Normal levels of cadmium in diet, urine, blood, and tissues of inhabitants of the United States

Cd was measured in the feces, urine, blood, and hair of U.S. inhabitants without known high Cd exposure in Chicago, Illinois, and Dallas, Texas, and in autopsy tissues of accident victims in Dallas. The average intake of Cd in food was estimated to be 13-16 microgram/d and was higher for males than females. The average levels of Cd were 0.59-0.77 microgram/l in urine, 0.09-0.11 microgram per 100 ml in blood, 0.83-1.10 microgram/g in hair, 21 microgram/g in kidney cortex, 1.2 microgram/g in liver, 0.067 microgram/g in muscle, 0.58 microgram/g in pancreas, and 0.040 microgram/g in fat. Hair Cd was higher for males than females. Cd levels increased with age in urine and all tissues and were higher in cigarette smokers than nonsmokers in urine, blood, and all tissues.     

Effects of aging on cadmium concentrations and renal dysfunction in inhabitants in cadmium‐polluted regions in Japan

The absorption of cadmium (Cd) may lead to Cd‐related diseases such as renal tubular dysfunction and bone disease, and it is known to take around 10–30 years to reduce Cd concentrations to half their original levels. Urinary β₂‐microglobulin (β₂‐MG), N‐acetyl‐β‐D‐glucosaminidase (NAG), protein, glucose and albumin were used as indicators of renal dysfunction caused by Cd exposure. Our previous study found that urinary Cd concentrations had increased recently and that age was more strongly associated with urinary β₂‐MG concentration than recent Cd body burden. Therefore, the purpose of the present study was to investigate the effect of aging on Cd concentrations and renal dysfunction. The Cd, β₂‐MG, NAG, protein, glucose and albumin concentrations in the urine of 40 Japanese subjects (20 females and 20 males) environmentally exposed to Cd were collected. They lived in the Kakehashi River basin and were divided into three age categories: 50–69, 70–79 and 80–99 years. Significant differences in urinary Cd and β₂‐MG concentrations were found among age groups, with urinary Cd levels tending to increase with age in both sexes. No significant correlations were found between urinary Cd and any indicators of renal dysfunction. The correlation between age, Cd and indicators of renal dysfunction was observed more clearly in females than in males. Age is more strongly correlated with indicators of renal dysfunction than Cd body burden. Copyright © 2017 John Wiley & Sons, Ltd.     

Inducibility of metallothionein biosynthesis in the whole soft tissue of zebra mussels Dreissena polymorpha exposed to cadmium,copper, and pentachlorophenol

Freshwater mussels Dreissena polymorpha (Pallas, 1771) were exposed to the elevated concentrations of Cd (10, 50, 100, and 500 μg/L), Cu (10, 30, 50, and 80 μg/L), and an organochlorinated pesticide, pentachlorophenol (PCP) (1, 10, and 100 μg/L). Induced synthesis of biomarker metallothionein (MT) and changes in concentrations of cytosolic Cd, Cu, and Zn in the whole soft tissue of mussels were monitored after a 7‐day laboratory exposure to the contaminants. A clear dose‐dependent elevation in the MT concentration was observed after exposure to Cd at doses of 10–100 μg/L, and this increase of MT content was accompanied with a linear increase of cytosolic Cd. Cd concentration of 500 μg/L caused no additional increase of MT and Cd in mussel cytosol, suggesting possible toxic effects due to exceeding cellular inducible/defense capacity. Cu exposure resulted with variable changes in MT concentrations, with no clear linear relationship between MT and Cu concentrations in water, although a progressive dose‐dependent accumulation of Cu in the soluble fraction of mussel tissues was recorded. A decrease of cytosolic Zn was evident at higher exposure concentrations of both metals used. PCP in concentrations applied was unable to induce MT synthesis, but the higher concentrations of PCP influenced the cytosolic metal concentrations. In conclusion, the results obtained confirm the specificity of MT induction in D. polymorpha as an biological response on metal stimulation, especially by cadmium, being more closely correlated to MT than copper within the ecologically relevant concentration range. The strong induction potential of cadmium as well as an absence of MT induction following exposure to PCP as an organic chemical contaminant are supporting evidences for usage of zebra mussel MT as a specific biomarker of Cd exposure in biomonitoring programs. © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

