High Doses Of Cadmium Research Articles

Important roles of heme-regulated eIF-2α kinase in cadmium-induced glycolysis under acute exposure.

Cadmium (Cd) is a well-known heavy metal pollutant that is a toxic threat to human health. Cadmium can induce anemia and is involved in metabolic disorders. Heme-regulated eIF2α kinase (HRI) is the main regulator of terminal erythropoiesis and is required to prevent anemia and toxicity in the liver and kidneys in response to various stresses including Cd exposure. However, the involvement of HRI in Cd-induced metabolic disorders remains unclear. In this study, we performed proteomics on plasma collected from wild-type and Hri knockout mice treated with or without 5 and 10 mg/kg Cd. In total, 382 proteins were identified and indicated that the number of proteins in wild-type (Wt) mice was 2.4-fold higher than that in Hri knockout mice after Cd exposure, indicating the requirement of HRI for Cd exposure responses. Proteins associated with glycolysis were the most upregulated after Cd exposure in Wt mice, while, the induction of glycolysis after Cd exposure was interrupted in Hri knockout mice, suggesting the involvement of HRI in Cd-induced glycolysis upon acute exposure. Our results will help identify potential targets involved in metabolic disorders following acute exposure to high doses of cadmium.

Cadmium exposure induces pyroptosis in testicular tissue by increasing oxidative stress and activating the AIM2 inflammasome pathway

High doses of cadmium (Cd) cause irreversible injury to the reproductive system, especially testicular tissue. Studies have shown that pyroptosis is involved in Cd-induced tissue damage, but whether pyroptosis is involved in damage to testicular tissue following Cd exposure remains unclear. To investigate the mechanism of pyroptosis in testicular injury induced by Cd exposure, we used 8-week-old male C57BL/6J mice subjected to consecutive 7 days of intraperitoneal injection of cadmium chloride (CdCl2) at concentrations of 0, 1.0 and 3.0 mg/kg. The results indicated that 3.0 mg/kg CdCl2 significantly decreased serum testosterone levels, sperm concentration and sperm motility, while increased LDH and IL-1β levels. Testicular HE staining indicated that Cd exposure damaged the interstitial cells and increased the atypical residual bodies. Fluorescence results indicated that 3.0 mg/kg CdCl2 increased ROS levels, DNA damage, and the number of TUNEL-positive seminiferous tubule cells in testicular tissue. Transcriptome analysis showed that Cd exposure mainly induced inflammatory and chemokine signaling pathways in testicular tissue, with upregulated mRNA levels of Aim2, and reduced mRNA levels of Nlrp3. Further analysis showed that 3.0 mg/kg CdCl2 increased the expression of testicular HO-1, SOD2, γH2AX and PARP-1, as well as the pyroptosis-related factors GSDMD, GSDME, Caspase-1, ASC and IL-1β. In conclusion, our results provide a possible mechanism by which Cd exposure activates the AIM2 pathway by increasing oxidative stress injury to induce pyroptosis in testicular tissue. This provides a new perspective on testicular damage caused by Cd exposure.

Molybdenum and cadmium co-induce oxidative stress and apoptosis through mitochondria-mediated pathway in duck renal tubular epithelial cells

High doses of molybdenum (Mo) and cadmium (Cd) cause adverse reactions on animals, but the joint toxic effects of Mo and Cd on duck renal tubular epithelial cells are not fully illustrated. To investigate the combined effects of Mo and Cd on oxidative stress and mitochondrial apoptosis in primary duck renal tubular epithelial cells, the cells were either treated with (NH4)6Mo7O24·4H2O (480, 960 μM Mo), 3CdSO4·8H2O (2.5, 5.0 μM Cd) or combination of Mo and Cd for 12 h, and then the joint cytotoxicity was evaluated. The results demonstrated that Mo or/and Cd exposure could induce release of intracellular lactate dehydrogenase, reactive oxygen species generation, acidification, increase levels of malondialdehyde and [Ca2+]i, decrease levels of glutathione, glutathione peroxidase, catalase, superoxide dismutase, total antioxidant capacity, Na+/K+-ATPase, Ca2+-ATPase, and mitochondrial membrane potential; upregulate mRNA levels of Caspase-3, Bak-1, Bax, and cytochrome C, inhibit Bcl-2 mRNA level, and induce cell apoptosis in a dose-dependent manner. Furthermore, the changes of these indicators in co-treated groups were more remarkable. The results indicated that exposure to Mo or/and Cd could induce oxidative stress and apoptosis via the mitochondrial pathway in duck renal tubular epithelial cells and the two metals may have a synergistic effect.

