed exposure to 20 potentially toxic metals among 55 recycling workers and 10 office workers at three formal e-waste recycling plants in Sweden. Workers at two of the plants were followed-up after 6months. We collected the inhalable fraction and OFC (37-mm) fraction of particles, using personal samplers, as well as spot samples of blood and urine. We measured metal concentrations in whole blood, plasma, urine, and air filters using inductively coupled plasma-mass spectrometry following acid digestion. The air sampling indicated greater airborne exposure, 10 to 30 times higher, to most metals among the recycling workers handling e-waste than among the office workers. The exposure biomarkers showed significantly higher concentrations of chromium, cobalt, indium, lead, and mercury in blood, urine, and/or plasma of the recycling workers, compared with the office workers. Concentrations of antimony, indium, lead, mercury, and vanadium showed close to linear associations between the inhalable particle fraction and blood, plasma, or urine. In conclusion, our study of formal e-waste recycling shows that workers performing recycling tasks are exposed to multiple toxic metals.
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Targeted uptake of folic acid-functionalized iron oxide nanoparticles by ovarian cancer cells in the presence but not in the absence of serum.
Nanomedicine
PUBLISHED: 01-12-2014
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Targeted delivery of nanoparticles to cells or tissues of interest is arguably the "holy grail" of nanomedicine. Using primary human macrophages and ovarian cancer cells, we evaluated the biocompatibility and specific targeting of folic acid (FA)-conjugated iron oxide nanoparticles with organic [poly(ethylene glycol), PEG] or inorganic (SiO2) intermediate surface coatings. Reduction of folate receptor-? expression using specific siRNA resulted in a significant decrease in cellular uptake of the SiO2-coated nanoparticles, but did not affect uptake of PEG-coated nanoparticles. Notably, specific (i.e. FA-dependent) uptake was observed only in the presence of serum proteins. The strategy presented here for receptor-mediated uptake of nanoparticles with pre-defined surface chemistry may enable targeting of nanoparticles for therapeutic and imaging applications.
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TrkB overexpression in mice buffers against memory deficits and depression-like behavior but not all anxiety- and stress-related symptoms induced by developmental exposure to methylmercury.
Front Behav Neurosci
PUBLISHED: 01-01-2014
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Developmental exposure to low dose of methylmercury (MeHg) has a long-lasting effect on memory and attention deficits in humans, as well as cognitive performance, depression-like behavior and the hippocampal levels of the brain-derived neurotrophic factor (Bdnf)in mice. The Bdnf receptor TrkB is a key player of Bdnf signaling. Using transgenic animals, here we analyzed the effect of the full-length TrkB overexpression (TK+) on behavior impairments induced by perinatal MeHg. TK overexpression in the MeHg-exposed mice enhanced generalized anxiety and cue memory in the fear conditioning (FC) test. Early exposure to MeHg induced deficits in reversal spatial memory in the Morris water maze (MWM) test and depression-like behavior in the forced swim test (FST) in only wild-type (WT) mice but did not affect these parameters in TK+ mice. These changes were associated with TK+ effect on the increase in Bdnf 2, 3, 4 and 6 transcription in the hippocampus as well as with interaction of TK+ and MeHg factors for Bdnf 1, 9a and truncated TrkB.T1 transcripts in the prefrontal cortex. However, the MeHg-induced anxiety-like behavior in the elevated plus maze (EPM) and open field (OF) tests was ameliorated by TK+ background only in the OF test. Moreover, TK overexpression in the MeHg mice did not prevent significant stress-induced weight loss during the period of adaptation to individual housing in metabolic cages. These TK genotype-independent changes were primarily accompanied by the MeHg-induced hippocampal deficits in the activity-dependent Bdnf 1, 4 and 9a variants, TrkB.T1, and transcripts for important antioxidant enzymes glyoxalases Glo1 and Glo2 and glutathione reductase Gsr. Our data suggest a role of full-length TrkB in buffering against memory deficits and depression-like behavior in the MeHg mice but propose the involvement of additional pathways, such as the antioxidant system or TrkB.T1 signaling, in stress- or anxiety-related responses induced by developmental MeHg exposure.
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Environmental exposure to metals and childrens growth to age 5 years: a prospective cohort study.
Am. J. Epidemiol.
PUBLISHED: 05-14-2013
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In this prospective cohort study, based on 1,505 mother-infant pairs in rural Bangladesh, we evaluated the associations between early-life exposure to arsenic, cadmium, and lead, assessed via concentrations in maternal and child urine, and childrens weights and heights up to age 5 years, during the period 2001-2009. Concurrent and prenatal exposures were evaluated using linear regression analysis, while longitudinal exposure was assessed using mixed-effects linear regression. An inverse association was found between childrens weight and height, age-adjusted z scores, and growth velocity at age 5 years and concurrent exposure to cadmium and arsenic. In the longitudinal analysis, multivariable-adjusted attributable differences in childrens weight at age 5 years were -0.33 kg (95% confidence interval (CI): -0.60, -0.06) for high (?95th percentile) arsenic exposure and -0.57 kg (95% CI: -0.88, -0.26) for high cadmium exposure, in comparison with children with the lowest exposure (?5th percentile). Multivariable-adjusted attributable differences in height were -0.50 cm (95% CI: -1.20, 0.21) for high arsenic exposure and -1.6 cm (95% CI: -2.4, -0.77) for high cadmium exposure. The associations were apparent primarily among girls. The negative effects on childrens growth at age 5 years attributable to arsenic and cadmium were of similar magnitude to the difference between girls and boys in terms of weight (-0.67 kg, 95% CI: -0.82, -0.53) and height (-1.3 cm, 95% CI: -1.7, -0.89).
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N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women.
Environ. Health Perspect.
PUBLISHED: 05-08-2013
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In humans, inorganic arsenic is metabolized to methylated metabolites mainly by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT polymorphisms are associated with arsenic metabolism efficiency. Recently, a putative N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) was found to methylate arsenic in vitro.
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Sex-specific effects of early life cadmium exposure on DNA methylation and implications for birth weight.
Epigenetics
PUBLISHED: 05-01-2013
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Dietary cadmium exposure was recently found to alter DNA methylation in adults, but data on effects early in life are lacking. Our objective was to evaluate associations between prenatal cadmium exposure, DNA methylation and birth weight. In total 127 mother-child pairs from rural Bangladesh were studied. For comparison, we included 56 children at 4.5 y. Cadmium concentrations in mothers blood (gestational week 14) and childrens urine were measured by ICPMS. Global DNA methylation was analyzed by Infinium HumanMethylation450K BeadChip in cord blood and childrens blood. Maternal cadmium exposure was associated with cord blood DNA methylation (p-value < 10 (-16) ). The association was markedly sex-specific. In boys, 96% of the top 500 CpG sites showed positive correlations (rS-values > 0.50), whereas most associations in girls were inverse; only 29% were positive (rS > 0.45). In girls we found overrepresentation of methylation changes in genes associated with organ development, morphology and mineralization of bone, whereas changes in boys were found in cell death-related genes. Several individual CpG sites that were positively associated with cadmium were inversely correlated with birth weight, although none statistically significant after correction for multiple comparisons. The associations were, however, fairly robust in multivariable-adjusted linear regression models. We identified CpG sites that were significantly associated with cadmium exposure in both newborns and 4.5-y-old children. In conclusion, cadmium exposure in early life appears to alter DNA methylation differently in girls and boys. This is consistent with previous findings of sex-specific cadmium toxicity. Cadmium-related changes in methylation were also related to lower birth weight.
