Zinc and cadmium specifically interfere with RNA-binding activity of human iron regulatory protein 1

The cellular pro-oxidative stress induced by high zinc concentrations or cadmium is most likely mediated by disruption of redox (mainly thiol) homeostasis or by mishandling of redox-active transition metals. The impact of zinc and cadmium on the main regulators of iron homeostasis in metazoans, the iron regulatory proteins (IRP) 1 and 2, has been probed with the human recombinant proteins. Using purified proteins or extracts of yeast producing human IRP, zinc and cadmium were shown to interfere with the IRE-binding activity of IRP1, but not with that of IRP2 or the aconitase activity of IRP1. The IRP1 active site cysteines in positions 437, 503 and 506 were not directly involved in the effects of zinc and cadmium. The loss of RNA-binding activity is due to the reversible and specific aggregation of the IRP1 apoprotein with zinc and cadmium, since precipitation did not occur with other divalent metals such as manganese, cobalt or magnesium. The reported data suggest a new mechanism for the biological toxicity of cadmium and high zinc concentrations by interference with iron metabolism.     

Effect of dietary calcium on cadmium absorption and retention in suckling rats

The effect of calcium supplementation on absorption and retention of cadmium in the suckling period was evaluated in Wistar rat pups of both sexes. Animals were maintained in the litters with the mother rats and supplemented with 1%, 3% or 6% calcium (as CaHPO₄×2H₂O) in cow's milk by artificial feeding from day of birth 6 through 14. All rats were exposed to cadmium (as CdCl₂×H₂O) either orally or parenterally. Oral cadmium dose of 0.5 mg/kg body weight a day was administered through nine-day period of calcium supplementation and parenteral cadmium dose was injected subcutaneously in a single dose of 0.5 mg Cd/kg body weight prior to calcium supplementation. On experimental day 10 (at the age of pups of 15 days) all animals were killed and the liver, kidneys, brain and carcass (body without organs and skin) were removed for element analyses. Cadmium and essential elements calcium, zinc and iron were analysed in the tissues by atomic absorption spectrometry. Results showed that after oral exposure cadmium concentrations in all calcium-supplemented groups were significantly decreased in the organs and carcass and that the effect was dose-related. No such effect of calcium was found after parenteral cadmium exposure. Calcium supplementation per se significantly increased calcium concentration in the carcass and had no effect on iron in organs and zinc in carcass. It was concluded that calcium supplementation during the suckling period could be an efficient way of reducing oral cadmium absorption and retention without affecting tissue essential trace element concentrations.     

Influence of dietary iron deficiency on acute metal intoxication

The influence of dietary iron deficiency on acute nickel, lead or cadmium toxicity as reflected by the induction of hepatic, renal and intestinal metallothionein (MT), disposition of the metals, and alterations in hematological parameters was investigated in rats. The administration of cadmium induced the hepatic, renal and intestinal MT while that of nickel or lead induced hepatic MT only. However, dietary iron deficiency did not influence the cadmium induced tissue MT but enhanced the ability of nickel or lead to restore the normal synthesis of renal and intestinal MT lowered under the influence of reduced body iron status. The accumulation of lead in liver and kidney and that of cadmium enhanced in liver only, while tissue deposition of nickel remained unaffected by iron deficiency. The induction of hepatic MT by three metals appears related to the concomitant rise in the hepatic zinc, calcium and iron levels in normal rats. However, dietary iron deficiency increased the hepatic zinc in response to nickel or cadmium and that of heptic calcium in response to lead.     