Citlivost vybran�ch polnohospod�rskych plod�n na olovo, kadmium a arz�n v skor�ch �t�di�ch individu�lneho v�vinu

This paper examines the influence of Pb+2, Cd+2 and As+3 on growth of roots in legumes (broad bean, soybean, pea) and cereals (barley, maize). Roots of germinating plants were exposed to two different levels of Pb+2 (300 and 500 mg*L-1), Cd+2 (100 and 300 mg*L-1) and As+3 (50 and 100 mg*L-1) during four day experiment. During this time, length of roots were daily measured. Toxicity of metal treatment on plant roots was calculated as phytotoxicity index (IP). In all cases, a moderate effect of lead treatment was observed (IP up to 56.67 %) while higher doses of cadmium and arsenic resulted in increase of IP above 50 %. In cases of barley and maize, the toxic effect of almost all test doses of the heavy metals was observed as soon as 24 hours after their application. Generally, a higher tolerance to tested metals showed roots of both bean cultivars (IP 16.27- 69.53 %), while the most sensitive reactions had roots of barley and soybean (IP > 50 %, excluding dose Pb 300).

A comparative ionomic approach focusing on cadmium effects in sunflowers (Helianthus annuus L.)

This work explores a comparative ionomic approach by evaluating sunflower growth under different cultivation conditions after adding ca. 50, 350 and 700mg of cadmium (as cadmium chloride) during the cultivation period. Treated and non-treated plants were also compared in terms of some monitored ions (63Cu+, 56Fe+, 31P16O+, 24Mg+, 55Mn+, 64Zn+) using ICP-MS. Besides necrosis, chlorosis was also detected in Cd-treated plants with the highest cadmium dose. Additionally, the uptake of cadmium produced an imbalance in copper and zinc sunflower homeostasis, as well as on other elements such as iron, phosphorus, magnesium and manganese considered essential for photosynthesis.

Combined effect of cadmium, lead, and UV rays on Bacillus cereus using comet assay and oxidative stress parameters

Exposure to environmental chemicals and oxidative stress particularly at low dose levels may produce additive or synergistic interactions not seen in single component exposure. Exposure to cadmium, lead, and ultraviolet rays occurs in many occupational settings, such as pigment and battery production, galvanization, and recycling of electric tools. However, little is known about interactions between heavy metals and ultraviolet rays. This study aimed to evaluate the interactions of ultraviolet rays of 254 nm (UV-B) with cadmium or lead on Bacillus cereus. B. cereus was treated with different concentrations of cadmium or lead followed by exposure to UV-B radiation as combined effect. Photoirradiation of B. cereus with UV-B with exposure to cadmium or lead results in DNA damage, cytotoxicity, depletion of glutathione, and formation of lipid peroxidation. UV-B rays alone enhanced glutathione production which was depleted with lead and high doses of cadmium. Lead alone does not increase DNA breaking. The mechanism behind these interactions might be repair inhibition of oxidative DNA damage, since a decrease in repair capacity will increase susceptibility to reactive oxygen species generated by cadmium or lead. Lipid peroxidation was increased with exposure to UV-B and cadmium or lead. DNA, glutathione, and lipid peroxidation can be used as biomarkers to identify possible environmental contamination in bacteria. One conclusion from this model is the existence of more than multiplicative effects for co-exposures of cadmium or lead and UV rays.

