Aleksandra Buha

Insight into the oxidative stress induced by lead and/or cadmium in blood, liver and kidneys.

Besides being important occupational hazards, lead and cadmium are nowadays metals of great environmental concern. Both metals, without any physiological functions, can induce serious adverse health effects in various organs and tissues. Although Pb and Cd are non-redox metals, one of the important mechanisms underlying their toxicity is oxidative stress induction as a result of the generation of reactive species and/or depletion of the antioxidant defense system. Considering that the co-exposure to both metals is a much more realistic scenario, the effects of these metals on oxidative status when simultaneously present in the organism have become one of the contemporary issues in toxicology. This paper reviews short and long term studies conducted on Pb or Cd-induced oxidative stress in blood, liver and kidneys as the most prominent target organs of the toxicity of these metals and proposes the possible molecular mechanisms of the observed effects. The review is also focused on the results obtained for the effects of the combined treatment with Pb and Cd on oxidative status in target organs and on the mechanisms of their possible interactions.

Cadmium Toxicity Revisited: Focus on Oxidative Stress Induction and Interactions with Zinc and Magnesium

Cadmium Toxicity Revisited: Focus on Oxidative Stress Induction and Interactions with Zinc and Magnesium Discovered in late 1817, cadmium is currently one of the most important occupational and environmental pollutants. It is associated with renal, neurological, skeletal and other toxic effects, including reproductive toxicity, genotoxicity, and carcinogenicity. There is still much to find out about its mechanisms of action, biomarkers of critical effects, and ways to reduce health risks. At present, there is no clinically efficient agent to treat cadmium poisoning due to predominantly intracellular location of cadmium ions. This article gives a brief review of cadmium-induced oxidative stress and its interactions with essential elements zinc and magnesium as relevant mechanisms of cadmium toxicity. It draws on available literature data and our own results, which indicate that dietary supplementation of either essential element has beneficial effect under condition of cadmium exposure. We have also tackled the reasons why magnesium addition prevails over zinc and discussed the protective role of magnesium during cadmium exposure. These findings could help to solve the problem of prophylaxis and therapy of increased cadmium body burden. Još o toksičnosti kadmija - s posebnim osvrtom na nastanak oksidacijskoga stresa i na interakcije s cinkom i magnezijem Iako je otkriven tek 1817. godine, kadmij je trenutačno jedan od najvažnijih onečišćivača životne i radne sredine. Štetno djeluje na bubrege, živčani sustav, kosti, reproduktivni sistem, a ima i genotoksične i karcinogene efekte. Nužna su dalja istraživanja vezana za mehanizme njegove toksičnosti, biomarkere efekata, kao i načine smanjenja rizika za zdravlje. Osim toga, do danas nije otkriven agens efikasan u terapiji trovanja kadmijem s obzirom na to da je kadmij intracelularni kation. U ovom radu dan je sažet pregled važnih mehanizama toksičnosti kadmija, kao što su nastanak oksidativnog stresa i interakcije s esencijalnim elementima, cinkom i magnezijem, na osnovi dostupnih literaturnih podataka, kao i naših ispitivanja koja upućuju na to da povećani unos navedenih esencijalnih elemenata pokazuje pozitivne efekte pri ekspoziciji kadmiju. Obrazložena je prednost suplementacije magnezijem pred suplementacijom cinkom i razmatrana preventivna uloga magnezija pri intoksikaciji kadmijem. Ovi su rezultati doprinos rješavanju problema profilakse i terapije trovanja kadmijem.

The impact of prolonged cadmium exposure and co-exposure with polychlorinated biphenyls on thyroid function in rats.

