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See detailCystic fibrosis is associated with a defect in apical receptor-mediated endocytosis in mouse and human kidney.
JOURET, François ULiege; Bernard, Alfred; Hermans, Cedric et al

in Journal of the American Society of Nephrology (2007), 18(3), 707-18

Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). Although CFTR is expressed in the kidney, no overwhelming renal phenotype has ... [more ▼]

Inactivation of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) causes cystic fibrosis (CF). Although CFTR is expressed in the kidney, no overwhelming renal phenotype has been documented in patients with CF. This study investigated the expression, subcellular distribution, and processing of CFTR in the kidney; used various mouse models to assess the role of CFTR in proximal tubule (PT) endocytosis; and tested the relevance of these findings in patients with CF. The level of CFTR mRNA in mouse kidney approached that found in lung. CFTR was located in the apical area of PT cells, with a maximal intensity in the straight part (S3) of the PT. Fractionation showed that CFTR co-distributed with the chloride/proton exchanger ClC-5 in PT endosomes. Cftr(-/-) mice showed impaired (125)I-beta(2)-microglobulin uptake, together with a decreased amount of the multiligand receptor cubilin in the S3 segment and a significant loss of cubilin and its low molecular weight (LMW) ligands into the urine. Defective receptor-mediated endocytosis was found less consistently in Cftr(DeltaF/DeltaF) mice, characterized by a large phenotypic heterogeneity and moderate versus mice that lacked ClC-5. A significant LMW proteinuria (and particularly transferrinuria) also was documented in a cohort of patients with CF but not in patients with asthma and chronic lung inflammation. In conclusion, CFTR inactivation leads to a moderate defect in receptor-mediated PT endocytosis, associated with a cubilin defect and a significant LMW proteinuria in mouse and human. The magnitude of the endocytosis defect that is caused by CFTR versus ClC-5 loss likely reflects functional heterogeneity along the PT. [less ▲]

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See detailImpact of iron and steel industry and waste incinerators on human exposure to dioxins, PCBs, and heavy metals: results of a cross-sectional study in Belgium.
Fierens, Sebastien; Mairesse, Helene; Heilier, Jean-Francois et al

in Journal of Toxicology and Environmental Health. Part A (2007), 70(3-4), 222-6

We evaluated the impact of two iron and steel plants and two municipal solid waste incinerators (MSWI) in Wallonia (Belgium) on the exposure of residents to dioxins, polychlorinated biphenyls (PCBs), and ... [more ▼]

We evaluated the impact of two iron and steel plants and two municipal solid waste incinerators (MSWI) in Wallonia (Belgium) on the exposure of residents to dioxins, polychlorinated biphenyls (PCBs), and heavy metals. In total, 142 volunteers living around these facilities were recruited and compared with 63 referents from a rural area with no industrial source of pollution. Information about smoking habits, dietary habits, anthropometric characteristics, residential history, and health status was obtained from a self-administered questionnaire. The volunteers provided blood under fasting conditions in order to evaluate the body burden of dioxins (17 polychlorinated dibenzo-p-dioxins/dibenzofurans [PCDD/Fs] congeners) and PCBs. Samples of blood and urine were also taken for the determination of cadmium, mercury, and lead. After adjustment for covariates, concentrations of cadmium, mercury, and lead in urine or blood were not increased in subjects living in the vicinity of MSWIs or sinter plants by comparison with referents. Residents around the sinter plants and the MSWI located in the industrial area had concentrations of dioxins and PCBs in serum similar to that of referents. By contrast, subjects living in the vicinity of the MSWI in the rural area showed significantly higher serum levels of dioxins (geometric mean, 38 vs. 24 pg TEQ/g fat) and coplanar PCBs (geometric mean, 10.8 vs. 7.0 pg TEQ/g fat). Although age-adjusted dioxin levels in referents did not vary with local animal fat consumption, concentrations of dioxins in subjects living around the incinerators correlated positively with their intake of local animal fat, with almost a doubling in subjects with the highest fat intake. These results indicate that dioxins and coplanar PCBs emitted by MSWIs can indeed accumulate in the body of residents who regularly consume animal products of local origin. [less ▲]