Interrelationships between cadmium, zinc and antioxidants in the liver of the rat exposed orally to relatively high doses of cadmium and zinc

Zinc (Zn) reduces cadmium (Cd)-induced toxicity in the liver although it increases Cd tissue burden in some conditions; hence, the present study is designed to study the relationships between Cd, Zn and antioxidants in the liver of rats exposed to Cd. Livers of male rats which received orally relatively high doses of Cd (200 mg Cd/L as Cd chloride or Cd (200 mg/L)+Zn (500 mg Zn as Zn chloride) during five weeks, were investigated. Cd induced an accumulation of Cd and Zn in parallel to depletion in important variables (GSH, GSH/GSSG, CuZn-SOD and GPx activities) and to elevation in others (Cd/Zn and GSSG). Cd, did not affect CuZn SOD/GPx, nor Mn-SOD in the liver. Cd accumulation, Cd/Zn, CuZn SOD activity and CuZn SOD/GPx, was increased remarkably under Zn action. Zn supply ameliorated GSH level and partially reversed the decrease in GSH/GSSG, but it did not ameliorate GPx activity. Analysis showed high correlations between Cd and the majority of the variables, while Zn was positively correlated with only GSSG. We suggest from our results that Zn has indirect ameliorative effects on Cd-induced toxicity in the liver and that the increase in Cd retention is probably the key mechanism modulating, in the case of relatively high doses of Cd, the antioxidant response during exposure to Cd and Zn.

Distribution of Heavy Metals in the Liver of Foetuses and Female Mice after Oral Administration during Pregnancy - a Histochemical Study

The aim of this work was to study the distribution of heavy metals and of subsequently developed morphological changes in the liver of female mice and their foetuses after oral administration of high doses of lead, mercury, and cadmium (0.03 mg of metal per mouse and day). Heavy metals were administered to pregnant female mice on days 9-20 of pregnancy. The animals were euthanised by cervical dislocation. Samples of mother and foetal liver were subsequently collected and processed by means of the common technique for light and electron microscopy. Histochemical reaction based on metal conversion into appropriate sulphide that conjugates with silver was used for detection of heavy metals. Deposits of heavy metals were found at the periphery of lobules of the central vein in the liver of female mice. On the contrary, in the liver of foetuses no predilection site for localisation of the reaction product could be identified. At the electron microscopy level, accumulation of heavy metals was connected as a rule with the occurrence of certain damage to some organelles. Deposits of the reaction product were located mainly in hepatocytes and Kupffer cells. Heavy metals were bound to the heterochromatin of cell nuclei, as well as to some cytoplasmic organelles, such as rough endoplasmic reticulum, mitochondria, ribosomes, and lysosomes. The presence of heavy metals was associated with obliteration of cisternae of the rough endoplasmic reticulum, separation of ribosomes, and destruction of lysosomes. Vacuolation of cell cytoplasm was also a frequent phenomenon. An interesting finding was the "contrasting" of structures containing nucleic acids. Accumulation of metals in the liver of pregnant mice and their foetuses observed in our study indicated that placental barrier does not protect the foetal organism against penetration of metals. Their higher accumulation in foetal compared to maternal liver can be explained by the intense metabolism of differentiating hepatocytes.

The effect of cadmium on brain cells in culture

Cadmium is a long-living heavy metal, abundantly present in the environment, which accumulates in the body. In this study, we investigated the effects of cadmium on the expression of molecular chaperones, and of certain cell-specific proteins, in a variety of brain cell types in culture, namely primary cultures of rat cortical neurons and astrocytes, a brain capillary endothelial cell line (RB4E.B cells), and pheochromocytoma cells (PC12), induced or not to differentiate by NGF treatment. The metal induces a dose-dependent increase of Hsp70 in all cell types. Responses to the metal are cell-specific in the case of Hsc70 and Hsp90: i) in astrocytes, as well as in PC12 cells, cadmium has no significant effect; ii) in endothelial cells, an increase of both proteins is clearly observable from 20 microM cadmium; iii) both Hsp90 and Hsc70 decrease in neurons treated with high doses of cadmium. Damage to the cytoskeleton in treated cells was also evident. Finally, we report that the metal at high doses induces a decrease of PIPPin (also known as CSD-C2), a putative RNA-binding protein highly expressed in neurons and probably involved in the regulation of histone replacement variant expression.