Endocrine-disrupting chemicals currently represent one of the major concerns and this study was aimed to investigate the effects of different doses of cadmium, widespread toxic metal, on the levels of thyroid hormones and to calculate Benchmark doses for these effects. Furthermore, the effects of co-exposure to cadmium and polychlorinated biphenyls on thyroid function were investigated. Six orally-treated groups of rats were receiving 0.3, 0.6, 1.25, 2.5, 5 and 10mgCd/kgb.w./day, five groups were orally treated with 0.5, 1, 2, 4 and 8mgPCBs/kgb.w./day, while nine groups of rats were orally-treated with different dose combinations of Cd and PCBs (0.6, 1.25 and 2.5mgCd/kgb.w. and 2, 4 and 8mgPCBs/kgb.w./day), during 28 days. Thyroid hormones were adversely affected by cadmium, with most prominent effect observed on triiodothyroxine levels indicating Cd interference with thyroid function at extrathyroidal level. Calculated Benchmark doses for Cd effects on thyroid hormones indicate triiodothyroxine as the most sensitive one that can be used as a basis for risk assessment. This study also implicates possible synergistic effects of Cd and PCBs on thyroid function as a consequence of their interference at different levels of thyroid homeostasis.

Route-dependent effects of cadmium/cadmium and magnesium acute treatment on parameters of oxidative stress in rat liver

The study was designed to evaluate and compare the effects of single oral (or) and intraperitoneal (i.p.) cadmium (Cd) administration on parameters of oxidative stress in liver of rats. Furthermore, investigation on protective effects of magnesium (Mg) or and i.p. pretreatment on the same parameters was performed. Wistar rats were administrated oral dose of Cd (30 mg Cd/kg b.w.)/Cd+Mg (30 mg Cd/kg b.w., 50 mg Mg/kg b.w.) or i.p. dose of Cd (1.5 mg Cd/kg b.w.)/Cd+Mg (1.5 mg Cd/kg b.w., 3 mg Mg/kg b.w.) and sacrificed after 24 h. In liver homogenates superoxide anion, malondialdehyde, non-protein sulfhydryl groups, total sulfhydryl groups content, and superoxide dismutase activity were determined. Cadmium intoxication caused the increase of superoxide anion and malondialdehyde levels and had negative effect on investigated parameters of antioxidant defense system, except on total sulfhydryl groups. The negative effect was more emphasized after i.p. Cd administration. Oral Mg pretreatment induced more pronounced positive effect than Mg given intraperitoneally that can be attributed, at least partly, to Cd and Mg interactions on the level of GIT. On the basis of the obtained results it can be concluded that both Cd and Cd+Mg effects on parameters of oxidative stress in rats liver are route-dependent.

Effects of oral and intraperitoneal magnesium treatment against cadmium-induced oxidative stress in plasma of rats.

Cadmium (Cd) has been recognised as one of the most important environmental and industrial pollutants, and up-to-date investigations have shown that one of the mechanisms of its toxicity is associated with the induction of oxidative stress. The aim of this study was to determine the connection between acute oral and intraperitoneal exposure to Cd and parameters indicative of oxidative stress in the plasma of rats, as well as to examine the potential protective effect of magnesium (Mg) in conditions of acute oral and intraperitoneal Cd poisoning. The experiment was performed on male albino Wistar rats (n=40) randomly divided into control group, Cdor group that received 30 mg kg-1 b.w. Cd by oral gavage, Cd+Mgor group that orally received 50 mg kg-1 b.w. Mg one hour before oral Cd, Cdip group that received 1.5 mg kg-1 b.w. Cd intraperitoneally, and Cd+Mgip group that intraperitoneally received 3 mg kg-1 b.w. Mg 10 min before intraperitoneal Cd. The animals were sacrifi ced 24 h after treatment and the following parameters were measured: superoxidedismutase activity, superoxide anion, total oxidative status, advanced oxidation protein products, and malondialdehyde. All parameters of oxidative stress in rat plasma were negatively affected by Cd treatment with more pronounced negative effects after intraperitoneal treatment, with the exception of superoxide dismutase (SOD) activity. Although both oral and intraperitoneal Mg pretreatment had protective effects, more pronounced benefi cial effects were observed after oral administration, since it managed to completely prevent Cd-induced changes in the investigated parameters. The observed results support the use of Mg as potential protective agent against toxic effects caused by Cd.