Developmental and sex differences in cadmium distribution and metallothionein induction and localization

Age- and sex-related differences in hepatic and renal distribution of cadmium (Cd) and the effect of Cd injection (10 mumol/kg) on tissue zinc (Zn), copper (Cu) and metallothionein (MT) levels were investigated in 2- to 84-day old rats. Renal Cd accumulation increased with age of the animal. Sex differences in renal Cd accumulation were noted in young animals where the 2- and 8-day old males had significantly greater concentration than the females. There were no clear effects of Cd on renal Zn. Renal Cu levels, however, were elevated in the adults. The adult females contained about twice as much MT as the adult males. Cd treatment had no effect on renal MT levels of 8- to 84-day old animals but depressed the levels in 2-day old. Age-related increase in hepatic Cd accumulation was also found; the pattern was more clear cut in females than in males. In addition, in the females the hepatic Cd concentration was significantly higher than in the males. Cd-injection significantly increased hepatic Zn and MT concentrations only in weaned animals. While there were no sex differences in MT levels in the young animals, the weaned females had significantly more MT than the corresponding males. Immunohistochemical staining for MT showed positive staining in both cytoplasm and nuclei of the parenchymal cells. The number of MT-positive nuclei was dependent on the relative MT concentration of the liver. In spite of the intense nuclear staining in 2-day old controls and 84-day old Cd-injected rats, less than 1% of the hepatic MT was present in the nuclear fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

锌金属硫蛋白对镉中毒小鼠肾损伤的修复作用

目的：研究锌金属硫蛋白（Zn-MT）对镉中毒小鼠肾损伤的修复作用。方法：以昆明种小鼠作为研究对象，染镉14d建立亚急性镉中毒模型，随后经口给予Zn-MT。收集24h尿液，测定尿N－乙酰－β－D－氨基葡萄糖苷酶（NAG酶）活性作为衡量肾脏损伤程度的一项指标，同时电镜观察肾组织形态学变化；测定并分析肾组织上清液中脂质过氧化代谢产物一丙二醛（MDA）水平、超氧化物歧化酶（SOD）、谷胱甘肽过氧化酶（GSH－Px)活性。结果：Zn-MT可明显降低肾组织中MDA水平，使肾组织中SOD、GSH－Px活力有一定程度的恢复，此时尿NAG酶活性降低表明肾损伤程度减轻，且上述作用呈明显的剂量－反应关系；电镜下观察到给予Zn-MT后肾组织形态学病变有所减轻。结论：Zn-MT可对镉中毒小鼠肾组织脂质过氧化损伤起到一定的修复作用。     

Increased Hepatic and Decreased Urinary Metallothionein in Rats after Cessation of Oral Cadmium Exposure

Abstract: We investigated the role of metallothionein (MT) in tissues after cessation of cadmium (Cd) exposure. Wistar rats of both genders were given CdCl₂ in drinking water at daily doses of 0, 2.5, 5.0 or 10.0 mg Cd/kg body‐weight for 12 weeks. Half of the animals were then killed; the others were given Cd‐free water for the following 16 weeks, i.e. until 28 weeks after start of the experiment (28‐week rats). We observed dose‐dependent increases in the levels of MT in the tissues of rats 12 weeks after beginning the experiment (12‐week rats). After the exposure ceased, levels of MT in the 28‐week rats changed in three ways: an increase in the liver, persistence in the kidney cortex and a decrease in the medulla, relative to those levels in their 12‐week counterparts. Biomarkers of kidney dysfunction were determined to be urinary MT (UMT) and urinary N‐acetyl‐β‐d ‐glucosaminidase (UNAG). After 12 weeks, we observed dose‐related statistically significant increases in UMT and UNAG in all of the Cd‐exposed groups. A statistically significant decrease for UNAG between the 12‐ and 28‐week rats occurred among males at the lowest Cd dose and for UMT in all of the Cd‐exposed groups. The unchanged tissue levels of MT in the kidney cortex suggest that decreased UMT is a sign either of (i) decreased transport of Cd‐MT from the liver via blood plasma to the renal tubules or (ii) increased tubular reabsorption and recovery of renal tubular function.     