Growth Inhibition Occurs Independently of Cell Mortality in Tomato (Solanum lycopersicum) Exposed to High Cadmium Concentrations

In order to analyze the adaptation potential of tomato shoots to a sudden increase in Cd concentration, tomato plants (Solanum lycopersicum L. var. Ailsa Craig) were exposed under controlled environmental conditions to a high dose of this heavy metal (250 microM CdCl2) in nutrient solution for 7 and 14 d. Both root and shoot growth was completely inhibited but all plants remained alive until the end of the treatment. Cell viability remained unaffected but the activity of the mitochondrial alternative pathway was stimulated by Cd stress at the expense of the cytochrome pathway. Cadmium concentration was higher in roots than in shoots and a decrease in the rate of net Cd translocation was noticed during the second week of stress. Cadmium decreased both leaf conductance (g(l)) and chlorophyll concentration. However, the effect on net CO2 assimilation remained limited and soluble sugars accumulated in leaves. Photochemical efficiency of PSII (Fv/Fm) was not affected despite a decrease in the number of reaction centers and an inhibition of electron transfer to acceptors of PSII. It is concluded that tomato shoot may sustain short term exposure to high doses of cadmium despite growth inhibition. This property implies several physiological strategies linked to both avoidance and tolerance mechanisms.

Oxidative stress and DNA damage induced by cadmium in the human keratinocyte HaCaT cell line: Role of glutathione in the resistance to cadmium

Cadmium affects the cellular homeostasis and generates damage via complex mechanisms involving interactions with other metals and oxidative stress induction. In this work we used a human keratinocyte cell line (HaCaT) as a model to study the oxidative damage induced by cadmium to cellular macromolecules, its effect on the antioxidant systems and the role of glutathione in cell protection toward cadmium toxicity. The cells were incubated for 24 and 48 h with cadmium (3, 15, 50 and 100 μM). High doses of cadmium were required to induce a cytotoxicity: 100 μM lead to 30% mortality after 24 h and 50% after 48 h. The oxidation of lipids and proteins and the DNA damage, respectively, assessed by thiobarbituric acid reactants determination, thiol group measurement and comet assay, were observed for 50–100 μM cadmium. The cytotoxic effects were strongly correlated to the cellular cadmium content. The glutathione peroxidase and the catalase activities were decreased, while the glutathione reductase activity and the glutathione concentration were increased after cadmium treatment. The superoxide dismutases activities were unchanged. A depletion in glutathione prior to cadmium exposure increased the cytotoxic effects and provoked DNA damage. Our results suggested that the hydroxyl radical could be the major compound involved in the oxidative stress generated by cadmium and that glutathione could play a major role in the protection of HaCaT cells from cytotoxicity but mostly from DNA damage induced by cadmium.

Effets du cadmium sur le métabolisme des lipides de plantules de colza ( Brassica napus L.)