Nonlinear responses to waterborne cadmium exposure in zebrafish. An in vivo study

Abstract Cadmium (Cd) has proved to be associated with numerous toxic effects in aquatic organisms via waterborne exposure. With a view to investigate Cd toxicity along a broad spectrum of exposures reaching from environmental to toxic, we employed adult zebrafish (Danio rerio) for an in vivo study. A number of 10 fish per tank were placed in 40 L tanks and were exposed for 30 days to 0.0, 5.0, 25, 50, 75, 100 and 1000 &mgr;g Cd per liter. There were 2 tanks for each Cd exposure (duplicate experiment). Mortality was recorded daily, dead fish were collected and tissue samples were obtained for histologic observation, whereas remaining tissues were stored for Cd burden determination. Surviving fish were collected at the end of the experiment. Median overall survival (OS) in days was found to be 9.0, 11.0, 8.0 and 7.0 for 25 &mgr;g/L, 50 &mgr;g/L, 75 &mgr;g/L and 100 &mgr;g/L respectively, with all of them showing mortality greater than 50%. Remarkably, fish exposed to the highest Cd concentration (1000 &mgr;g/L) survived the longest exhibiting a mean OS of 29.2 days. Cd determination in fish tissue was conducted with an in house ICP‐MS method and levels ranged from 3.1 to 29.1 ng/mg. Log Cd tissue levels were significantly correlated with the log Cd exposure levels (r = 0.535, p < 0.001). The highest Cd burden was determined for fish exposed to 1000 &mgr;g Cd /L (mean = 12.2 ng/mg). Histopathology supported these results. Our findings disclose a deviation in toxic responses through the range of Cd concentrations, leading to nonlinear responses. These differentiated responses, could be linked to hormesis phenomena. Graphical abstract Figure. No Caption available. HighlightsTissue Cd accumulation is dose dependent but not time dependent.Fish exposed to the highest administered exposure survived the longest.Histopathological findings support nonlinear responses.Unanticipated mortality and histopathology responses in zebrafish could be associated to hormesis phenomena.High dose exposure resulting in less adverse effects is attributed to mechanisms stimulated at low doses.

Polychlorinated biphenyls as oxidative stress inducers in liver of subacutely exposed rats: implication for dose-dependence toxicity and benchmark dose concept.

Hepatotoxicity is one of the well-documented adverse health effects of polychlorinated biphenyls (PCBs)-persistent organic pollutants widely present in the environment. Although previous studies suggest possible role of oxidative stress, the precise mechanisms of PCB-induced ROS production in liver still remain to be fully assessed. The aim of this study was to evaluate the effects of different doses of PCBs on the parameters of oxidative stress and to investigate whether these effects are dose dependent. Furthermore, a comparison between calculated benchmark doses (BMD) and estimated NOAEL values for investigated parameters, was made. Six groups of male albino Wistar rats (7 animals per group) were receiving Aroclor 1254 dissolved in corn oil in the doses of 0.5, 1, 2, 4, 8, 16 mg PCBs/kg b.w./day by oral gavage during 28 days while control animals were receiving corn oil only. The following parameters of oxidative stress were analyzed in liver homogenates: superoxide dismutase activity, glutathione, malondialdehyde (MDA) and total protein thiol levels. Hepatic enzymes AST, ALT, ALP and protein albumin were also determined in serum as clinical parameters of liver function. Collected data on the investigated parameters were analyzed by the BMD method. The results of this study demonstrate that subacute exposure to PCBs causes induction of oxidative stress in liver with dose-dependent changes of the investigated parameters, although more pronounced adverse effects were observed on enzymatic than on non-enzymatic components of antioxidant protection. The obtained values for BMD and NOAEL support the use of BMD concept in the prediction of health risks associated with PCBs exposure. Furthermore, our results implicate possible use of MDA in PCBs risk assessment, since MDA was the most sensitive investigated parameter with calculated low critical effect dose of 0.07 mg/kg b.w.