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers

Purpose

Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect.

Methods

Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (μ-Alb), beta-2-microglobulin (β₂-MG), retinol binding protein (RBP), N-acetyl-β-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey.

Results and conclusions

The median Cd-B, Cd-U, Pb-B were: 0.8 μg/l (IQR = 0.5, 1.2), 0.5 μg/g creatinine (IQR = 0.3, 0.8) and 158.5 μg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., μ-Alb and β2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.     

Lead,mercury, and cadmium in blood and their relation to diet among Swedish adults

The aim of the present study was to examine the body burden of lead (Pb), mercury (Hg), and cadmium (Cd) in blood among Swedish adults and the association between blood levels, diet and other lifestyle factors.The study was based on a subgroup (n = 273) of the national survey Riksmaten 2010–2011 (4-day food records and questionnaire). Lead, Hg, and Cd were measured in whole blood, and Cd additionally in urine, by mass or fluorescence spectrometry methods.The median values (5–95th percentiles) of the metals in blood were as follows; Pb: 13.4 (5.8–28.6) μg/L, Hg: 1.13 (0.31–3.45) μg/L, and Cd: 0.19 (0.09–1.08) μg/L. All three metals increased with increasing age. Lead levels in blood were positively associated with intakes of game and alcohol, Hg was related to fish intake, and blood Cd related to smoking and low iron stores and to a low meat intake.Body burdens of the studied metals were generally below health based reference values, but several individuals had blood Pb levels above the reference point for possible nephrotoxic and developmental neurotoxic effects. As health effects cannot be excluded, individuals with high Pb exposure should aim at decreasing their body burden, both from food and from other exposure routes.     

Effects of cadmium ingestion on plasma and osmoregulatory hormone concentrations in male and female Pekin ducks

Effects of ingested cadmium (Cd) on body mass and plasma, urine, salt-gland secretion, and osmoregulatory hormone concentrations were assessed in male and female Pekin ducks, Anas platyrhynchos, acclimated to 450 mM NaCl over 6 wk and then held an additional 13 wk on 300 mM NaCl (prolonged saline exposure). Groups of six birds ate diets containing 0 (control), 50 (low-Cd diet), or 300 (high Cd diet) micrograms Cd/g food. Ducks that ingested Cd, especially females, lost body mass. Cadmium ingestion did not affect salt-gland secretion concentration. Control males had higher plasma osmolality and lower relative plasma volume. These increased in both sexes during saline acclimation. The high-Cd diet suppressed the increase in plasma osmolality in both sexes, but a rise in relative plasma volume occurred only in females. Following prolonged exposure to saline, plasma osmolality and relative plasma volume were reduced in control ducks but further elevated in ducks on the high-Cd diet. Cadmium ingestion suppressed the increase in urine osmolality that occurred in control ducks during saline acclimation. Neither saline acclimation nor Cd ingestion affected plasma concentrations of arginine vasotocin or prolactin. Arginine vasotocin was not correlated with plasma osmolality; prolactin was negatively correlated with plasma osmolality, but only in males. Cadmium suppressed the increase in angiotensin II that occurred at higher salinities in control and low-Cd males. This study examined the effects of gradually increasing body cadmium content on osmotic homeostasis. Cadmium affected plasma and urine, but not salt-gland secretion, concentrations and some of these responses were sexually disparate. Cadmium did not affect osmoregulatory hormones (arginine vasotocin and prolactin) by which observed changes in plasma concentration might have been influenced.     