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Occupational exposure to arsenic and risk of nonmelanoma skin cancer in a multinational European study.
Int. J. Cancer
PUBLISHED: 04-03-2013
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Occupational studies show a high risk of lung cancer related to arsenic exposure by inhalation; however, only a few studies, and with conflicting results, previously examined a potential link between arsenic exposure at work and skin cancer. The aim of this study is to assess airborne arsenic exposures at the workplace and to quantify associations with nonmelanoma skin cancer (NMSC). The study sample consists of 618 incident cases of NMSC and 527 hospital-based controls aged 30-79 years from Hungary, Romania and Slovakia. Exposures were evaluated by local experts using occupational histories. Information on host factors and other exposures was collected and used to adjust the associations of interest using multivariable logistic regression. The lifetime prevalence of exposure to work-related arsenic is 23.9% for cases and 15.5% for controls. No significant association between arsenic exposure in the workplace and NMSC was detected, although an increased adjusted odd ratio was observed for participants with higher cumulative lifetime workplace exposure to arsenic in dust and fumes compared to referents [odds ratios (OR) = 1.94, 95% confidence interval (CI) = 0.76-4.95]. There is evidence for modification of the workplace arsenic-NMSC association by work-related sunlight exposure in women, with a markedly increased adjusted OR in the presence of workplace sunlight exposure (OR = 10.22, 95% CI = 2.48-42.07). Workplace coexposure to arsenic and sunlight may thus pose an increased risk of NMSC.
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Polymorphisms in iron homeostasis genes and urinary cadmium concentrations among nonsmoking women in Argentina and Bangladesh.
Environ. Health Perspect.
PUBLISHED: 02-14-2013
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Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cd is absorbed via iron transporters.
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Efficient arsenic metabolism--the AS3MT haplotype is associated with DNA methylation and expression of multiple genes around AS3MT.
PLoS ONE
PUBLISHED: 01-14-2013
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Arsenic is a very potent toxicant. One major susceptibility factor for arsenic-related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase AS3MT on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in AS3MT on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N?=?103) and from cord blood from new-borns in Bangladesh (N?=?127). AS3MT SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major AS3MT haplotype, associated with more efficient arsenic metabolism, showed increased methylation of AS3MT (p?=?10(-6)) and also differential methylation of several other genes within about 800 kilobasepairs: CNNM2 (p<10(-16)), NT5C2 (p<10(-16)), C10orf26 (p?=?10(-8)), USMG5 (p?=?10(-5)), TRIM8 (p?=?10(-4)), and CALHM2 (p?=?0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between AS3MT haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of AS3MT and CNNM2 (r(s)?=?-0.22 to -0.54), and with increased expression of NT5C2 and USMG5 (r(s)?=?0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the AS3MT haplotype status strongly predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism.
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Arsenic Exposure Affects Plasma Insulin-Like Growth Factor 1 (IGF-1) in Children in Rural Bangladesh.
PLoS ONE
PUBLISHED: 01-01-2013
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Exposure to inorganic arsenic (As) through drinking water during pregnancy is associated with lower birth size and child growth. The aim of the study was to assess the effects of As exposure on child growth parameters to evaluate causal associations.
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Elevated manganese concentrations in drinking water may be beneficial for fetal survival.
PLoS ONE
PUBLISHED: 01-01-2013
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Elevated exposure to the essential element manganese (Mn) can be toxic. Manganese concentrations in ground water vary considerably, and reported associations between Mn and early-life mortality and impaired development have raised concern. We assessed the effects of drinking water Mn exposure during pregnancy upon fetal and infant survival.
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Occupational exposure to ultraviolet radiation and risk of non-melanoma skin cancer in a multinational European study.
PLoS ONE
PUBLISHED: 01-01-2013
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Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation.
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Retinol may counteract the negative effect of cadmium on bone.
J. Nutr.
PUBLISHED: 10-26-2011
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Cadmium and high vitamin A intake are both proposed risk factors for low bone mineral density (BMD), but potential interactions have not been studied. Within the Womens Health in the Lund Area, a population-based study in southern Sweden, we measured retinol in serum among 606 women aged 54-64 y. Data on BMD were measured by DXA at the distal forearm. Parathyroid hormone (PTH), bone alkaline phosphatase (bALP), and osteocalcin in serum and deoxypyridinoline (DPD) and cadmium in urine were available. Associations were evaluated using multivariable-adjusted linear regression analysis. Serum retinol concentrations (median, 1.9; range, 0.97-4.3 ?mol/L) were inversely associated with the bone formation markers bALP and osteocalcin (P ? 0.04) and with PTH (P = 0.07) and tended to be positively associated with BMD (P = 0.08) but not with the bone resorption marker DPD, indicating different effects on bone compared to urinary cadmium (median, 0.66; range, 0.12-3.6 nmol/mmol creatinine). Women with serum retinol less than the median and cadmium greater than the median had lower BMD than those with retinol greater than the median and cadmium less than the median (P = 0.016 among all women and P = 0.010 among never-smokers). Our findings suggest that adequate vitamin A status may counteract the adverse association between cadmium and BMD.
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Temporal and seasonal variability of arsenic in drinking water wells in Matlab, southeastern Bangladesh: a preliminary evaluation on the basis of a 4 year study.
J Environ Sci Health A Tox Hazard Subst Environ Eng
PUBLISHED: 09-02-2011
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Temporal and seasonal variability of As concentrations in groundwater were evaluated in As-affected areas of Matlab, southeastern Bangladesh. Groundwater samples from 61 randomly selected tubewells were analyzed for As concentrations over a period of three years and four months (from July 2002 to November 2005) and monitored seasonally (three times a year). The mean As concentrations in the sampled tubewells decreased from 153 to 123 ?g/L during July 2002 to November 2005. Such changes were pronounced in tubewells with As concentration >50 ?g/L than those with As concentrations <50 ?g/L. Similarly, individual wells revealed temporal variability, for example some wells indicated a decreasing trend, while some other wells indicated stable As concentration during the monitoring period. The mean As concentrations were significantly higher in Matlab North compared with Matlab South. The spatial variations in the mean As concentrations may be due to the differences in local geological conditions and groundwater flow patterns. The variations in mean As concentrations were also observed in shallow (<40 m) and deep (>40 m) wells. However, to adequately evaluate temporal and seasonal variability of As concentration, it is imperative to monitor As concentrations in tubewells over a longer period of time. Such long-term monitoring will provide important information for the assessment of human health risk and the sustainability of safe drinking water supplies.
