A physiologically based model for the ingestion of chromium(III) and chromium(VI) by humans.

A physiologically based model of human chromium kinetics has been developed, based on an existing physiologically based model of human body and bone growth (O'Flaherty, 1993, Toxicol. Appl. Pharmacol. 118, 16-29; 1995a, Toxicol. Appl. Pharmacol. 131, 297-308; 2000, Toxicol. Sci. 55, 171-18) and an existing physiologically based model of chromium kinetics in rats (O'Flaherty, 1996, Toxicol. Appl. Pharmacol. 138, 54-64). Key features of the adapted model, specific to chromium, include differential absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in all body fluids and tissues, modest incorporation of chromium into bone, and concentration-dependent urinary clearance consistent with parallel renal processes that conserve chromium efficiently at ambient exposure levels. The model does not include a physiologic lung compartment, but it can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions generally containing up to 10 mg/day of soluble inorganic salts of either Cr(III) (chromic chloride, CrCl(3)) or Cr(VI) (potassium dichromate, K(2)Cr(2)O(7)) (Finley et al., 1997, Toxicol. Appl. Pharmacol. 142, 151-159; Kerger et al., 1996, Toxicol. Appl. Pharmacol. 141, 145-158; Paustenbach et al., 1996, J. Toxicol. Environ. Health 49, 453-461). In one of the studies, in which the chromium was ingested in orange juice, urinary clearance was observed to be more rapid than when inorganic chromium was ingested. Chromium kinetics were shown not to be dependent on the oxidation state of the administered chromium except in respect to the amount absorbed at these ambient and moderate-to-high exposures. The fraction absorbed from administered Cr(VI) compounds was highly variable and was presumably strongly dependent on the degree of reduction in the gastrointestinal tract, that is, on the amount and nature of the stomach contents at the time of Cr(VI) ingestion. The physiologically based model is applicable to both single-dose oral studies and chronic oral exposure, in that it adequately reproduced the time dependence of blood plasma concentrations and rates of urinary chromium excretion in one of the subjects who, in a separate experiment, ingested daily 4 mg of an inorganic Cr(VI) salt in 5 subdivided doses of 0.8 mg each for a total of 17 days. The high degree of variability of fractional absorption of Cr(VI) from the gastrointestinal tract leads to uncertainty in the assignment of a meaningful value to this parameter as applied to single Cr(VI) doses. To model chronic oral chromium exposure at ambient or moderately above-ambient levels, the physiologically based model in its present form should be usable with urinary clearance set to a constant value of 1-2 liters/day and the gastrointestinal absorption rate constants set at 0.25/day for Cr(III) and 2.5/day for Cr(VI). The model code is given in full in the Appendix.     

The expression of RKIP, RhoGDI, galectin, c-Myc and p53 in gastrointestinal system of Cr(VI)-exposed rats

Hexavalent chromium (CrVI) is considered to be a risk factor in the formation of human cancer. Raf kinase inhibitor protein (RKIP), Rho‐GDIα, galectin, c‐Myc and p53 play important roles in cancer formation. The purpose of this study was to determine if Cr(VI) induces the formation of gastrointestinal cancer. We explored the expression of RKIP, Rho‐GDIα, galectin, c‐Myc and p53 in the colon and stomach in rats exposed to chromium (CrVI). Thirty Wistar rats were divided into six groups which were chronically fed with 250, 500, 750, 1000 and 1250 ppm Na₂Cr₂O₇ and water for 60 days. The level of Cr(VI) was determined by electrothermal atomic absorption spectrometry. The expression of RKIP, Rho‐GDIα, galectin, c‐Myc and p53 of stomach and colon was measured by western blot. The gene expression of RKIP, Rho‐GDIα, galectin, c‐Myc and p53 of the stomach and colon was determined by RT‐PCR. The results showed that the expression of p53 and Rho‐GDIα was decreased in the stomach and colon of rats with Cr(VI) treatment. The expression of RKIP was decreased in the stomach and colon of rats treated with high‐dose Cr(VI). The expression of c‐Myc and gelectin‐1 was increased in the stomach and colon of rats with Cr(VI) treatment. We concluded that the anomalous expression of RKIP, Rho‐GDIα, galectin, c‐Myc and p53 might be a dangerous index of cancer formation in the stomach and colon of rats with Cr(VI) exposure. Copyright © 2011 John Wiley & Sons, Ltd.     

Genetic studies in a cluster of mucopolysaccharidosis type VI patients in Northeast Brazil

Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by deficiency of arylsulphatase B. The incidence of MPS VI is very low, usually less than 1 case for every 1,000,000 newborns. In Northeast Brazil we identified in the county of Monte Santo (52,360 inhabitants) thirteen patients with MPS VI. The aim of this work was to identify the mutation(s) present in these patients and analyze intragenic SNPs to define possible haplotypes. The 13 MPS VI patients were found to be homozygous for the p.H178L mutation. All patients have the same haplotype for the intragenic SNPs. Based on current data, the prevalence of MPS VI in this region is estimated as 1:5,000 newborns. These results, together with pedigree analysis, strongly suggest a founder effect accounting for the high frequency of p.H178L mutation in this area. This reinforces the need of a comprehensive community genetics program for this area.     

Annexins I and II show differences in subcellular localization and differentiation-related changes in human epidermal keratinocytes

The annexins are a family of calcium-dependent phospholipid-binding proteins whose in vitro properties have led to a number of hypotheses suggesting their cellular functions, including membrane fusion in exocytosis and endocytosis. To investigate the topography and possible functions of these proteins we compared the subcellular localization of annexins I, II, IV and VI in skin sections and in cultured epidermal keratinocytes by immunostaining. We found that annexin I staining was in a granular pattern in the monolayer epithelial cells but in an envelope pattern in the stratified keratinocytes. This finding corroborates previous reports that annexin I crosslinks to form cornified envelopes in the mid-epidermis and explains the absence of staining above that level. It is unlikely that this protein is related to exocytosis in the granular layer of the epidermis. In comparison, annexin II staining was also granular and was detected in all nucleated epidermal cells as bands at the cell periphery. However, only annexin II was detected extracellularly among the top layer of cultured cells. The intracellular linear envelope pattern of annexin I and the intercellular pattern of annexin II suggest their interactions with the membrane cytoskeleton in other biological functions. Taken together, both annexins undergo different differentiation-related changes. While methanol fixation enhanced staining of annexin I, it diminished staining of annexin II. Their opposite responses to methanol fixative suggests a different molecular organization of the two annexins with phospholipid in the cell membrane. Annexins IV and VI were predominantly confined to dermal cells including ductal and myoepithelial cells and were not detected in cultured keratinocytes using either cold methanol fixative or prefixation labeling.