Sex and age differences in mercury distribution and excretion in methylmercury-administered mice

Sex differences in mercury distribution and excretion after single administration of methylmercury chloride (MMC, 5 mg/kg) were studied in mice. A sex difference in urinary mercury excretion was found in sexually mature mice (age of 7 wk) of C57BL/6N and BALB/cA strains. Males showed higher mercury levels in urine than females, though no significant difference was found in fecal mercury levels 24 h post exposure to MMC. The higher urinary excretion rates in males accounted for significant lowering of mercury levels in the brain, liver, and blood, but not in the kidney, which showed higher values. At 5 min, however, these sex difference was found only in the kidney, showing higher levels in males. Changes in mercury distribution with time were studied in C57BL/6N mice. The brain mercury increased in both sexes up to 3 d, and decreased only in males on d 5. Liver and blood mercury decreased with time in both sexes, and these were constantly higher in females than in males. Renal mercury in males decreased to similar levels to females on d 3. The sex differences at various ages were studied with C57BL/6N mice 24 h after dosing. Two-week-old mice, the youngest in this study, did not show significant sex difference in the mercury distribution and excretion, and their urinary mercury levels were much lower as compared to the older mice. Then, urinary mercury excretion in both sexes increased at 4 wk of age and then decreased at 45 wk of age. At 4, 7, 10, and 45 wk of age, males showed higher urinary mercury levels than females. These studies demonstrated sex and age differences in the mercury distribution and urinary excretion after methylmercury administration in mice. From these findings, it has been suggested that urinary mercury excretion may be related to sex hormones, especially androgens.     

Kidney synthesizes less metallothionein than liver in response to cadmium chloride and cadmium-metallothionein

Acute exposure to Cd produces liver injury, whereas chronic exposure results in kidney injury. Tolerance to the hepatotoxicity is observed during chronic exposure to Cd due to the induction of metallothionein (MT). The nephrotoxicity produced by chronic Cd exposure purportedly results from renal uptake of Cd-metallothionein (CdMT) synthesized in liver. The change in target organ from liver to kidney might be due to a lower amount of MT synthesized in the kidney in response to CdMT. Therefore, the purpose of the present study was to quantitate hepatic and renal MT induced by CdCl2 and CdMT. MT levels in mice were quantitated using the Cd-heme assay 24 hr after administration of CdCl2 (0.5-3.0 mg Cd/kg) and CdMT (0.1-0.5 mg Cd/kg). In both liver and kidney, MT reached higher levels following administration of CdCl2 (220 and 60 micrograms/g, respectively) than of CdMT (25 and 35 micrograms/g, respectively), probably because higher dosages of CdCl2 than CdMT are tolerated. CdMT produced 19 and 3 micrograms MT/micrograms Cd in liver and kidney, respectively, while CdCl2 produced 11 and 6 micrograms MT/micrograms Cd, respectively. In conclusion, induction of MT occurs in both the liver and kidney after administration of CdCl2 and CdMT. However, the kidney is less responsive than the liver to the induction of MT by both forms of Cd, which may contribute to making the kidney the target organ of toxicity during chronic Cd exposure.     