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Characterization of new potential anticancer drugs designed to overcome glutathione transferase mediated resistance.
Mol. Pharm.
PUBLISHED: 08-30-2011
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Resistance against anticancer drugs remains a serious obstacle in cancer treatment. Here we used novel strategies to target microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) that are often overexpressed in tumors and confer resistance against a number of cytostatic drugs, including cisplatin and doxorubicin (DOX). By synthetically combining cisplatin with a GST inhibitor, ethacrynic acid, to form ethacraplatin, it was previously shown that cytosolic GST inhibition was improved and that cells became more sensitive to cisplatin. Here we show that ethacraplatin is easily taken up by the cells and can reverse cisplatin resistance in MGST1 overexpressing MCF7 cells. A second and novel strategy to overcome GST mediated resistance involves using GST releasable cytostatic drugs. Here we synthesized two derivatives of DOX, 2,4-dinitrobenzenesulfonyl doxorubicin (DNS-DOX) and 4-mononitrobenzenesulfonyl doxorubicin (MNS-DOX) and showed that they are substrates for MGST1 and GSTP (releasing DOX). MGST1 overexpressing cells are resistant to DOX. The resistance is partially reversed by DNS-DOX. Interestingly, the less reactive MNS-DOX was more cytotoxic to cells overexpressing MGST1 than control cells. It would appear that, by controlling the reactivity of the prodrug, and thereby the DOX release rate, selective toxicity to MGST1 overexpressing cells can be achieved. In the case of V79 cells, DOX resistance proportional to GSTP expression levels was noted. In this case, not only was drug resistance eliminated by DNS-DOX but a striking GSTP-dependent increase in toxicity was observed in the clonogenic assay. In summary, MGST1 and GSTP resistance to cytostatic drugs can be overcome and cytotoxicity can be enhanced in GST overexpressing cells.
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Persistent exposure to arsenic via drinking water in rural Bangladesh despite major mitigation efforts.
Am J Public Health
PUBLISHED: 07-21-2011
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Elevated arsenic levels in tube-well water in Bangladesh have prompted extensive mitigation projects. We evaluated the effectiveness of long-term mitigation efforts by longitudinally measuring arsenic exposure in pregnant women and their children, the most susceptible population groups.
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Relation between dietary cadmium intake and biomarkers of cadmium exposure in premenopausal women accounting for body iron stores.
Environ Health
PUBLISHED: 07-08-2011
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Cadmium is a widespread environmental pollutant with adverse effects on kidneys and bone, but with insufficiently elucidated public health consequences such as risk of end-stage renal diseases, fractures and cancer. Urinary cadmium is considered a valid biomarker of lifetime kidney accumulation from overall cadmium exposure and thus used in the assessment of cadmium-induced health effects. We aimed to assess the relationship between dietary cadmium intake assessed by analyses of duplicate food portions and cadmium concentrations in urine and blood, taking the toxicokinetics of cadmium into consideration.
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Early life low-level cadmium exposure is positively associated with increased oxidative stress.
Environ. Res.
PUBLISHED: 04-20-2011
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Environmental exposure to cadmium (Cd) is known to induce oxidative stress, a state of imbalance between the production of reactive oxygen species (ROS) and the ability to detoxify them, in adults. However, data are lacking on potential effects in early-life. We evaluated urinary concentrations of 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG), a recognized marker of oxidative DNA damage, in relation to Cd exposure in 96 predominantly breast-fed infants (11-17 weeks of age) in rural Bangladesh. Urinary 8-oxodG was measured using liquid chromatography tandem mass spectrometry and Cd in urine and breast milk by inductively coupled plasma mass spectrometry. Median concentration of 8-oxodG was 3.9 nmol/L, urinary Cd 0.30 ?g/L, and breast-milk Cd 0.13 ?g/L. In linear regression analyses, urinary 8-oxodG was positively associated with Cd in both urine (p=0.00067) and breast milk (p=0.0021), and negatively associated with body weight (kg; p=0.0041). Adjustment for age, body weight, socio-economic status, urinary arsenic, as well as magnesium, calcium, and copper in breast milk did not change the association between Cd exposure and urinary 8-oxodG. These findings suggest that early-life low-level exposure to Cd via breast milk induces oxidative stress. Further studies are warranted to elucidate whether this oxidative stress is associated with impaired child health and development.
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Gender and age differences in mixed metal exposure and urinary excretion.
Environ. Res.
PUBLISHED: 03-28-2011
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Little is known about the variation in exposure to toxic metals by age and gender and other potential modifying factors. We evaluated age and gender differences by measurements of metal/element concentrations in urine in a rural population in Matlab, Bangladesh, in three age groups: 8-12 (N=238), 14-15 (N=107) and 30-88 (N=710) years of age, living in an area with no point sources of metal exposure but where elevated water arsenic concentrations are prevalent.
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Maternal cadmium exposure during pregnancy and size at birth: a prospective cohort study.
Environ. Health Perspect.
PUBLISHED: 03-23-2011
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Cadmium (Cd) is an embryotoxic and teratogenic metal in a variety of animal species, but data from humans are limited.
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Biomarker of chronic cadmium exposure in a population residing in the vicinity of a zinc producing plant.
Sci. Total Environ.
PUBLISHED: 03-23-2011
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Measurements of cadmium (Cd) in air, soil and moss have shown elevated concentrations in residential areas close to a zinc smelter in Norway. This study aimed to evaluate whether men and women residing in the area with elevated Cd concentrations in air and soil had increased levels of Cd and microproteins in urine. An invitation to participate was mailed to 200 persons residing close to the zinc smelter and to 200 controls from an area more than 4 km away from the smelter. They were asked to complete a questionnaire, and to deliver a urine sample for analysis of cadmium (CdU), mercury (HgU), lead (PbU) and ?1-microglobulin (ProteinHC). Two hundred and six participants (response rate 52%), between 19 and 88 years of age, were included. Results were analysed by multiple-adjusted linear and logistic regression. CdU was not significantly different between individuals in the two residence areas. Only ten individuals had CdU concentrations exceeding European Food Safety Authority (EFSA) critical value of 1 ?g/g creatinine, whereas 35 persons (22% of the women vs. 11% of the men) had CdU concentrations higher than 0.66 ?g/g creatinine, which EU suggested to be sufficiently protective for the general population. Smoking was the predominant contributing factor to values of elevated CdU. There was a tendency of higher CdU, although not statistically significant, amongst people regularly consuming fruit, berries and vegetables grown in their own garden near the smelter area. Home address in the polluted area was not a significant determinant. There was a positive correlation between CdU and ProteinHC in urine, but no significant difference was found for ProteinHC between residents from polluted area and controls. In spite of demonstrated industrial emissions of cadmium, the results do not indicate elevated cadmium exposure or kidney damage in the polluted area compared to the control area.