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See detailDecrease of serum concentrations of dioxins and PCBs in Belgium between 2000 and 2003
Fierens, Sébastien; Heilier, Jean-François; Eppe, Gauthier ULiege et al

in Organohalogen Compounds (2005), 67

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See detailContribution of tobacco smoking to dioxin accumulation: opposite effects according to gender
Fierens, Sébastian; Eppe, Gauthier ULiege; Focant, Jean-François ULiege et al

in Organohalogen Compounds (2004), 66

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See detailDioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: findings in a population-based study in Belgium
Fierens, S.; Mairesse, H.; Heilier, J. F. et al

in Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals (2003), 8(6), 529-534

Dioxins and polychlorinated biphenyls (PCBs) are persistent organic pollutants widely distributed in the food chain, which is the main source of human exposure. Their effects on human health at background ... [more ▼]

Dioxins and polychlorinated biphenyls (PCBs) are persistent organic pollutants widely distributed in the food chain, which is the main source of human exposure. Their effects on human health at background exposure levels are still poorly understood. Recent epidemiological evidence suggests a possible association between these pollutants and diabetes. We report here the results of a population-based study in Belgium on 257 (142 women and 115 men) environmentally exposed subjects, including 10 cases of endometriosis and nine cases of diabetes. Seventeen 2,3,7,8-polychlorinated dibenzodioxins/dibenzofurans (PCDD/Fs or dioxins), four coplanar PCBs (International Union of Pure and Applied Chemistry [IUPAC] nos 77, 81, 126 and 169) and 12 PCB markers ( IUPAC nos 3, 8, 28, 52, 101, 118, 138, 153, 180, 194, 206 and 209) were quantified in serum fat from fasting blood samples in order to estimate the body burden of these pollutants. Whilst no difference was found between women with endometriosis and their controls, diabetic patients had significantly increased serum levels of dioxins, coplanar PCBs and the 12 PCB markers. After adjustment for age and other covariates, serum total toxic equivalent activity (sum of PCDD/Fs and coplanar PCBs) and 12 PCB marker concentrations in diabetics were 62% (p=0.0005) and 39% (p=0.0067) higher, respectively, than in controls. The risk of diabetes was significantly increased in subjects in the top decile for adjusted concentrations of dioxins (odds ratio 5.1, 95% confidence interval [CI] 1.18-21.7), coplanar PCBs (odds ratio 13.3, 95% CI 3.31-53.2) or 12 PCB markers (odds ratio 7.6, 95% CI 1.58-36.3). These findings warrant further studies to assess the significance of the associations between diabetes and environmental exposure to polychlorinated pollutants. [less ▲]

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See detailDioxin accumulation in residents around incinerators
Fierens, S.; Mairesse, H.; Hermans, C. et al

in Journal of Toxicology and Environmental Health. Part A (2003), 66(14), 1287-1293

To evaluate the human exposure impact of municipal waste incinerators, dioxin and coplanar polychlorinated biphenyl (PCB) concentrations were determined in blood of 84 subjects who resided approximately ... [more ▼]

To evaluate the human exposure impact of municipal waste incinerators, dioxin and coplanar polychlorinated biphenyl (PCB) concentrations were determined in blood of 84 subjects who resided approximately 18 yr in the vicinity of two old incinerators, one located in a rural area (n = 51) and the other in an industrial area (n = 33). These subjects were compared with 63 controls from an unpolluted area. While no change was found in contaminant levels in residents living around the incinerator in the industrial area, subjects residing around the incinerator in the rural area possessed significantly higher serum levels of dioxins (38 vs. 24 pg TEQ/g fat) and coplanar PCBs (10 vs. 7 pg TEQ/g fat) than controls. These results were confirmed by multiple-regression analysis, showing that residence around the incinerator in the rural area (partial r(2) = .18) was the major contributor to dioxin accumulation followed by age (partial r(2) = .07). A two-way analysis of variance (ANOVA) on age-adjusted dioxin levels revealed a significant interaction between residence around incinerators and the consumption of fat from local origin, especially bovine and poultry products. Although age-adjusted dioxin levels in controls did not vary with local animal fat consumption, concentrations of dioxins in subjects living around the incinerators increased proportionally to their intake of local animal fat, with almost a doubling in subjects with a fat intake higher than 150 gfat/wk. Extrapolation from these data suggests that a significant increase of dioxin body burden is likely to occur only when dioxin emissions exceed 5 ng TEQ/Nm(3), a threshold considerably above most emissions standards currently in force. [less ▲]