Treatment of rape seedlings with increasing CdCl 2 concentrations in the culture medium resulted in a cadmium accumulation within plant tissues, which increased with external metal dose; such accumulation was more important in roots than in leaves. Biomass production was severely inhibited, even at low cadmium concentration. In leaves, quantities of chloroplastic lipids, monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), sulfolipids (SL) and phosphatidylglycerol (PG) decreased sharply under metallic treatment. However, contents of extrachloroplastic lipids, mainly phosphatidylcholine (PC) and phosphatidylethanolamine (PE) increased significantly. In contrast to leaves, contents of root phospholipids decreased. Likewise, levels of tri-unsaturated fatty acids: linolenic (C18:3) and hexadecatrienoïc (C16:3) dropped in leaves of treated seedlings as compared to those of controls, suggesting that heavy metals induced an alteration in the fatty acid desaturation process or a stimulation of their peroxidation. Also, trans palmitoleic acid (C16:1-trans) level in PG decreased considerably. In roots, there was a slight decrease in C18:3 level, with a concomitant increase in the C18:2 percentage. Radioactive labelling of leaf lipids with (1- 14C) acetate allowed to show that fatty acid biosynthesis was noticeably altered at the highest cadmium dose used (50 μM). Biosynthesis of tri-unsaturated fatty acids was also inhibited which may explain the decline in non-labelled lipid contents. Results showed that metallic ion seems to affect selectively chloroplastic membranes due to an inhibition of polyunsaturated fatty acid biosynthesis. Moreover, a lipid peroxidation occurred in our case because of the spectacular increase of malondialdehyde (MDA) content observed in cadmium treated leaves. To cite this article: N. Ben Youssef et al., C. R. Biologies 328 (2005).

Differential expression of Cu/Zn superoxide dismutase mRNA during exposures to heavy metals in rockbream ( Oplegnathus fasciatus)

A full-length complementary DNA clone (789 bp) encoding Cu/Zn superoxide dismutase (Cu/Zn SOD) was isolated from the liver cDNA library of a marine fish, rockbream ( Oplegnathus fasciatus). The rockbream SOD cDNA contained a 462 bp open reading frame (ORF) encoding 154 amino acids. Deduced amino acid sequence of rockbream SOD shared relatively high identity with teleost (78–91%) and mammalian (64–70%) orthologues. The SOD transcripts were ubiquitously detected in all the tissues examined including brain, gill, intestine, kidney, liver, muscle, skin and spleen determined by RT-PCR and northern dot blot hybridization. Based on semi-quantitative RT-PCR, real-time PCR and/or scanning densitometry of RNA dot blot hybridization, the transcriptional level of SOD gene was differentially affected by various experimental exposures to heavy metals. Intraperitoneal injections (0, 1, 2, 5 or 10 mg CdCl 2 per kg body weight for 48 h) and immersion treatments (0, 25, 50 or 100 μM of cadmium, copper or zinc for 96 h) revealed that (1) the expression of SOD at mRNA level was generally dependent upon the exposure doses of heavy metals, (2) the stimulation of SOD transcripts was more apparent in liver than kidney and gill, and (3) that cadmium was more potent to induce the expression of SOD than copper and zinc. Immersion exposures using high (25 μM Cd) and low (2 or 5 μM) doses of cadmium for prolonged periods up to 14 (high dose) or 28 (low doses) days also showed that the levels of SOD transcripts were higher with longer durations and higher concentrations. Results from the present study indicate that assessment of transcriptional activity of fish SOD gene at mRNA level might be useful as a sensitive molecular biomarker system to address the oxidative stress caused by heavy metal pollutants in fish.

Caco‐2 Cells on Snapwell® Membranes and the Ussing Chamber System as a Model for Cadmium Transport In Vitro