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The association between active/passive smoking and toxic metals among pregnant women in Greece.
Xenobiotica
PUBLISHED: 03-07-2011
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Exposure to toxic metals during pregnancy may have detrimental effects on foetal development. We assessed the role of sociodemographic characteristics and active and passive smoking on blood concentrations of metals (As, Cd, Pb, Hg, Sb, U, Mn and Mo). Venous blood drawn from 50 pregnant women, randomly selected from the mother-child birth cohort Rhea. Extensive questionnaire data on active and passive smoking were collected. Urinary cotinine was measured to validate self-reported exposure and non-smoking status. Smokers had higher concentrations of Cd (1.0 µg/L) as compared with non-smokers (0.29 µg/L, P?
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Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells.
Toxicol. Appl. Pharmacol.
PUBLISHED: 03-04-2011
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Engineered nanoparticles are being considered for a wide range of biomedical applications, from magnetic resonance imaging to "smart" drug delivery systems. The development of novel nanomaterials for biomedical applications must be accompanied by careful scrutiny of their biocompatibility. In this regard, particular attention should be paid to the possible interactions between nanoparticles and cells of the immune system, our primary defense system against foreign invasion. On the other hand, labeling of immune cells serves as an ideal tool for visualization, diagnosis or treatment of inflammatory processes, which requires the efficient internalization of the nanoparticles into the cells of interest. Here, we compare novel monodispersed silica-coated iron oxide nanoparticles with commercially available dextran-coated iron oxide nanoparticles. The silica-coated iron oxide nanoparticles displayed excellent magnetic properties. Furthermore, they were non-toxic to primary human monocyte-derived macrophages at all doses tested whereas dose-dependent toxicity of the smaller silica-coated nanoparticles (30nm and 50nm) was observed for primary monocyte-derived dendritic cells, but not for the similarly small dextran-coated iron oxide nanoparticles. No macrophage or dendritic cell secretion of pro-inflammatory cytokines was observed upon administration of nanoparticles. The silica-coated iron oxide nanoparticles were taken up to a significantly higher degree when compared to the dextran-coated nanoparticles, irrespective of size. Cellular internalization of the silica-coated nanoparticles was through an active, actin cytoskeleton-dependent process. We conclude that these novel silica-coated iron oxide nanoparticles are promising materials for medical imaging, cell tracking and other biomedical applications.
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Nickel deposited on the skin-visualization by DMG test.
Contact Derm.
PUBLISHED: 01-29-2011
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Nickel is the most common cause of contact allergy and an important risk factor for hand eczema. Visualization techniques may be powerful in showing exposures. The dimethylglyoxime (DMG) test might be used to establish skin exposure to nickel.
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Arsenic exposure and risk of spontaneous abortion, stillbirth, and infant mortality.
Epidemiology
PUBLISHED: 09-25-2010
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Millions of people worldwide are drinking water with elevated arsenic concentrations. Epidemiologic studies, mainly cross-sectional in design, have suggested that arsenic in drinking water may affect pregnancy outcome and infant health. We assessed the association of arsenic exposure with adverse pregnancy outcomes and infant mortality in a prospective cohort study of pregnant women.
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Arsenic methylation efficiency increases during the first trimester of pregnancy independent of folate status.
Reprod. Toxicol.
PUBLISHED: 08-18-2010
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Exposure to inorganic arsenic during pregnancy may negatively influence the offspring, though efficient metabolism of arsenic to dimethylarsinic acid (DMA) likely reduces the health risks. This study aimed to evaluate methylation of arsenic over the entire pregnancy and the influence of nutritional status. We studied longitudinally the arsenic metabolite pattern in the urine of 324 pregnant women exposed to arsenic via drinking water and food in rural Bangladesh. Metabolism of arsenic to DMA increased markedly over the course of pregnancy, with the greatest improvement occurring in the first trimester, along with a marked decrease in the most risk-associated monomethylated metabolite. This improvement in methylation was not associated with nutritional status, including vitamin B(12) and folate. Efficient methylation to DMA was associated with improved urinary excretion of arsenic, relative to blood arsenic concentrations, indicating that micronutrient-independent up-regulation of arsenic metabolism already in early pregnancy may provide protection for the fetus.
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High-level exposure to lithium, boron, cesium, and arsenic via drinking water in the Andes of northern Argentina.
Environ. Sci. Technol.
PUBLISHED: 08-13-2010
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Elevated concentrations of arsenic in drinking water are common worldwide, however, little is known about the presence of other potentially toxic elements. We analyzed 31 different elements in drinking water collected in San Antonio de los Cobres and five surrounding Andean villages in Argentina, and in urine of the inhabitants, using ICP-MS. Besides confirmation of elevated arsenic concentrations in the drinking water (up to 210 microg/L), we found remarkably high concentrations of lithium (highest 1000 microg/L), cesium (320 microg/L), rubidium (47 microg/L), and boron (5950 microg/L). Similarly elevated concentrations of arsenic, lithium, cesium, and boron were found in urine of the studied women (N=198): village median values ranged from 26 to 266 microg/L of arsenic, 340 to 4550 microg/L of lithium, 34 to 531 microg/L of cesium, and 2980 to 16,560 microg/L of boron. There is an apparent risk of toxic effects of long-term exposure to several of the elements, and studies on associations with adverse human health effects are warranted, particularly considering the combined, life-long exposure. Because of the observed wide range of concentrations, all water sources used for drinking water should be screened for a large number of elements; obviously, this applies to all drinking water sources globally.
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Spatial patterns of fetal loss and infant death in an arsenic-affected area in Bangladesh.
Int J Health Geogr
PUBLISHED: 08-02-2010
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Arsenic exposure in pregnancy is associated with adverse pregnancy outcome and infant mortality. Knowledge of the spatial characteristics of the outcomes and their possible link to arsenic exposure are important for planning effective mitigation activities. The aim of this study was to identify spatial and spatiotemporal clustering of fetal loss and infant death, and spatial relationships between high and low clusters of fetal loss and infant death rates and high and low clusters of arsenic concentrations in tube-well water used for drinking.
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Lithium in drinking water and thyroid function.
Environ. Health Perspect.
PUBLISHED: 07-05-2010
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High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function.
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Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism.
Environ. Health Perspect.
PUBLISHED: 05-21-2010
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Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases.
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Arsenic and cadmium in food-chain in Bangladesh--an exploratory study.