Comparative evaluation of four urinary tubular dysfunction markers,with special references to the effects of aging and correction for creatinine concentration

Comparative evaluation was made on alpha(1)-microglobulin (alpha(1)-MG), beta(2)-microglobulin (beta(2)-MG), retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG), as a marker of renal tubular dysfunction after environmental exposure to cadmium (Cd), with special references to the effects of aging and correction for creatinine concentration. For this purpose, a previously established database of 817 never-smoking Japanese women (at the ages of 20 to 74 years) on hematological [hemoglobin, serum ferritin (FE), etc.] and urinary parameters [alpha(1)-MG, beta(2)-MG, creatinine (cr), and a specific gravity] was revisited. For the present analysis, the database was supplemented by the data on RBP and NAG in urine. The exposure of the women to Cd was such that the geometric mean Cd in urine was 1.3 microg/g cr. Among the four tubular dysfunction markers, NAG showed the closest correlation with Cd, followed by alpha(1)-MG and then beta(2)-MG, and RBP was least so although the correlations were all statistically significant. The observed values of the markers gave the best results, whereas correction for a urine specific gravity gave poorer correlation, and it was the worst when correction for creatinine concentration was applied. Age was the most influential confounding factor. The effect of age appeared to be attributable at least in part to the fact that both creatinine and, to a lesser extent, the specific gravity decreased as a function of age. Iron deficiency anemia of sub-clinical degree as observed among the women did not affect any of the four tubular dysfunction markers. In conclusion, NAG and alpha(1)-MG, rather beta(2)-MG or RBP, are more sensitive to detect Cd-induced tubular dysfunction in mass screening. The use of uncorrected observed values of the markers rather than traditional creatinine-corrected values is recommended when comparison covers people of a wide range of ages.     

Cadmium-induced hepatic and renal injury in chronically exposed rats: likely role of hepatic cadmium-metallothionein in nephrotoxicity

Rats were injected sc with 0.5 mg Cd/kg, 6 days/week, for up to 26 weeks. Hepatic and renal function and tissue Cd and metallothionein (MT) content were determined in tissues and plasma at various times after Cd injection. Cd in liver and kidney increased linearly for the first 10 weeks of treatment, but thereafter hepatic concentrations of Cd decreased by 33% whereas the content of Cd in kidney remained constant. MT in liver and kidney increased linearly during the first 12 weeks of Cd treatment to 4400 and 2300 micrograms MT/g, respectively, but rose only slightly thereafter. Circulating concentrations of MT progressively increased beginning 2 weeks after Cd treatment and were approximately 10 times control values in rats dosed with Cd for 12 or more weeks. Plasma activities of alanine and aspartate aminotransferase exhibited a time course similar to that observed with MT, and were elevated as early as the sixth week of Cd exposure. Sharp increases in activities of these enzymes also occurred after 10 to 12 weeks of dosing. Hepatic microsomal metabolism of benzo[a]pyrene and ethylmorphine was severely attenuated beginning 4 weeks after Cd. Renal injury occurred after hepatic damage, as evidenced by decreased in vitro p-aminohippuric acid uptake beginning 8 weeks after exposure. Urine outflow increased threefold 11 weeks after Cd exposure began, while urinary protein and Cd excretion increased beginning at Week 9. These data indicate the liver is a major target organ of chronic Cd poisoning, and suggest that Cd-induced hepatic injury, via release of Cd-MT, may play an important role in the nephrotoxicity observed in response to long-term exposure to Cd.     

Pharmacokinetics/pharmacodynamics (PK/PD) modeling of risks of kidney toxicity from exposure to cadmium: estimates of dietary risks in the U.S. population