The transport of cadmium across Caco‐2 monolayers in vertical alignment, in combination with the Ussing chamber technique, was investigated. The Caco‐2 cells were grown in Dulbecco's Modified Eagle Medium and the cells were seeded on six‐well Snapwell® polycarbonate inserts (Costar) at a density of 3 × 105 cells/cm2. Accumulation and transport studies were performed after 14 days, when the cells had formed a monolayer. Cells were evaluated for confluence by monitoring of transepithelial electric resistance (TEER) during the whole cell growth phase and by inspection with a confocal laser scanning microscope. Electrophysiological measurements were made on cell monolayers mounted in Ussing chambers. The tissue parameters potential difference (dP0), current (I C), and short‐circuit current (I SC), as well as TEER, were recorded. There was no significant influence of transport direction (apical–basolateral or basolateral–apical) on cadmium absorption. Exposure of Caco‐2 cells to different cadmium concentrations resulted in a reduction of cadmium accumulation in Caco‐2 cells from 38% (at 1 µM Cd) to 13% (at 10 µM Cd). At all cadmium concentrations (except 5 µM), the actual cadmium transport was approximately 5%. Time course of cadmium accumulation showed an initial rapid phase followed by a phase of slow cadmium accumulation. Transport from inner cell to receiving side took place at a constant speed. Exposure of Caco‐2 cells to high doses of cadmium (>100 µM) resulted in a reduced TEER. It can be concluded that a combination of Caco‐2 cell model and Ussing chamber system represents an appropriate model for simulation of cadmium absorption and probably for investigations of transport processes of other heavy metals.

Pronounced induction of testicular PGF2$alpha; and suppression of testosterone by cadmium?prevention by zinc

In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F2α (PGF2α) production, adult male Sprague–Dawley rats were exposed to CdCl2 by subcutaneous injections. Dose–response as well as temporal–response experiments were performed, and PGF2α levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 μmol/kg) caused a dramatic elevation of testicular PGF2α, which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF2α levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 μmol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF2α synthesis (22.3-fold) detected after exposure to 20 μmol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF2α levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF2α but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF2α production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.

Environmental exposure to cadmium at a level insufficient to induce renal tubular dysfunction does not affect bone density among female Japanese farmers

Some recent research suggests that environmental exposure to cadmium, even at low levels, may increase the risk of osteoporosis, and that the bone demineralization is not just a secondary effect of renal dysfunction induced by high doses of cadmium as previously reported. To investigate the effect of exposure to cadmium at a level insufficient to induce kidney damage on bone mineral density (BMD) and bone metabolism, we conducted health examinations on 1380 female farmers from five districts in Japan who consumed rice contaminated by low-to-moderate levels of cadmium. We collected peripheral blood and urine samples and medical and nutritional information, and measured forearm BMD. Analysis of the data for subjects grouped by urinary cadmium level and age-related menstrual status suggested that cadmium accelerates both the increase of urinary calcium excretion around the time of menopause and the subsequent decrease in bone density after menopause. However, multivariate analyses showed no significant contribution of cadmium to bone density or urinary calcium excretion, indicating that the results mentioned above were confounded by other factors. These results indicate that environmental exposure to cadmium at levels insufficient to induce renal dysfunction does not increase the risk of osteoporosis, strongly supporting the established explanation for bone injury induced by cadmium as a secondary effect.

Pronounced induction of testicular PGF(2 alpha) and suppression of testosterone by cadmium-prevention by zinc.

In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(2 alpha) (PGF(2 alpha)) production, adult male Sprague-Dawley rats were exposed to CdCl(2) by subcutaneous injections. Dose-response as well as temporal-response experiments were performed, and PGF(2 alpha) levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 micromol/kg) caused a dramatic elevation of testicular PGF(2 alpha), which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF(2 alpha) levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 micromol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF(2 alpha) synthesis (22.3-fold) detected after exposure to 20 micromol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF(2 alpha) levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF(2 alpha) but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF(2 alpha) production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.

Immunohistochemical and ultrastructural changes in the renal cortex of cadmium-treated rats.