J Health Popul Nutr
PUBLISHED: 05-18-2010
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Arsenic contamination of tubewell water is a major public-health problem in Bangladesh. In the recent years, the use of shallow and deep tubewell water for irrigation and the use of excess amount of cheap fertilizers and pesticides containing cadmium pose a serious threat of contamination of arsenic and cadmium in food. In an exploratory study, arsenic and cadmium were measured in foods from Matlab, a rural area in Bangladesh, that is extensively affected by arsenic and the economy is agriculture-based. Raw and cooked food samples were collected from village homes (households, n=13) and analyzed to quantify concentrations of arsenic and cadmium using atomic absorption spectrophotometry. Washing rice with water before cooking reduced the concentration of arsenic in raw rice by 13-15%. Rice, when cooked with excess water discarded, showed a significant decrease in arsenic concentration compared to that cooked without discarding the water (p<0.001). In contrast, concentration of cadmium did not decrease in cooked rice after discarding water. Cooked rice with discarded water had significantly lower concentration of arsenic compared to raw rice (p=0.002). Raw rice had higher concentration of arsenic compared to raw vegetables (p<0.001); however, no such difference was found for cadmium. Compared to raw vegetables (e.g. arum), concentration of arsenic increased significantly (p=0.024) when cooked with arsenic-contaminated water. Thus, the practice of discarding excess water while cooking rice reduces the concentration of arsenic but not of cadmium in cooked rice. However, water generally not discarded when cooking vegetables to avoid loss of micronutrients consequently retains arsenic. The results suggest that arsenic and cadmium have entered the food-chain of Bangladesh, and the cooking practices influence the concentration of arsenic but not of cadmium in cooked food.
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Spatial modelling of individual arsenic exposure via well water: evaluation of arsenic in urine, main water source and influence of neighbourhood water sources in rural Bangladesh.
J Environ Monit
PUBLISHED: 04-14-2010
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Arsenic concentrations in well water often vary even within limited geographic areas. This makes it difficult to obtain valid estimates of the actual exposure, as people may take their drinking water from different wells. We evaluated a spatial model for estimation of the influence of multiple neighbourhood water sources on the actual exposure, as assessed by concentrations in urine in a population in rural Bangladesh. In total 1307 individuals (one per bari, group of families) were randomly selected. Arsenic concentrations of urine and water were analysed. Simple average and inverse distance weighted average of arsenic concentrations in the five nearest water sources were calculated for each individual. Spatial autocorrelation was evaluated using Morans I statistics, and spatial regression models were employed to account for spatial autocorrelation. The average distance from a household to the nearest tube-well was 32 metres (Inter-Quartile Range 1-49 metres). Water arsenic concentrations of the reported main water sources were significantly correlated with concentrations in urine (R(2) = 0.41, rho < 0.0001, R(2) for women = 0.45 and for men = 0.36). General model fit improved only slightly after spatial adjustment for neighbouring water sources (pseudo-R(2) = 0.53, spatial lag model), compared to covariate adjusted regression coefficient (R(2) = 0.46). Arsenic concentration in urine was higher than arsenic in main water source with an intercept of 57 microg L(-1), indicating exposure from food. A suitable way of estimating an individuals past exposure to arsenic in this rural setting, where influence of neighbouring water sources was minimal, was to consider the reported main source of drinking water.
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Arsenic exposure in pregnancy increases the risk of lower respiratory tract infection and diarrhea during infancy in Bangladesh.
Environ. Health Perspect.
PUBLISHED: 04-07-2010
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Previous studies have reported associations between prenatal arsenic exposure and increased risk of infant mortality. An increase in infectious diseases has been proposed as the underlying cause of these associations, but there is no epidemiologic research to support the hypothesis.
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Burden of cadmium in early childhood: longitudinal assessment of urinary cadmium in rural Bangladesh.
Toxicol. Lett.
PUBLISHED: 02-26-2010
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Chronic cadmium exposure is associated with many adverse health effects in adults, but little is known about the scenario early in life. This study assessed cadmium exposure and body burden in young children, born to women with known cadmium exposure via rice. As part of our ongoing population-based, longitudinal study of health effects of early-life toxicants exposure in rural Bangladesh, we measured cadmium in urine of about 350 children at 1.5 and 5 years of age, and in 92 children at 3 months of age. Median cadmium concentrations in urine were 0.30, 0.16 and 0.30 microg/L at 3 months, 1.5 and 5 years of age, respectively (0.6 microg/L in mothers). Cadmium concentrations in infants urine correlated with concentrations in maternal breast milk, saliva, and urine. As expected, concentrations in urine increased from 1.5 to 5 years of age. Rice (median 47 microgCd/kg) is most likely the main source of exposure. In conclusion, we found unexpectedly high cadmium exposure among children in rural Bangladesh. Urinary cadmium concentrations were particularly elevated at 3 months of age, indicating limited reabsorption and accumulation of cadmium in the kidneys, known to be the main site of cadmium burden in older children and adults.
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Recent applications of benchmark dose method for estimation of reference cadmium exposure for renal effects in man.
Toxicol. Lett.
PUBLISHED: 02-24-2010
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The initial sign of cadmium (Cd)-induced renal effects is tubular damage, followed by glomerular damage. For the prevention of Cd-induced renal effects, it is essential to establish the reference exposure below which the risk of adverse health effects is low. In earlier Japanese studies, the estimated reference exposure of creatinine (cre)-adjusted urinary cadmium for renal tubular effect ranged from 1.6 to 4.0 microg/g cre in men and 2.3 to 4.6 microg/g cre in women. The benchmark dose (BMD) is defined as the exposure that corresponds to a certain response change from the background. The lower 95% confidence limit of the BMD (BMDL) can be used in risk assessment as a replacement for the no observed adverse effect level. This is a review of all relevant BMDL of Cd exposure for renal effects estimated so far. Based on studies in Japan, the best estimate is considered to be 1.5-3.2 microg/g cre for urinary Cd, 0.09-0.13 mg/kg for rice Cd concentration, and 0.9-1.4 g Cd for lifetime Cd intake. These BMDLs for renal effects were generally lower than the reference exposure expected from earlier studies, indicating the importance of further discussion regarding comprehensive measures to decrease the Cd exposure in the general population.
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Skin deposition of nickel, cobalt, and chromium in production of gas turbines and space propulsion components.
Ann Occup Hyg
PUBLISHED: 02-11-2010
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Skin exposure to nickel, cobalt, and chromium may cause sensitization and allergic contact dermatitis and it is known that many alloys and platings may release significant amounts of the metals upon contact with skin. Occupational exposure to these sensitizing metals has been studied in different settings with regards to airborne dust and different biological end points, but little is known about deposition on skin from airborne dust and direct contact with materials containing the metals. In this study, skin deposition was studied in 24 workers in an industry for development and manufacturing of gas turbines and space propulsion components. The workers were employed in three departments, representing different exposure scenarios: tools sharpening of hard metal items, production of space propulsion structures, and thermal application of different metal-containing powders. A novel acid wipe sampling technique was used to sample metals from specific skin surfaces on the hands and the forehead of the workers. Total amounts of nickel, cobalt, and chromium were measured by inductively coupled plasma mass spectrometry. The result showed that nickel, cobalt, and chromium could be detected on all skin surfaces sampled. The highest level of nickel was 15 microg cm(-2) h(-1), the highest for cobalt was 4.5 microg cm(-2) h(-1), and for chromium 0.6 microg cm(-2) h(-1). The three departments had different exposures regarding the metals. The highest levels of nickel on the skin of the workers were found in the thermal applications department, cobalt in the tools sharpening department, and chromium in the space propulsion components department. In conclusion, the workers exposure to the metals was more likely to come from direct skin contact with items, rather than from airborne dust, based on the fact that the levels of metals were much higher on the fingers than on the back side of the hands and the forehead. The skin exposure levels of nickel and cobalt detected are judged capable to induce sensitization and elicit allergic contact dermatitis.