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See detailIncreased dioxin/PCB body burden in diabetics: findings in a population-based study in Belgium
Fierens, S.; Mairesse, H.; Heilier, H. et al

in Organohalogen Compounds (2003), 60-65

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See detailPCDD/F and non-ortho PCB body burden of the general population in Wallonia, Belgium: impact of different sources of environmental pollution
Fierens, S.; Mairesse, Hélène; Focant, Jean-François ULiege et al

in Organohalogen Compounds (2002), 55

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See detailThe Belgian PCB/dioxin incident: analysis of the food chain contamination and health risk evaluation.
Bernard, Alfred; Broeckaert, Fabrice; De Poorter, Geert et al

in Environmental Research (2002), 88(1), 1-18

The Belgian PCB incident occurred at the end of January 1999 when a mixture of polychlorinated biphenyls (PCBs) contaminated with dioxins was accidentally added to a stock of recycled fat used in the ... [more ▼]

The Belgian PCB incident occurred at the end of January 1999 when a mixture of polychlorinated biphenyls (PCBs) contaminated with dioxins was accidentally added to a stock of recycled fat used in the production of animal feeds. Although signs of poultry poisoning were noticed by February, 1999, the source and the extent of the contamination were discovered only in May 1999, when it appeared that more than 2500 farms could have been supplied with contaminated feeds. This resulted in a major food crisis, which rapidly extended to the whole country and could be resolved only by the implementation of a large PCB/dioxin food monitoring program. Screening for PCB contamination was based on the determination of the seven PCB markers. When PCB concentrations exceeded the tolerance levels of 0.1 (milk), 0.2 (poultry, bovine, and pig meat), or 1 (animal feed) microg/g fat, dioxins (17 PCDD/Fs congeners) were also determined. At the end of December 1999, the database contained the results of more than 55,000 PCB and 500 dioxin analyses. The study of PCB levels and profiles in contaminated feeds delivered to poultry or pig farms confirmed that the Belgian PCB incident was due to a single source of PCB oil introduced into the food chain at the end of January 1999. This PCB oil had a congeners pattern closely matched to a mixture of Aroclor 1260/1254 in the proportion 75/25. The total amount of PCBs added to recycled fats was estimated at 50 kg (sum of the seven markers) or approximately 150 kg total PCBs, which corresponds to about 100 liters of PCB oil. This PCB mixture contained about 1g TEQ dioxins (more than 90- contributed by PCDFs) and about 2g TEQ dioxin-like PCBs. The proportions of PCB 52 and 101 congeners were fairly constant in animal feeds, excluding the possibility of secondary contamination due to fat recycling from contaminated animals. The highest concentrations of PCBs and dioxins were found in poultry and especially in the reproduction animals (hens and chicks), which showed the classical manifestations of chick edema disease. The pigs were also affected but to a lesser extent and no sign of intoxication was observed. The study of PCB/dioxin patterns and of the PCB:dioxin ratios revealed major differences in the metabolism of these compounds by farm animals. Whereas the PCBs:dioxins ratio was fairly constant in all poultry products with a mean value similar to that found in contaminated feeds (50,000), in pigs this ratio was both much higher and more variable (values up to 10,000,000), reflecting a faster elimination of dioxins than PCBs in these animals. These metabolic differences also emerged from the PCB and dioxin patterns which were altered much more in pigs than in poultry. Although the most contaminated food products (chicken meat) had PCB and dioxin levels more than 100 times above maximal recommended values, it is unlikely that this incident could have caused adverse effects in the general population of Belgium. A doubling of the PCB and dioxin burden of the young adult population would require the consumption of, respectively, 10 and 20 highly contaminated meals. In view of the very limited proportion of the poultry chain effectively contaminated during the incident (around 2%), such an extreme scenario was quite improbable for the general population except perhaps for farmers consuming their own products. But even in that case, it would have meant going back to the levels in the 1980s or attaining the body burden of subjects regularly eating contaminated seafood. [less ▲]

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See detailCrystal Structure of Human Peroxiredoxin 5, a Novel Type of Mammalian Peroxiredoxin at 1.5 Ǻ Resolution
Declercq, Jean-Paul; Evrard, Christine ULiege; Clippe, André et al

in Journal of Molecular Biology (2001), 311

The peroxiredoxins define an emerging family of peroxidases able to reduce hydrogen peroxide and alkyl hydroperoxides with the use of reducing equivalents derived from thiol-containing donor molecules ... [more ▼]