An analysis of epidemiological studies of associations between exposure to cadmium and kidney toxicity was conducted. Dose-response functions relating low-molecular-weight (LMW) proteinuria to various indices of cadmium dose (dietary cadmium intake, urinary cadmium excretion, or tissue cadmium burden) were obtained from 15 studies of diverse exposures (occupational, general environmental, environmental contamination). Estimates of the dose corresponding to probabilities of LMW proteinuria of 0.1, 0.15, or 0.2 were transformed from the reported dose units into corresponding estimates of target organ dose (microgram Cd/g renal cortex, RC) by simulation using a pharmacokinetics (PK) model. The median RC associated with a 0.1 probability (RC10M) of LMW proteinuria was predicted to be 153 micrograms Cd/g cortex (95% confidence interval [CI]: 84-263). The lower confidence limit on the RC10M (RC10L, 84 micrograms/g cortex) was predicted to be attained with a constant chronic intake of 1 microgram/kg/d in females or 2.2 micrograms/kg/d in males. The RC10L was 2.5-5 times higher than the median RCs predicted to result from dietary cadmium intake in U.S. nonsmokers (microgram Cd/g cortex: 33, females; 17, males) and 1.6-3 times higher than the corresponding 95th percentile RCs (53, females; 27, males). Additional exposure from smoking cigarettes (approximately 20 cigarettes/d, 3 micrograms Cd inhaled/d) was predicted to increase the median RC (microgram/g cortex) by approximately 45-70% (48, females; 29, males); however, predicted 95th percentile RCs for smokers (66, females; 38, males) were lower than the RC10L. These results indicate that, for most of the U.S. population, dietary-derived risks are likely to be negligible, in the absence of exposures from other sources.     

Sex differences in blood genotoxic and cytotoxic effects as a consequence of vanadium inhalation: micronucleus assay evaluation

ABSTRACT: Vanadium is an environmental pollutant attached to the smallest air suspended particles that enters into the respiratory tract reaching the systemic circulation. The oxidative state of this element and sex are factors related to its toxicity. In this study, we explored sex‐associated genotoxic and cytotoxic differences in a mouse experimental model. Mice inhaled V₂O₅ (0.02 M) 2 h/twice a week; blood samples were obtained at 24 h and every week until the end of the 4‐week exposure. Samples were processed for fluorochrome‐mediated viability and a micronucleus assay in slides pre‐covered with acridine orange (AO). The results showed that males were more susceptible to genotoxicity during the exposure in contrast to the females. In peripheral blood leukocytes, no cytotoxic differences were observed in both, females or males, but the decrease in circulating reticulocytes provides evidence of the metal's cytotoxic effect on the bone marrow (BM). A significant decrease in reticulocytes was observed during the experiment independent of the animal's sex. The present findings might be explained by the interaction of the metal with the enzymes that control erythropoiesis or a direct effect on erythropoietin production might explain our findings; however, an absence of the genotoxic effects in females could be a consequence of the protective effect against oxidative stress by their higher estrogen levels. This study contributes to a better understanding of the mechanisms by which vanadium induces adverse effects in biological systems. Copyright © 2013 John Wiley & Sons, Ltd.     

Correlation between environmental low-dose cadmium exposure and early kidney damage: A comparative study in an industrial zone vs. a living quarter in Shanghai,China

To investigate heavy metal exposure in an industrial zone vs. a living quarter in Shanghai and explore the relationship between the heavy metal source and urine cadmium (Cd) and early kidney damage. Blood lead and urine Cd, manganese (Mn), mercury (Hg), arsenic (As) and EKD indexes were compared between residents in Exposure group (n = 168) and Control group (n = 168). It was found that PM_2.5 level in Exposure group was significantly higher than that in Control group, and serum Cys-C and urine Cd, NAG, mAlb, KIM-1 and Cd-MT levels in Exposure group were also significantly higher than those in Control group, suggesting that differences in urine Cd and heavy metal levels between the residents of the two groups may be due to different PM_2.5 concentrations in the environments of the two areas. Cd accumulation within the human body can induce kidney damage, probably through its potential hazard to the proximal tubular epithelial cells.     

Metallothionein excretion in urine upon cadmium exposure: Its relationship with liver and kidney cadmium

The relationships between quantities of accumulated cadmium in the liver and kidney and those of metallothionein in urine was studied in occupationally exposed workers and experimentally exposed rats. Cadmium-exposed workers who had been employed at a cadmium production plant for periods of 8–29 years had significantly higher levels of cadmium in both liver and kidney and excreted significantly larger amounts of metallothionein in urine when compared with workers who had been employed for less than 1 year, with office workers at the plant or with control subjects having no known occupational exposure to cadmium. The excretion of metallothionein in urine of the cadmium-exposed workers appeared to be related to the levels of cadmium in both liver and kidney. A similar dose-effect relationship was also observed among rats given repeated subcutaneous injections of 5 μmol CdCl₂/kg. However, in the rats the metallothionein excretion increased markedly when the liver and renal cortex Cd levels exceeded approximately 300 μg/g and 200 μg/g, respectively. It appears that urinary metallothionein may be a useful biological indicator of liver and kidney cadmium levels.     