The effects of age and sex on seven elements of Sprague-Dawley rat organs

This study reports age-related changes in 7 element (iron, copper, zinc, manganese, mercury, cadmium and lead) concentrations in the liver, kidney and brain of male and female Sprague-Dawley rats from 1 to 364 days of age. Atomic absorption spectrometry was used for the measurements. Copper, mercury and cadmium in the male and female kidneys increased from weaning until 127 days of age, as did iron concentrations in the female liver and kidney. After 127 days, especially, the copper concentration in the female kidney and cadmium concentration in the male and female kidney increased further. Consistent and statistically significant (P less than 0.05) sex differences in element concentrations were found for three elements (iron, copper and zinc). Except for the zinc concentration in the liver from 50 to 72 days, iron (in liver and kidney), zinc (in kidney) and copper (in liver, kidney and brain) concentrations in female rats during the adult stage, were all higher than those of male rats. Isolated differences for other elements (manganese, mercury and cadmium) were also found. The data will be helpful when setting up long-term animal investigations of the biological effect of elements.     

Influence of zinc on lotic plants

SUMMARY. The toxicity of zinc to Hormidium rivulare Kütz. in laboratory culture media is decreased by rises in the levels of magnesium, calcium and phosphate, and increased by rises in pH and cadmium. The effects of all these are sufficiently marked that they may be expected to have considerable importance in the field. In contrast, assays with sodium, chloride and sulphate showed no detectable influence of these ions on zinc toxicity.
When applied at higher concentrations, calcium was always more effective than magnesium, but the reverse was sometimes true at lower concentrations. Both magnesium and phosphate were more effective in reducing zinc toxicity with zinc-tolerant populations than with zinc-sensitive ones. Cadmium was highly toxic, either alone or in combination with zinc; however, calcium had a proportionately greater effect in reducing cadmium toxicity than zinc toxicity. The toxic effects of zinc and cadmium were synergistic, and it seems probable that the presence of cadmium at levels of 0.01 mgl⁻¹ and above will usually lead to a significant increase in the toxicity of any zinc also present. Cadmium (in the absence of zinc) was 34 times more toxic than zinc to a zinc + cadmium sensitive population, and 15.5 times more toxic to a zinc + cadmium tolerant population. Because of the synergistic response, cadmium had an even greater effect in the presence of zinc.     

Effects of trace elements on membrane fluidity.

According to the Fluid Mosaic Model, a biological membrane is a two-dimensional fluid of oriented proteins and lipids. The lipid bilayer is the basic structure of all cell and organelle membranes. Cell membranes are dynamic, fluid structures, and most of their molecules are able to move in the plane of the membrane. Fluidity is the quality of ease of movement and represents the reciprocal value of membrane viscosity. Fluid properties of biological membranes are essential for numerous cell functions. Even slight changes in membrane fluidity may cause aberrant function and pathological processes. Several evidences suggest that trace elements, e.g., iron, copper, zinc, selenium, chromium, cadmium, mercury and lead may influence membrane fluidity. The interaction of heavy metals with cellular membranes may contribute to explain, at least partially, the toxicity associated with these metals.     

Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure

Recognizing the similarities between Huntington's disease (HD) pathophysiology and the neurotoxicology of various metals, we hypothesized that they may exhibit disease-toxicant interactions revealing cellular pathways underlying neurodegeneration. Here, we utilize metals and the ST Hdh mouse striatal cell line model of HD to perform a gene–environment interaction screen. We report that striatal cells expressing mutant Huntingtin exhibit elevated sensitivity to cadmium toxicity and resistance to manganese toxicity. This neuroprotective gene–environment interaction with manganese is highly specific, as it does not occur with iron, copper, zinc, cobalt, cadmium, lead, or nickel ions. Analysis of the Akt cell stress signaling pathway showed diminished activation with manganese exposure and elevated activation after cadmium exposure in the mutant cells. Direct examination of intracellular manganese levels found that mutant cells have a significant impairment in manganese accumulation. Furthermore, YAC128Q mice, a HD model, showed decreased total striatal manganese levels following manganese exposure relative to wild-type mice. Thus, this disease-toxicant interaction screen has revealed that expression of mutant Huntingtin results in heightened sensitivity to cadmium neurotoxicity and a selective impairment of manganese accumulation.     