The peroxiredoxins define an emerging family of peroxidases able to reduce hydrogen peroxide and alkyl hydroperoxides with the use of reducing equivalents derived from thiol-containing donor molecules such as thioredoxin, glutathione, trypanothione and AhpF. Peroxiredoxins have been identified in prokaryotes as well as in eukaryotes. Peroxiredoxin 5 (PRDX5) is a novel type of mammalian thioredoxin peroxidase widely expressed in tissues and located cellularly to mitochondria, peroxisomes and cytosol. Functionally, PRDX5 has been implicated in antioxidant protective mechanisms as well as in signal transduction in cells. We report here the 1.5 Ǻ resolution crystal structure of human PRDX5 in its reduced form. The crystal structure reveals that PRDX5 presents a thioredoxin-like domain. Interestingly, the crystal structure shows also that PRDX5 does not form a dimer like other mammalian members of the peroxiredoxin family. In the reduced form of PRDX5, Cys47 and Cys151 are distant of 13.8 Ǻ although these two cysteine residues are thought to be involved in peroxide reductase activity by forming an intramolecular disul®de intermediate in the oxidized enzyme. These data suggest that the enzyme would necessitate a conformational change to form a disulfide bond between catalytic Cys47 and Cys151 upon oxidation according to proposed peroxide reduction mechanisms. Moreover, the presence of a benzoate ion, a hydroxyl radical scavenger, was noted close to the active-site pocket. The possible role of benzoate in the antioxidant activity of PRDX5 is discussed. [less ▲]

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See detailEffects of exposure to cadmium on calcium metabolism : a population study
Staessen, Jan; Amery, Antoon; Bernard, Alfred et al

in British Journal of Industrial Medicine (1991), 48

The objective was to investigate the hypothesis that environmental exposure to cadmium may affect calcium metabolism in the population at large. The 1987 participants (965 men and 1022 women), from 20 to ... [more ▼]

The objective was to investigate the hypothesis that environmental exposure to cadmium may affect calcium metabolism in the population at large. The 1987 participants (965 men and 1022 women), from 20 to 80 years old, constituted a random sample of the population of four Belgian districts. The urinary excretion of cadmium, a mesure of lifetime exposure, averaged 9.3 nmo/24h in men (range 0.4-324 nmol/24h) and 7.1 nmol/24h (range 0.1-71 nmol/24h) in women. Serum alkaline phosphatase activity and the urinary excretion of calcium correlated significantly and positively with urinary cadmium excretion in both men and women, and serum total calcium concentration negatively with urinary cadmium excretion in men only. The regression coefficients obtained after adjustment for significant covariates indicated that when urinary cadmium excretion increased twofold, serum alkaline phosphatase activity and urinary calcim excretion rose by 3-4% and 0.25 mmol/24h respectively, whereas in men serum total calcium concentration fell by 6 µmol/l. After adjustment for significant covariates the relation between serum total calcium concentration and urinary cadmium excretion was not significant in women. The findings suggest that even at environmental exposure levels calcium metabolism is gadually affected, as cadmium accumulates in the body. The morbidity associated with this phenomenon in industrialised countries remains presently unknown and requires further investigation. [less ▲]

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See detailHealth effects of environmental exposure to cadmium: objectives, design and organization of the Cadmibel
Lauwerys, Robert; Amery, Antoon; Bernard, Alfred et al

in Environmental Health Perspectives (1990), 87

Cadmium is a cumulative environmental pollutant. For the general population mainly exposed by the oral route and through tobacco smoke inhalation, the kidney is the critical organ. Belgium is the ... [more ▼]

Cadmium is a cumulative environmental pollutant. For the general population mainly exposed by the oral route and through tobacco smoke inhalation, the kidney is the critical organ. Belgium is the principal producer of cadmium in Europe, and certain areas of the country are polluted by cadmium mainly because of past emissions from nonferrous industries. Preliminary studies carried out in one polluted area have suggested that environmental pollution might lead to an increased uptake of cadmium by the human body and possibly to health effects. Thus, a large-scale morbidity study has been initiated to assess the validity of this hypothesis. The present paper describes the protocol of this study. Its main objectives are to determine to what extent environmental exposure to cadmium resulting from industrial emissions may lead to accumulation of the metal in the human organism; to establish whether or not environmental exposure may induce renal changes and/or influence blood pressure; and to assess the acceptable internal dose of cadmium for the genral population. The study design takes advantage of the fact that biological indicators of exposure, body burden, and early nephrotoxic effects of cadmium ar available, which increase the likelihood of detecting a cause-effect relationship. [less ▲]

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