| Occupational or environmental exposure to cadmium (Cd) can give rise to adverse health effects, particularly kidney damage, as a result of Cd accumulation in the kidneys. Cd-induced kidney damage is characterized by proximal tubular reabsorptive dysfunction, the earliest manifestations of which are increased urinary excretion of low-molecular-weight proteins such as urinary metallothionein (UMT) andβ2-microglobulin (UB2M), etc. An important toxicological feature of cadmium is its extremely long biological half-time in the organism. Once absorbed, cadmium is efficiently retained in the organism and accumulates throughout life. The prognosis of Cd-induced kidney dysfunction after the cessation of or reduction in Cd-exposure is concerned by researchers all over the world.In late 2006 we followed up the residents in Cd-polluted areas in Zhejiang Province, China, after the 1998 survey. In the pilot study conducted in 1995, the Cd content of rice produced in the highly-polluted area was found as high as 3.7 mg Cd/kg, and thus, the consumption of rice grown locally was identified as the most important determinant of Cd exposure among the residents. Since the year 1996 the residents living in the Cd-contaminated areas stopped to eat rice in their own fields and turned to rice from non-polluted areas. Data of a number of 148 individuals who were examined both in the 1995 and 1998 surveys were picked up to investigate the evolution of kidney function after reduction in Cd-exposure. Based on defined cut-off points of specific kidney markers, the prevalence of adverse renal effects in 1995 and 1998 were compared to each other, indicating that the Cd-induced renal dysfunction might be reversible if UCd concentration was low-level before exposure decreasing, otherwise it might be irreversible or aggravated. Even so, it was still unknown what would happen in a longer time perspective. Therefore, a number of 475 residents who participated in the 1998 survey were followed up in 2006. In order to evaluate the changes in renal function among the population after reduction in Cd-exposure for years, the cut-off values of kidney markers were redefined considering the aging effect and the prevalence of kidney dysfunction in 1998 and 2006 was compared to each other. To find out how the prevalence of impaired kidney function develops after cessation of exposure, and how that development relates to the initial exposure level, three different biomarkers of kidney effects were assessed:urinary N-acetyl-β-D-glucosaminidase (UNAG), UB2M and albumin (UALB). For these biomarkers we also investigated how predicitive an impaired level was for future impairment in the same individual. This study over eight years shows clearly that albuminuria from cadmium exposure (at the here observed exposure levels) is a reversible effect that recovers after cessation of exposure. For the markers of tubular effects, a tendency towards improvement, but not complete recovery, was observed for UNAG, but only among women. Maybe there is also some improvement for UB2M, but then only in relatively young individuals. The pattern previously indicated in a smaller three-year study, with improvements for individuals with low exposure levels and impairment for those with high exposure levels did not repeat itself. Based on the individual level, the study demonstrates that an impaired UNAG value is very little prognostic for the result of a future sampling for UNAG. In contrast, an impaired UB2M value is a strong predictor of impaired values also in the future.Animal studies with well-defined exposure doses, duration and route, can help understand the process of evolution of renal function after changes of Cd-exposure. In one experiment, Wistar male rats pre-treated with zinc (Zn) or copper (Cu), were administered with CdMT, to observe the ratios of Zn/Cd, Cu/Cd in liver metallothionein (MT) induced by zinc or copper. It was concluded that Zn bound to MT was more easily replaced by Cu than Cd bound to MT. The non-MT-bound Zn in liver tissues may be one of the explanations for the difference. In another one, to investigate the role of MT in tissues after cessation of Cd-exposure, Wistar rats of both genders were exposed to Cd via drinking water for 12 weeks, and then exposure was stopped; the animals were monitored for the following 16 weeks, i.e., until 28 weeks after start of the experiment. We observed that the levels of immunohistochemically determined MT in rat liver and kidneys were responsive to chronic oral Cd exposure. Once the exposure ceased, the present study confirmed a decreased Cd burden in the liver tissue and found increased hepatic MT levels. The decreased UNAG levels in the lowest-dose group and the decreased UMT levels in the urine in all of the dose groups after cessation of exposure might reflect a partial recovery of renal tubular function and decreased transport of CdMT from the liver. These findings should also contribute to our understanding of the events taking place in tissues after cessation of Cd exposure in humans.Recent developments in proteomic technologies have provided tools for discovering and identifying disease-associated biomarkers. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) analysis was performed on urine samples for Wistar male rats orally exposed to Cd via drink water. The samples collected at different time points of the exposure, demonstrated a time-dependant increase in the density of protein/peptides peaks at the range of 2000-5000 Da,8000-12000 Da and 17000-19000 Da. The dose-effect relationship was also found between dose groups and the density of those peaks. This experiment revealed the time-related and dose-related changes of urinary protein patterns under Cd-exposure, which might be a good start to investigate the Cd nephrotoxicity and its prognosis from a proteomic perspective. Because of the limited information provided by SELDI analysis, two-dimensional gel electrophoresis (2DE) was performed to profile urinary proteins from animals (rats exposed to Cd via drinking water) and humans (residents living in the Cd-contaminated areas in southeast China). The silver-staining images showed a similar pattern of protein spots for the urine from rats of the same gender at the same dose, but varied patterns for individuals of human. In spite of that, both urinary proteome of Cd-induced renal dysfunction (rats) and its prognosis (human) indicated increasing spots located in the low-molecular-weight area. Furthermore, by labeling urinary proteins with different fluorescent dyes, the 2D difference gel electrophoresis (2D-DIGE) analysis revealed 95 protein spots for rats and 78 for humans, the expression levels of which were altered during cadmium exposure.36 protein spots up-regulated in rat urines and 21 in human urines (>1.49-fold changes and P<0.05) were picked up for subsequent identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) followed by peptide mass fingerprinting. Some of them were identified as Serum albumin, NAG, Ig kappa chain C region, human alpha-1-microglobulin/bikunin precursor (Protein AMBP) and rat alpha-2u-globulin. The elevated excretion of urinary NAG and albumin (both of which are widely used in the study of Cd nephrotoxicity), and probably Protein AMBP, was a sign of impaired renal function. Ig Kappa chain may increase when the capacity of tubular reabsorption decrease. Although not all urinary biomarkers related to cadmium toxicity were covered by our findings, the present study should be regarded as exploratory in an attempt to profile cadmium-induced proteinuria with proteomic techniques.
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