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Lifetime exposure to arsenic in residential drinking water in Central Europe.
Int Arch Occup Environ Health
PUBLISHED: 01-28-2010
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Methods and results are presented for an arsenic exposure assessment integral to an epidemiological case-control study of arsenic and cancer-the European Commission funded ASHRAM (Arsenic Health Risk Assessment and Molecular Epidemiology) study carried out in some counties of Hungary, Romania and Slovakia.
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Chronic exposure to cadmium and arsenic strongly influences concentrations of 8-oxo-7,8-dihydro-2-deoxyguanosine in urine.
Free Radic. Biol. Med.
PUBLISHED: 01-27-2010
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Exposure to arsenic (As), cadmium (Cd), and lead (Pb) may generate oxidative stress, which can be assessed by 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) in urine, a sensitive marker of oxidatively damaged DNA. We have evaluated oxidative stress induced by chronic mixed exposure to As, Cd, and Pb, as well as the influence of As metabolism and nutritional status, i.e., levels of ferritin (Ft), selenium (Se), zinc (Zn), and manganese (Mn) and body weight. 8-OxodG was measured in urine from 212 women in early pregnancy from Matlab, in rural Bangladesh, using LC-MS/MS. Cd and Pb were analyzed in urine and erythrocytes, and Se, Mn, and Zn were analyzed in erythrocytes, all by ICPMS. As and As metabolites were analyzed in urine by HPLC-ICPMS. Ferritin was analyzed in plasma by radioimmunoassay. The median concentration of 8-oxodG was 8.3 nmol/L (adjusted for specific gravity), range 1.2-43, corresponding to a median of 4.7 microg/g creatinine, range 1.8-32. 8-OxodG was positively associated with urinary Cd (beta=0.32, p< 0.001), urinary As (beta=0.0007, p=0.001), the fraction of the monomethylated arsenic metabolite in urine (beta=0.0026, p=0.004), and plasma Ft (beta=0.20, p< 0.001). A joint effect was seen for urinary Cd and As, but whether this effect was additive or multiplicative was difficult to discern.
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Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood.
Environ. Health Perspect.
PUBLISHED: 01-24-2010
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Arsenic (As) exposure during pregnancy induces oxidative stress and increases the risk of fetal loss and low birth weight.
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Benchmark dose for cadmium-induced osteoporosis in women.
Toxicol. Lett.
PUBLISHED: 01-19-2010
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We applied a hybrid approach to estimate the benchmark dose (BMD) and the lower 95% confidence limit (BMDL) for cadmium-induced bone effects in a population with low environmental exposure. Morning urine samples were collected by 794 Swedish women, aged 53-64 years, participating in a population-based study. We measured urinary cadmium (U-Cd), a marker of long-term exposure, and bone mineral density, expressed as its T-score (reference: 20-year old women) of the non-dominant wrist. BMD and BMDL, adjusted for relevant covariates, corresponding to an additional risk (BMR) of 5% or 10% were calculated, with the background risk at zero exposure set at 1% or 5%. With a BMR of 5% and a background risk of having low bone mineral density (at U-Cd = 0) of 1% or 5% (corresponding to T-score cut-offs -2.75 and -2.09, respectively), the BMD of U-Cd ranged 1.8-3.7 microg/g creatinine, and the BMDL ranged 1.0-2.1 microg/g creatinine. For a 5% BMR of osteoporosis (T-score < -2.5), the BMD was 2.9 microg/g creatinine and the BMDL 1.6 microg/g creatinine. The lowest obtained BMD of U-Cd for wrist bone mineral density was only slightly higher than the lowest reference concentration previously reported for cadmium-related kidney effects. Our results provide additional scientific support for the low tolerably weekly intake (TWI) of cadmium set by the European Food Safety Authority in 2009.
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Pre- and postnatal arsenic exposure and child development at 18 months of age: a cohort study in rural Bangladesh.
Int J Epidemiol
PUBLISHED: 01-19-2010
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Exposure to arsenic through drinking water has been associated with impaired cognitive function in school-aged children in cross-sectional studies; however, there are few longitudinal studies and little information on effects of exposure in early life when the brain is generally most vulnerable.
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Arsenic in drinking water and adult mortality: a population-based cohort study in rural Bangladesh.
Epidemiology
PUBLISHED: 10-03-2009
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Arsenic is a potent human carcinogen and toxicant. Elevated concentration of arsenic in drinking water is a major public-health problem worldwide. We evaluated risks of adult mortality (due to cancer and cardiovascular and infectious diseases) in relation to arsenic exposure through drinking water.
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Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions.
Mutat. Res.
PUBLISHED: 09-26-2009
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The susceptibility to arsenic (As)-induced diseases differs greatly between individuals, probably to a large extent due to genetic differences in arsenic metabolism. The aim for this study was to identify genetic variants affecting arsenic metabolism.
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Accumulation of cadmium in human placenta interacts with the transport of micronutrients to the fetus.
Toxicol. Lett.
PUBLISHED: 08-13-2009
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Cadmium (Cd) is a widespread, highly toxic environmental pollutant known to accumulate in human placenta. The aim of the present study was to elucidate to what extent the accumulation of Cd in human placenta interacts with the transport of micronutrients to the fetus. Cd and micronutrients were measured in placenta and umbilical cord blood from 44 non-smoking, rural Bangladeshi women, using ICPMS. Metallothionein (MT) protein expression was determined in placenta using Western blot. Cd in placenta (median 110 microg/kg dry weight, 20 microg/kg wet weight) was positively associated with maternal urinary Cd. It was also positively associated with Cd in umbilical cord blood (median 0.16 microg/kg), but negatively associated with zinc (Zn; median 3mg/kg) in umbilical cord blood. Umbilical cord blood Zn was positively associated with birth anthropometry measures, and the Cd-related impairment of Zn in umbilical cord blood seemed to decrease size at birth. In multivariate analysis, MT protein expression was associated with Cd (positively) in placenta, but not with Zn or copper (Cu) in placenta. In conclusion, the Cd concentrations in placenta were clearly elevated, which seemed to impair Zn transfer to the fetus. Induction of MT explained the placental accumulation of Cd, but not the impairment of Zn transport.
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Effects of arsenic on maternal and fetal health.
Annu. Rev. Nutr.
