Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers exposed to trichloroethylene.
ABSTRACT Epidemiological studies suggest that trichloroethylene (TCE) exposure may be associated with renal cancer. The biological mechanisms involved are not exactly known although nephrotoxicity is believed to play a role. Studies on TCE nephrotoxicity among humans, however, have been largely inconsistent. We studied kidney toxicity in Chinese factory workers exposed to TCE using novel sensitive nephrotoxicity markers. Eighty healthy workers exposed to TCE and 45 comparable unexposed controls were included in the present analyses. Personal TCE exposure measurements were taken over a 2-week period before urine collection. Ninety-six percent of workers were exposed to TCE below the current US Occupational Safety and Health Administration permissible exposure limit (100 ppm 8h TWA), with a mean (SD) of 22.2 (35.9) ppm. Kidney injury molecule-1 (KIM-1) and Pi-glutathione S transferase (GST) alpha were elevated among the exposed subjects as compared with the unexposed controls with a strong exposure-response association between individual estimates of TCE exposure and KIM-1 (P < 0.0001). This is the first report to use a set of sensitive nephrotoxicity markers to study the possible effects of TCE on the kidneys. The findings suggest that at relatively low occupational exposure levels a toxic effect on the kidneys can be observed. This finding supports the biological plausibility of linking TCE exposure and renal cancer.
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ABSTRACT: Kidney injury molecule-1 (KIM-1, also named TIM-1 and HAVCR-1) was identified as the most highly upregulated protein in the proximal tubule of the kidney after injury. This protein is present with injury in multiple species including man, and also after a large number of acute and chronic insults to the kidney. It is a type-1 membrane protein whose ectodomain is released into the lumen of the tubule. The ectodomain is heavily glycosylated and stable and appears in the urine after injury. It has been qualified by the United States Food and Drug Administration and the European Medicines Agency for preclinical assessment of nephrotoxicity and on a case-by-case basis for clinical evaluation. As a biomarker in humans, its utility has been demonstrated in acute and chronic injury and in renal cell carcinoma, a condition similar to injury, where there is dedifferentiation of the epithelial cell. KIM-1 is a phosphatidylserine receptor which recognizes apoptotic cells directing them to lysosomes. It also serves as a receptor for oxidized lipoproteins and hence is important for uptake of components of the tubular lumen which may be immunomodulatory and/or toxic to the cell. KIM-1 is unique in being the first molecule, not also present on myeloid cells, that transforms kidney proximal epithelial cells into semi-professional phagocytes. Data suggest that KIM-1 expression is protective during early injury, whereas in chronic disease states, prolonged KIM-1 expression may be maladaptive and may represent a target for therapy of chronic kidney disease.Transactions of the American Clinical and Climatological Association 01/2014; 125:293-9.
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ABSTRACT: Little, M.P., Kwon, D., Doi, K., Simon, S.L., Preston, D.L., Doody, M.M., Lee, T., Miller, J.S., Kampa, D.M., Bhatti, P., Tucker, J.D., Linet, M.S., Sigurdson, A.J., Association of Chromosome Translocation Rate with Low Dose Occupational Radiation Exposures in U.S. Radiologic Technologists. Radiat. Res. 182, 1-17 (2014). Chromosome translocations are a well-recognized biological marker of radiation exposure and cancer risk. However, there is uncertainty about the lowest dose at which excess translocations can be detected, and whether there is temporal decay of induced translocations in radiation-exposed populations. Dosimetric uncertainties can substantially alter the shape of dose-response relationships; although regression-calibration methods have been used in some datasets, these have not been applied in radio-occupational studies, where there are also complex patterns of shared and unshared errors that these methods do not account for. In this paper we evaluated the relationship between estimated occupational ionizing radiation doses and chromosome translocation rates using fluorescent in situ hybridization in 238 US radiologic technologists selected from a large cohort. Estimated cumulative red-bone-marrow doses (mean 29.3 mGy, range 0-135.7 mGy) were based on available badge-dose measurement data and on questionnaire-reported work-history factors. Dosimetric assessment uncertainties were evaluated using regression-calibration, Bayesian, and Monte-Carlo maximum-likelihood methods, taking account of shared and unshared error, and adjusted for overdispersion. There was a significant dose response for estimated occupational radiation exposure, adjusted for questionnaire-based personal diagnostic radiation, age, sex, and study group (5.7 translocations per 100 whole-genome cell equivalents per Gy, 95% CI 0.2, 11.3, p=0.0440). A significant increasing trend with dose continued to be observed for individuals with estimated doses <100 mGy. For combined estimated occupational and personal diagnostic medical radiation exposures, there was a borderline-significant modifying effect of age (p=0.0704), but little evidence (p>0.5) of temporal decay of induced translocations. The three methods of analysis to adjust for dose uncertainty gave similar results. In summary, chromosome translocation dose-response slopes were detectable down to <100 mGy, and were compatible with those observed in other radiation-exposed populations. However, there are substantial uncertainties in both occupational and other (personal diagnostic medical) doses that may be imperfectly taken into account in our analysis.Radiation Research 06/2014; 182(1):1-17. DOI:10.1667/RR13413.1 · 2.45 Impact Factor
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ABSTRACT: Trichloroethylene (TCE) is an effective solvent for a variety of organic materials. Since the wide use of TCE as industrial degreasing of metals, adhesive paint and polyvinyl chloride production, TCE has turned into an environmental and occupational toxicant. Exposure to TCE could cause severe hepatotoxicity; however, the toxic mechanisms of TCE remain poorly understood. Recently, we reported that SET protein mediated TCE-induced cytotoxicity in L-02 cells. Here, we further identified the proteins related to SET-mediated hepatic cytotoxicity of TCE using the techniques of DIGE (differential gel electrophoresis) and MALDI-TOF–MS/MS. Among the 20 differential proteins identified, 8 were found to be modulated by SET in TCE-induced cytotoxicity and three of them (cofilin-1, peroxiredoxin-2 and S100-A11) were validated by Western-blot analysis. The functional analysis revealed that most of the identified SET-modulated proteins are apoptosis-associated proteins. These data indicated that these proteins may be involved in SET-mediated hepatic cytotoxicity of TCE in L-02 cells.Toxicology Letters 05/2014; DOI:10.1016/j.toxlet.2014.02.028 · 3.36 Impact Factor