Low iron diet and parenteral cadmium exposure in pregnant rats: the effects on trace elements and fetal viability

The effects of latent iron deficiency combined with parenteral subchronic or acute cadmium exposure during pregnancy on maternal and fetal tissue distribution of cadmium, iron and zinc, and on fetal viability were evaluated. Timed-pregnant Sprague-Dawley rats were fed on semisynthetic test diets with either high iron (240 mg kg) or low iron (10 mg kg), and concomitantly exposed to 0, 3 or 5 mg cadmium (as anhydrous CdCl₂) per kilogram body weight. Animals were exposed to cadmium from gestation day 1 through 19 by subcutaneously implanted mini pumps (Subchronic exposure) or on gestation day 15 by a single subcutaneous injection (Acute exposure). All rats were killed on gestation day 19. Blood samples, selected organs and fetuses were removed and prepared for element analyses by atomic absorption spectrometry. Low iron diet caused decreases in maternal body weight, maternal and fetal liver weights, placental weights and tissue iron concentrations. By cadmium exposure, both subchronic and acute, tissue cadmium concentrations were increased and the increase was dose-related, maternal liver and kidney zinc concentrations were increased, and fetal zinc concentration was decreased. Cadmium concentration in maternal liver was additionally increased by low iron diet. Acute cadmium exposure caused lower maternal body and organ weights, high fetal mortality, and decreased fetal weights of survivors. In conclusion, parenteral cadmium exposure during pregnancy causes perturbations in essential elements in maternal and fetal compartments. Acute cadmium exposure in the last trimester of gestation poses a risk for fetal viability especially when combined with low iron in maternal diet.     

Biotoxicity of lead: influence of various factors

Environmental sources of lead are multiple, and a number of factors influence their toxicity. However, with the exception of tetramethyl and tetraethyl lead, the particular compound of lead seems to have relatively little influence on toxicity compared with the particle size of the source and the route and frequency of exposure. Susceptibility to lead toxicity is greater among immature animals and very young children because of their higher levels of lead ingestion, greater absorption from the gastrointestinal tract, higher percent lead retention in tissues, and greater reactivity of organs, particularly the central nervous system. Marginal nutritional status also increases susceptibility to lead toxicity. Dietary factors influencing toxicity of lead include total calories, calcium, iron, zinc, fat, ascorbic acid, and protein. Although vitamin D, specifically the metabolite 1,25-dihydroxycholecalciferol, increases lead absorption in vitamin D-deficient animals, clinical studies have shown that lead-burdened children have reduced rather than elevated plasma 1,25-dihydroxycholecalciferol levels. Bioavailability of lead, as shown by tissue lead concentrations, is not always an adequate predictor of lead toxicity. For example, concurrent exposure to cadmium results in higher toxicity of lead to the hematopoietic system, but lowers tissue lead levels substantially. Low dietary calcium increases the total body burden of lead but disproportionately increases the deposition of lead in nonosseous tissues.     

Selenium interactions and toxicity: a review

Selenium is an essential trace element for mammals. Through selenoproteins, this mineral participates in various biological processes such as antioxidant defence, thyroid hormone production, and immune responses. Some reports indicate that a human organism deficient in selenium may be prone to certain diseases. Adverse health effects following selenium overexposure, although very rare, have been found in animals and people. Contrary to selenium, arsenic and cadmium are regarded as toxic elements. Both are environmental and industrial pollutants, and exposure to excessive amounts of arsenic or cadmium can pose a threat to many people’s health, especially those living in polluted regions. Two other elements, vanadium and chromium(III) in trace amounts are believed to play essential physiological functions in mammals. This review summarizes recent studies on selenium interactions with arsenic and cadmium and selenium interactions with vanadium and chromium in mammals. Human studies have demonstrated that selenium may reduce arsenic accumulation in the organism and protect against arsenic-related skin lesions. Selenium was found to antagonise the prooxidant and genotoxic effects of arsenic in rodents and cell cultures. Also, studies on selenium effects against oxidative stress induced by cadmium in various animal tissues produced promising results. Reports suggest that selenium protection against toxicity of arsenic and cadmium is mediated via sequestration of these elements into biologically inert conjugates. Selenium-dependent antioxidant enzymes probably play a secondary role in arsenic and cadmium detoxification. So far, few studies have evaluated selenium effects on chromium(III) and vanadium actions in mammals. Still, they show that selenium may interact with these minerals. Taken together, the recent findings regarding selenium interaction with other elements extend our understanding of selenium biological functions and highlight selenium as a potential countermeasure against toxicity induced by arsenic and cadmium.     