PUBLISHED: 07-07-2009
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Arsenic, which is commonly found in drinking water, is a potent toxicant, but little is known about its effects on maternal health. Arsenics modes of action include enzyme inhibition and oxidative stress as well as immune, endocrine, and epigenetic effects. A couple of studies reported increased blood pressure and anemia during pregnancy. Susceptibility to arsenic is dependent on the biomethylation, which occurs via one-carbon metabolism. Methylarsonic acid and dimethylarsinic acid are main metabolites in urine, and elevated methylarsonic acid is considered a general risk factor. Arsenic easily passes the placenta, and a few human studies indicate a moderately increased risk of impaired fetal growth and increased fetal and infant mortality. The fetus and infant are probably partly protected by the increased methylation of arsenic during pregnancy and lactation; the infant is also protected by low arsenic excretion in breast milk. Early-life exposure may induce changes that will become apparent much later in life.
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Maternal and early life exposure to manganese in rural Bangladesh.
Environ. Sci. Technol.
PUBLISHED: 05-21-2009
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Manganese exposure and biomarker concentrations during early pregnancy and lactation were investigated in 408 women living in an area with elevated concentrations of both arsenic and manganese in drinking water derived from wells. About 40% of the water samples had manganese concentrations above the World Health Organizations guideline value and showed a strong inverse correlation with arsenic concentrations. Water manganese was found to correlate to urine concentrations, but not to blood or breast milk concentrations. No correlations were found among manganese concentrations in urine, blood, or breast milk. Compared to other populations, manganese concentrations in both urine and blood, but not breast milk, were elevated in the Bangladeshi women and more similar to those of occupationally exposed groups. The lack of associations with water manganese is likely due to variable exposure via water and food, and differences in bioavailability, as well as a complex and/or strict regulation of intestinal manganese absorption, in turn being influenced by nutritional as well as physiological and genetic factors. The results indicate that elevated maternal manganese exposure does not necessarily lead to exposure of breast-fed infants, stressing the importance of breast feeding in high manganese areas. However, the implications of fetal exposurefrom elevated maternal exposure need further investigation.
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Population toxicokinetic modeling of cadmium for health risk assessment.
Environ. Health Perspect.
PUBLISHED: 05-06-2009
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Cadmium is a widespread environmental pollutant that has been shown to exert toxic effects on kidney and bones in humans after long-term exposure. Urinary cadmium concentration is considered a good biomarker of accumulated cadmium in kidney, and diet is the main source of cadmium among nonsmokers.
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Effect of arsenic exposure during pregnancy on infant development at 7 months in rural Matlab, Bangladesh.
Environ. Health Perspect.
PUBLISHED: 03-10-2009
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Exposure to arsenic-contaminated drinking water during pregnancy is associated with low birth weight and fetal loss, and there is concern that the infants development may be affected.
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Impact of smoking and chewing tobacco on arsenic-induced skin lesions.
Environ. Health Perspect.
PUBLISHED: 02-26-2009
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We recently reported that the main reason for the documented higher prevalence of arsenic-related skin lesions among men than among women is the result of less efficient arsenic metabolism.
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Arsenic induces telomerase expression and maintains telomere length in human cord blood cells.
Toxicology
PUBLISHED: 02-23-2009
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Inorganic arsenic (iAs) is a human carcinogen, well known as a clastogenic compound. To evaluate the molecular mechanism of arsenite (iAs(III)) toxicity, we investigated the effects on cell growth and apoptosis, telomere length, telomerase expression, as well as the formation of reactive oxygen species (ROS) in male and female human cord blood cells in vitro. Incubation with iAs(III) at the concentration of 0.0001 microM increased telomerase mRNA and protein expression maintained both telomere length and cellular growth, and induced mRNA over-expression of the two oncogenes ras and myc. Our results suggest that female cord blood cells are more sensitive than male ones to iAs(III) induced telomerase stimulation at low concentrations, possibly related to the increased expression of ras and myc oncogenes. On the contrary, at the concentration of 1 microM, iAs(III) decreased telomerase expression and telomere length, and induced apoptosis, necrosis and production of reactive oxygen species. Buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, markedly increased the percentage of apoptotic cells, suggesting that GSH is fundamental for detoxification of iAs(III) in cord blood cells. The reactive oxygen species (ROS) scavenger, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), protected cord blood cells from iAs(III) toxicity, and prevented telomere shortening and telomerase down-modulation. It can be concluded that telomerase expression and telomere length are associated with iAs(III) induced cell death, via production of reactive oxygen species, as well as with iAs(III) induced effects on cell differentiation processes and rate of cell growth.
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Cadmium-induced bone effect is not mediated via low serum 1,25-dihydroxy vitamin D.
Environ. Res.
PUBLISHED: 02-14-2009
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Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmiums toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 microg/L) or high (0.66-2.1 microg/L) urinary cadmium, within a cross-sectional population-based womens health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH)(2)D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH)(2)D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH)(2)D. Hence, decreased circulating levels of 1,25(OH)(2)D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone.
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Arsenic exposure during pregnancy and size at birth: a prospective cohort study in Bangladesh.
Am. J. Epidemiol.
PUBLISHED: 02-10-2009
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The authors evaluated the association of prenatal arsenic exposure with size at birth (birth weight, birth length, head and chest circumferences). This prospective cohort study, based on 1,578 mother-infant pairs, was conducted in Matlab, Bangladesh, in 2002-2003. Arsenic exposure was assessed by analysis of arsenic in urine collected at around gestational weeks 8 and 30. The association of arsenic exposure with size at birth was assessed by linear regression analyses. In analysis over the full range of exposure (6-978 microg/L), no dose-effect association was found with birth size. However, significant negative dose effects were found with birth weight and head and chest circumferences at a low level of arsenic exposure (<100 microg/L in urine). In this range of exposure, birth weight decreased by 1.68 (standard error (SE), 0.62) g for each 1-microg/L increase of arsenic in urine. For head and chest circumferences, the corresponding reductions were 0.05 (SE, 0.03) mm and 0.14 (SE, 0.03) mm per 1 microg/L, respectively. No further negative effects were shown at higher levels of arsenic exposure. The indicated negative effect on birth size at a low level of arsenic exposure warrants further investigation.
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Highly active dimeric and low-activity tetrameric forms of selenium-containing rat thioredoxin reductase 1.
Free Radic. Biol. Med.