The aim of this study was to determine the cadmium-induced immunohistochemical and morphological changes in the renal cortex of adult male rats exposed to high doses of cadmium for 30 d. Animals used as controls received a standard diet and water ad libitum. The animals used for this study received 15 ppm CdCl2 in their drinking water for 1 mo. The mean arterial pressure (MAP), the mean blood Cd level, and the mean tissue Cd content were significantly higher when compared to controls (p < 0.01). Immunohistochemical studies demonstrated a weak labeling to type IV collagen and laminin, but a strong labeling to fibronectin in the renal cortex of the Cd-treated animals when compared to controls. The ultrastructural alterations found in Cd-treated rats were a diminution in the amount of filtration slits, increased fusion of foot processes in epithelial cells of the glomeruli, increase of lysosomal structures and pinocytic vesicles as well as large mitochondria in proximal tubule cells, and degenerated cells in distal tubules. Additionally, the glomerular basement membrane was slightly thickened. In conclusion, cadmium toxicity results in alterations in the renal extracellular matrix and tubular or glomerular cells, which could play an important role in renal dysfunction.

Cadmium distribution and toxicity in tissues of small rodents.

The aim of the present paper is to discuss the accumulation and distribution of cadmium (Cd) in the various tissues of animals, the interactions of cadmium with other elements, and the damage to tissues caused by this metal. Cadmium is not physiologically or biochemically essential to an organism. It is absorbed via the gastrointestinal tract and lungs and accumulated in various tissues, mainly the kidneys and liver. The distribution of cadmium between various tissues depends on many endogenous and exogenous factors. Cadmium is bound to a low-molecular-weight protein, metallothionein (MT), and to high-molecular-weight proteins. This metal has a great affinity to thiol groups. Cadmium binds also to O- and N-containing ligands. The distribution of cadmium between organs differs markedly depending on the chemical form of administered Cd and the duration of exposure. Acute exposure results in a different distribution pattern throughout the body than does chronic exposure. Long-term exposure to high doses of cadmium may cause biochemical and functional changes in some critical organs. Cadmium can influence the absorption and distribution of essential elements and can replace them in enzymes. Metallothionein and glutathione play important roles in the transport of metals and in detoxification processes. Reported findings are mainly the results of experiments on laboratory animals. The lack of data concerning the localization of cadmium in various tissues of wild species is noticeable and there is a great need for such data.

Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate.

Cadmium is a known human carcinogen based on findings of lung cancer in exposed populations. A more controversial target site for cadmium is the human prostate gland, for which some studies indicate a link between cadmium exposure and cancer. Our work in various strains of Wistar rats has shown that cadmium can induce tumors in the ventral lobe of the prostate. The relevance of this type of lesion to human prostate cancer has been questioned because the ventral lobe of the rat prostate, unlike the dorsolateral lobe, has no embryological homolog in the human gland. In this study we investigated the chronic toxic and carcinogenic effects of cadmium in the Noble (NBL/Cr) rat, with particular attention to lesions of the prostate. Cadmium chloride (CdCl2) was given as a single sc injection (0, 1, 2, 4, 8, 16, or 32 micromol/kg) to groups (initially n = 30) of 10-week-old rats. Rats were observed for up to 72 weeks following exposure. In rats that were injected with the lower doses of cadmium (< or =4 micromol/kg), a clear dose-related increase in proliferative lesions of the dorsolateral prostate occurred (0 micromol/kg = 36% incidence, 1 micromol/kg = 62%, 2 micromol/kg = 65%; 4 micromol/kg = 79%; trend p < 0.003). Lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells, without stromal invasion. At higher doses (> or =8 micromol/kg) the proliferative-lesion response in the dorsolateral prostate gradually declined to near control levels (8 micromol/kg = 63%; 16 micromol/kg = 60%; 32 micromol/kg = 52%). The loss of prostatic response at the higher doses of cadmium was probably due to loss of testicular function secondary to cadmium treatment. This was reflected in a very high incidence (>90%) of lesions, indicative of testicular hypofunction, including tubular degeneration, mineralization, and interstitial (Leydig) cell tumors, at doses in excess of 16 micromol/kg. Malignant injection-site sarcomas occurred at the two highest doses of cadmium, while pituitary adenomas were elevated by cadmium exposure at the highest dose. These results show that cadmium induces proliferative lesions in the dorsolateral prostate of the Noble rat, a model having a presumed relevance to human prostate cancers.