Manganese is highly effective in protecting cells from cadmium intoxication

Cadmium poisoning results in cell death. Although several intracellular pathways have been identified in this response, transport systems responsible for cadmium entry into cells remain poorly understood and controversial. Here, we analyzed the effects of several divalent cations on cadmium toxicity in different cell types. We found that zinc, previously reported as a protective agent against cadmium poisoning, is actually much less efficient than manganese. We show that manganese dramatically reduces cadmium intake, and that this is associated with the inhibition of our recently reported sustained activation of ERK, characteristic of cadmium intoxication. Finally, we show that this inhibition of cadmium entry and ERK-sustained activation perfectly correlates with a high cellular resistance to cadmium exposure. Our results, together with previously published data, support the idea that the yet to be characterized manganese transporter system(s) may be responsible for cadmium entry into cells.     

Cadmium-induced alterations in essential trace element homoeostasis in the tissues of scallop Mizuhopecten yessoensis

Studies were performed regarding the effect of cadmium accumulation on the levels of essential elements (copper, zinc and iron) in the tissues of a marine bivalve mollusc, Mizuhopecten yessoensis, exposed to cadmium at 250 ppb during 2 weeks. It was found that the concentration of cadmium in the tissues increased in the order gonads < gills < hepatopancreas < kidney during exposure time. However, the highest value of concentration factor was recorded in the gills. Our data demonstrate that cadmium accumulation in all mollusc tissues is followed by the alterations in copper, zinc and iron concentration, but that the pattern of these changes varies with each tissue. Cadmium had the most pronounced effects on essential trace element homoeostasis in the kidney. The present study suggests that levels of the essential metals in a particular tissue can be modified depending on the level of cadmium accumulation. The possible mechanisms of the effects of cadmium on the essential trace elements are discussed.     

Iron regulatory protein 1 is not an early target of cadmium toxicity in mice, but it is sensitive to cadmium stress in a human epithelial cell line

Disruption of iron homeostasis at the levels of intestinal absorption or erythropoiesis contributes to cadmium toxicity. Cellular iron homeostasis in metazoans is maintained by the iron regulatory proteins (IRPs) that regulate the synthesis of proteins involved in the transport, use, and storage of iron. The effect of cadmium intoxication on this regulatory system has been investigated in a cellular model of human epithelium. Cadmium exposure of HeLa cells did not activate the IRPs; rather, the amount of these proteins relative to that of housekeeping proteins decreased. Accordingly, the transferrin receptor mRNA level decreased upon cadmium insult. In a more integrated investigation, separate groups of mice had free access to different doses of cadmium in drinking water for 3 weeks. Cadmium accumulated in all analyzed organs, but its concentration in mouse tissues did not correlate with changes of the activity of the IRPs. The intoxicated mice did not show any sign of anemia, indicating that iron homeostasis was not immediately disrupted after the onset of cadmium accumulation. These data establish that cadmium destabilizes IRPs in mammalian cells, but that iron imbalance is not an early event of cadmium intoxication.     