PUBLISHED: 01-17-2009
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Mammalian thioredoxin reductase 1 (TrxR1) is a selenoprotein that contains a selenocysteine (Sec) residue at the penultimate C-terminal position. When rat TrxR1 is expressed recombinantly in Escherichia coli, partial truncation at the Sec-encoding UGA gives rise to additional protein species that lack Sec. Phenylarsine oxide (PAO) Sepharose can subsequently be used to enrich the Sec-containing protein and yield activity corresponding to that of native enzyme. Herein we extensively purified recombinant rat TrxR1 over PAO Sepharose, which gave an enzyme with about 53 U/mg specific activity. Surprisingly, only about 65% of the subunits of this TrxR1 preparation contained Sec, whereas about 35% were protein products derived from UGA truncation. Further analyses revealed a theoretical maximal specific activity of 70-80 U/mg for the homodimeric enzyme with full Sec content, i.e., significantly higher than that reported for native TrxR1. We also discovered the formation of highly stable noncovalently linked tetrameric forms of TrxR1, having full FAD content but about half the specific activity in relation to the selenium content compared to the dimeric protein. The characterization of these different forms of recombinant TrxR1 revealed that inherent turnover capacity of the enzyme must be revised, that multimeric states of the protein may be formed, and that the yield of bacterial selenoprotein production may be lower than earlier reported. The biological significance of the hitherto unsurpassed high specific activity of the enzyme involves the capacity to support a higher turnover in vivo than previously believed. The tetrameric forms of the protein could represent hitherto unknown regulatory states of the enzyme.
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Cadmium interacts with the transport of essential micronutrients in the mammary gland - a study in rural Bangladeshi women.
Toxicology
PUBLISHED: 01-08-2009
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Although the concentrations of the toxic metal cadmium in breast milk are generally low (< 1 microg/L), experimental studies indicated neurobehavioral and endocrine effects in the suckling offspring. The aim of the present study was to elucidate how cadmium is transported to breast milk by assessing interactions with essential micronutrients. The study is nested into a food and micronutrient supplementation trial conducted among pregnant women in Matlab, a rural area in Bangladesh, where malnutrition is prevalent and the cadmium exposure is relatively high. We measured cadmium in breast milk (BM-Cd; median 0.14 microg/kg; range <0.050-1.0 microg/kg), in erythrocytes (Ery-Cd; median 1.5 microg/kg; range 0.46-4.8 microg/kg) and in urine (U-Cd; median 0.63 microg/L; range 0.050-4.5 microg/L), using inductively coupled plasma mass spectrometry (ICPMS). We found a significant positive association between Ery-Cd and BM-Cd and a breast milk-plasma ratio of approximately 3-4, indicating no barrier against cadmium transport from plasma to breast milk. BM-Cd was positively associated with manganese (r(s)=0.56; p<0.01) and iron (r(s)=0.55; p<0.01) in breast milk, but not with plasma ferritin. On the other hand, BM-Cd was negatively associated with BM-Ca (r(s)=-0.17; p=0.05), indicating that cadmium inhibits the transport of calcium to breast milk. In conclusion, the present study may indicate that cadmium shares common transporters with iron and manganese for transfer to breast milk, but inhibits secretion of calcium to breast milk.
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Impaired arsenic metabolism in children during weaning.
Toxicol. Appl. Pharmacol.
PUBLISHED: 01-06-2009
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Methylation of inorganic arsenic (iAs) via one-carbon metabolism is a susceptibility factor for a range of arsenic-related health effects, but there is no data on the importance of arsenic metabolism for effects on child development.
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Effects of in utero arsenic exposure on child immunity and morbidity in rural Bangladesh.
Toxicol. Lett.
PUBLISHED: 01-04-2009
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Chronic exposure to arsenic, a potent carcinogen and toxicant, via drinking water is a worldwide public health problem. Because little is known about early-life effects of arsenic on immunity, we evaluated the impact of in utero exposure on infant immune parameters and morbidity in a pilot study. Pregnant women were enrolled at 6-10 weeks of gestation in Matlab, a rural area of Bangladesh, extensively affected by arsenic contamination of tubewell water. Women (n=140) delivering at local clinics were included in the study. Anthropometry and morbidity data of the pregnant women and their children, as well as infant thymic size by sonography were collected. Maternal urine and breast milk were collected for immune marker and arsenic assessment. Maternal urinary arsenic during pregnancy showed significant negative correlation with interleukin-7 (IL-7) and lactoferrin (Ltf) in breast milk and child thymic index (TI). Urinary arsenic was also positively associated with fever and diarrhea during pregnancy and acute respiratory infections (ARI) in the infants. The effect of arsenic exposure on ARI was only evident in male children. The findings suggest that in utero arsenic exposure impaired child thymic development and enhanced morbidity, probably via immunosuppression. The effect seemed to be partially gender dependent. Arsenic exposure also affected breast milk content of trophic factors and maternal morbidity.
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Early exposure to toxic metals has a limited effect on blood pressure or kidney function in later childhood, rural Bangladesh.
Int J Epidemiol
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Chronic exposure to toxic metals such as arsenic and cadmium has been implicated in the development of kidney and cardiovascular diseases but few studies have directly measured exposure during inutero and early child development.
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Metals and trace element concentrations in breast milk of first time healthy mothers: a biological monitoring study.
Environ Health
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Breast milk is the best source of nutrition for the newborn infant. However, since all infants cannot be breast-fed, there is a need for background data for setting adequate daily intakes. Previously, concentration data on major essential elements and some toxic elements in breast milk, based on different analytical techniques, have been published. There is no recent study on a large number of metals and trace elements in breast milk, using a sensitive analytical method for determination of low element concentrations.
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Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: effect of arsenic metabolism and genotype.
Metallomics
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Arsenic is carcinogenic, possibly partly through epigenetic mechanisms. We evaluated the effects of arsenic exposure and metabolism on DNA methylation. Arsenic exposure and methylation efficiency in 202 women in the Argentinean Andes were assessed from concentrations of arsenic metabolites in urine (inorganic arsenic, methylarsonic acid [MMA], and dimethylarsinic acid [DMA]), measured by HPLC-ICPMS. Methylation of CpGs of the tumor suppressor gene p16, the DNA repair gene MLH1, and the repetitive elements LINE1 was measured by PCR pyrosequencing of blood DNA. Genotyping (N = 172) for AS3MT was performed using Sequenom™, and gene expression (N = 90) using Illumina DirectHyb HumanHT-12 v3.0. Median arsenic concentration in urine was 230 ?g L(-1) (range 10.1-1251). In linear regression analysis, log(2)-transformed urinary arsenic concentrations were positively associated with methylation of p16 (? = 0.14, P = 0.0028) and MLH1 (? = 0.28, P = 0.0011), but not with LINE1. Arsenic concentrations were of borderline significance negatively correlated with expression of p16 (r(s) = -0.20; P = 0.066)), but not with MLH1. The fraction of inorganic arsenic was positively (? = 0.026; P = 0.010) and DMA was negatively (? = -0.017, P = 0.043) associated with p16 methylation with no effect of MMA. Carriers of the slow-metabolizing AS3MT haplotype were associated with more p16 methylation (P = 0.022). Arsenic exposure was correlated with increased methylation, in blood, of genes encoding enzymes that suppress carcinogenesis, and the arsenic metabolism efficiency modified the degree of epigenetic alterations.
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Possible positive selection for an arsenic-protective haplotype in humans.
Environ. Health Perspect.
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Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite.
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