Effect of Magnesium Supplementation on the Distribution Patterns of Zinc, Copper, and Magnesium in Rabbits Exposed to Prolonged Cadmium Intoxication

The present study is designed to investigate whether magnesium (Mg) supplementation may prevent Cd-induced alterations in zinc (Zn), copper (Cu), and magnesium (Mg) status in rabbits. For this purpose, the concentrations of Zn, Cu, and Mg were estimated in blood, urine, and organs (brain, heart, lungs, liver, kidney, spleen, pancreas, skeletal muscle, and bone) of rabbits given Cd (10 mg/kg b.w.) and rabbits cotreated with Mg (40 mg/kg b.w.) orally, as aqueous solutions of Cd chloride and Mg acetate every day for 4 weeks. Samples were mineralized with conc. HNO3 and HClO4 (4:1) and metals concentrations were determined by atomic absorption spectrophotometry (AAS). Magnesium supplementation succeeded to overcome Cd-induced disbalance of investigated bioelements. Beneficial effects of Mg were observed on Zn levels in blood and urine, on Cu levels in urine, and on Mg levels in blood. Magnesium pretreatment also managed to counteract or reduce all Cd-induced changes in levels of Cu and Mg in organs, while it did not exert this effect on Zn levels. These findings suggest that enhanced dietary Mg intake during Cd exposure can have at least partly beneficial effect on Cd-induced alterations in homeostasis of zinc, copper, and magnesium.

Interactions between cadmium and decabrominated diphenyl ether on blood cells count in rats—Multiple factorial regression analysis

The objective of this study was to assess toxicity of Cd and BDE-209 mixture on haematological parameters in subacutely exposed rats and to determine the presence and type of interactions between these two chemicals using multiple factorial regression analysis. Furthermore, for the assessment of interaction type, an isobologram based methodology was applied and compared with multiple factorial regression analysis. Chemicals were given by oral gavage to the male Wistar rats weighing 200-240g for 28days. Animals were divided in 16 groups (8/group): control vehiculum group, three groups of rats were treated with 2.5, 7.5 or 15mg Cd/kg/day. These doses were chosen on the bases of literature data and reflect relatively high Cd environmental exposure, three groups of rats were treated with 1000, 2000 or 4000mg BDE-209/kg/bw/day, doses proved to induce toxic effects in rats. Furthermore, nine groups of animals were treated with different mixtures of Cd and BDE-209 containing doses of Cd and BDE-209 stated above. Blood samples were taken at the end of experiment and red blood cells, white blood cells and platelets counts were determined. For interaction assessment multiple factorial regression analysis and fitted isobologram approach were used. In this study, we focused on multiple factorial regression analysis as a method for interaction assessment. We also investigated the interactions between Cd and BDE-209 by the derived model for the description of the obtained fitted isobologram curves. Current study indicated that co-exposure to Cd and BDE-209 can result in significant decrease in RBC count, increase in WBC count and decrease in PLT count, when compared with controls. Multiple factorial regression analysis used for the assessment of interactions type between Cd and BDE-209 indicated synergism for the effect on RBC count and no interactions i.e. additivity for the effects on WBC and PLT counts. On the other hand, isobologram based approach showed slight antagonism for the effects on RBC and WBC while no interactions were proved for the joint effect on PLT count. These results confirm that the assessment of interactions between chemicals in the mixture greatly depends on the concept or method used for this evaluation.

Cadmium Exposure as a Putative Risk Factor for the Development of Pancreatic Cancer: Three Different Lines of Evidence

Although profoundly studied, etiology of pancreatic cancer (PC) is still rather scant. Exposure to cadmium (Cd), a ubiquitous metal associated with well-established toxic and carcinogenic properties, has been hypothesized to one putative cause of PC. Hence, we analyzed recently published observational studies, meta-analyses, and experimental animal and in vitro studies with the aim of summarizing the evidence of Cd involvement in PC development and describing the possible mechanisms. Consolidation of epidemiological data on PC and exposure to Cd indicated a significant association with an elevated risk of PC among general population exposed to Cd. Cadmium exposure of laboratory animals was showed to cause PC supporting the findings suggested by human studies. The concordance with human and animal studies is buttressed by in vitro studies, although in vitro data interpretation is problematic. In most instances, only significant effects are reported, and the concentrations of Cd are excessive, which would skew interpretation. Previous reports suggest that oxidative stress, apoptotic changes, and DNA cross-linking and hypermethylation are involved in Cd-mediated carcinogenesis. Undoubtedly, a significant amount of work is still needed to achieve a better understanding of the Cd involvement in pancreatic cancer which could facilitate prevention, diagnosis, and therapy of this fatal disease.