Effects of cadmium administration on the endogenous metal balance in rats

The concentrations of cadmium and other metal ions in selected organs, urine, and blood of female rats were measured after exposure to cadmium chloride through their diet or by oral or intravenous administration. The hematological and urinary variations were followed for 4 wk. Body weight gain and the weights of livers and kidneys from all treated groups were not significantly different from the controls. No gross morphological changes were observed in any of the tissues studied at necropsy. The accumulation of cadmium occurred in the liver and kidney. The zinc levels in these organs were elevated relative to controls, in all treated groups regardless of dose and exposure route. Copper was elevated in the liver, kidney, bone, and blood of animals subject to intravenous administration of cadmium. Hepatic iron was decreased in the dietary and orally treated groups, but was not affected in the intravenous study group. The level of magnesium in kidney was increased for all exposure routes, but that of liver was increased only in the intravenously injected groups. The changes in the concentrations of sodium, potassium, calcium, and phosphorus did not follow a specific pattern and varied from organ to organ, depending on the exposure route. The discussion includes a relationship between tissue injury and the alteration of tissue essential element concentrations.     

Trace element nutrition of infants--molecular approaches.

Newborn infants are exposed to widely varying intakes of trace elements, but little is known about their ability to homeostatically adjust to these intakes. Recent discoveries of several metal ion transporters in the small intestine are likely to enhance our understanding of molecular mechanisms regulating trace element absorption. Iron absorption is regulated by divalent metal ion transporter 1 (DMT1) and ferroportin 1 (FPN1). Studies on human infants have shown that young infants cannot regulate iron absorption, whereas older infants can. Our studies on infant rat pups show that there is no regulation of DMT1 and FPN1 at young age, but that this develops at older age. These findings may explain adverse effects of iron supplementation on growth in young human infants. Zinc absorption in the small intestine is regulated by the transporters ZnT1, ZnT2, ZnT4 and Zip-4 and zinc status affects the expression of these transporters in an attempt to achieve zinc homeostasis. Copper absorption is regulated by the transporters Ctrl, Atp7A and Atp7B, and exposure to copper at early age affects the expression and cellular localization of these proteins, affecting copper uptake and transport. To date, most studies on homeostatic regulation of trace mineral absorption have been done in cell systems and animal models; further studies on human infants are needed. The consequences of trace element interactions during infancy also need to be investigated in more detail.     

Detection of sulfur-containing compounds in control and cadmium-exposed rat organs by high-performance liquid chromatography--vacuum-ultraviolet inductively coupled plasma-atomic emission spectrometry (HPLC-ICP)

Sulfur-containing compounds in biological samples were separated by high-performance gel permeation chromatography and detected with a vacuum-ultraviolet inductively coupled plasma-atomic emission spectrometer. Distribution profiles of sulfur in the supernatants of liver, kidney, spleen, lung, and pancreas of control and cadmium-exposed rats were determined along with cadmium, copper, iron, phosphorus, and zinc profiles. Changes in sulfur distribution were induced by cadmium exposure not only in the metallothionein fraction, but also in the high-molecular-weight protein fraction, indicating the effect of cadmium exposure on diverse endogenous sulfur-containing compounds. Glutathione and taurine also were detected simultaneously as distinct peaks.     

Zinc adaptation and resistance to cadmium toxicity in mammalian cells: molecular insight by proteomic analysis

To identify proteins involved in cellular adaptive responses to zinc, a comparative proteome analysis between a previously developed high zinc- and cadmium-resistant human epithelial cell line (high zinc-resistant HeLa cells, HZR) and the parental HeLa cells has been carried out. Differentially produced proteins included cochaperones, proteins associated with oxido-reductase activities, and ubiquitin. Biochemical pathways to which these proteins belong were probed for their involvement in the resistance of both cell lines against cadmium toxicity. Among ER stressors, thapsigargin sensitized HZR cells, but not HeLa cells, to cadmium toxicity more acutely than tunicamycin, implying that these cells heavily relied on proper intracellular calcium distribution. The similar sensitivity of both HeLa and HZR cells to inhibitors of the proteasome, such as MG-132 or lactacystin, excluded improved proteasome activity as a mechanism associated with zinc adaptation of HZR cells. The enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) was overproduced in HZR cells as compared to HeLa cells. It transforms HPP to homogentisate in the second step of tyrosine catabolism. Inhibition of HPPD decreased the resistance of HZR cells against cadmium, but not that of HeLa cells, suggesting that adaptation to zinc overload and increased HPP removal are linked in HZR cells.     

Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects

Copper, zinc and iron are essential metals for different physiological functions, even though their excess can lead to biological damage. This review provides a background of toxicity related to copper, iron and zinc excess, biological mechanisms of their homeostasis and their respective roles in the apoptotic process. The antioxidant action of metallothionein has been highlighted by summarizing the most important findings that confirm the role of zinc in cellular protection in relation to metallothionein expression and apoptotic processes. In particular, we show that a complex and efficient antioxidant system, the induction of metallothionein and the direct action of zinc have protective roles against oxidative damage and the resulting apoptosis induced by metals with redox proprieties. In addition, to emphasize the protective effects of Zn and Zn-MT in Cu and Fe-mediated oxidative stress-dependent apoptosis, some aspects of apoptotic cell death are shown. The most widely used cytochemical techniques also have been examined in order to critically evaluate the available data from a methodological point of view. The observations on the role of Zn and MT could potentially develop new applications for this metal and MT in biomedical research.     

Human TRPV5 and TRPV6: Key players in cadmium and zinc toxicity

TRPV5 and TRPV6 are two major calcium transport pathways in the human body maintaining calcium homeostasis. TRPV5 is mainly expressed in the distal convoluted and connecting tubule where it is the major, regulated pathway for calcium reabsorption. TRPV6 serves as an important calcium entry pathway in the duodenum and the placenta. Previously, we showed that human TRPV6 (hTRPV6) transports several heavy metals. In this study we tested whether human TRPV5 (hTRPV5) also transports cadmium and zinc, and whether hTRPV5 together with hTRPV6 are involved in cadmium and zinc toxicity. The hTRPV5 mRNA and protein were expressed in HEK293 cells transiently transfected with pTagRFP-C1-hTRPV5. The overexpression of the hTRPV5 protein at the plasma membrane was revealed by cell surface biotinylation and immunofluorescence techniques. We observed that both cadmium and zinc permeate hTRPV5 in ion imaging experiments using Fura-2 or Newport Green DCF. Our results were further confirmed using whole-cell patch clamp technique. Transient overexpression of hTRPV5 or hTRPV6 sensitized cells to cadmium and zinc. Toxicity curves of cadmium and zinc were also shifted in hTRPV6 expressing HEK293 cells clones. Our results suggest that TRPV5 and TRPV6 are crucial gates controlling cadmium and zinc levels in the human body especially under low calcium dietary conditions, when these channels are maximally upregulated.     

Dietary Exposure to Lead and Cadmium in Yugoslavia

Abstract

Lead exposure still represents a matter of health concern especially in Yugoslavia. To assess the exposure of normal urban population to lead and cadmium through food, a preliminary monitoring was performed on a small group of urban population. Lead, cadmium and some essential elements (calcium, zinc, iron, copper and manganese) were analysed in collected duplicate diet samples and compared to similar population in Sweden. We found that dietary exposure to lead and cadmium is similar to other countries although Yugoslav urban population is exposed to much higher concentrations of lead in air than in cities of developed countries, due to high lead in gasoline. However, daily intake of some essential elements was significantly lower.

Also populations living around lead smelters in various parts of Yugoslavia are still exposed to elevated environmental lead and cadmium levels. To assess the exposure of the population living in this area, a cumulative long-term exposure to lead was determined by measuring lead in deciduous teeth. Concentrations of lead and cadmium in vegetables, soil and meals from the same region were also analysed. Values obtained for lead and cadmium in food products grown in exposed and control area were found to be related to respective concentrations of these elements in soil as well as to the distance from the smelter. Meals prepared in this region show the same trend, revealing very high intake particularly of lead.

The influence of nutritional factors, i.e. dietary calcium on lead metabolism, was also studied. Blood lead concentration was determined in two groups of peasant women living in two regions with different dietary calcium intake. Lower blood lead values were found in the higher dietary calcium intake region.