Induction and binding of Cd, Cu, and Zn to metallothionein in carp (Cyprinus carpio) using HPLC-ICP-TOFMS.

The binding of Cd, Cu, and Zn to metallothionein in carp was studied under control and acute Cd exposure scenarios. Carp were exposed to different Cd concentrations for 96 h. Total (Cu, Cd, Zn)-MT levels were determined by the cadmium thiomolybdate saturation assay. Total tissue and cytosolic Cd, Cu, and Zn concentrations were determined by ICP-MS. The cytosolic metal speciation was determined by high pressure liquid chromatography (size-exclusion [SE] in combination with anion exchange [AE]) directly coupled to an inductively coupled plasma time of flight mass spectrometer (ICP-TOFMS). This coupled technique allows the chromatographic separation and online determination of the metals associated to the protein fractions separated. Very strong differences in the tissue compartmentalization and cytosolic speciation of the metals were observed. For example, over 30% of cytosolic zinc was bound to MT in liver while this was only 2% in the kidneys although total cytosolic levels were considerably higher. Induction of metallothionein during cadmium exposure was also tissue specific, displaying different response patterns in gills, liver, and kidney. Cadmium accumulated much stronger in liver and kidney compared to the gills and the latter also showed much lower MT levels. The renal MT-induction was more sensitive to Cd exposure than the hepatic MT induction since a significant increase of Cd-MT and total MT levels occurred at lower tissue Cd concentrations in the kidney in comparison to the liver, except for the highest Cd exposure level where a drastic 10-fold increase in hepatic Cd-MT was observed. At this Cd exposure level also an apparent spill over of zinc to the high molecular weight fraction was observed in the kidneys.     

Co‐exposure to aluminum and acrylamide disturbs expression of metallothionein,proinflammatory cytokines and induces genotoxicity: Biochemical and histopathological changes in the kidney of adult rats

The individual toxic effects of aluminum and acrylamide are known but there is no data on their combined effects. The present study investigates the toxic effects after combined exposure to these toxicants on: (i) oxidative stress during combined chronic exposure to aluminum and acrylamide on kidney function (ii) correlation of oxidative stress with metallothionein (MT) and inflammatory cytokines expression, DNA damage, and histopathological changes. Rats were exposed to aluminum (50 mg/kg body weight) in drinking water and acrylamide (20 mg/kg body weight) by gavage either individually or in combination for 3 weeks. Exposure rats to aluminum chloride or acrylamide alone and in combination induced nephrotoxicity, as evidenced by a decrease in the 24‐h urine volume and uric acid levels in plasma and an increase of plasma creatinine, urea, and blood urea nitrogen levels. Nephrotoxicity was objectified by a significant increase in malondialdehyde level, advanced oxidation protein, and protein carbonyl contents, whereas reduced glutathione, nonprotein thiol, vitamin C levels, catalase, and glutathione peroxidase activities showed a significant decline. Superoxide dismutase activity and its gene expression were increased. Aluminum and acrylamide co‐exposure exhibited synergism in various biochemical variables and also in DNA damage. Kidney total MT levels and genes expression of MT1, MT2, and proinflammatory cytokines were increased. All these changes were supported by histopathological observations. Co‐exposure to aluminum and acrylamide exhibited synergism and more pronounced toxic effects compared with their individual effects based on various biochemical variables, genotoxic, and histopathological changes. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1044–1058, 2016.