Metal-induced neurotoxicity in a RAGE-expressing C. elegans model.

Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.

Zn Supplement-Antagonized Cadmium-Induced Cytotoxicity in Macrophages In Vitro: Involvement of Cadmium Bioaccumulation and Metallothioneins Regulation.

Cadmium (Cd) is a toxic metal leading to multiple forms of organ damage. Zinc (Zn) was reported as a potential antagonist against Cd toxicity. The present study investigates the antagonistic effect of Zn (20 µM) on Cd (20 or 50 µM) cytotoxicity in macrophages in vitro. The results shows that Cd exposure caused dose-dependent morphologic and ultrastructural alterations in RAW 264.7 macrophages. Zn supplement significantly inhibited Cd cytotoxicity in RAW 264.7 or HD-11 macrophages by mitigating cell apoptosis, excessive ROS output, and mitochondrial membrane depolarization. Notably, Zn supplement for 12 h remarkably prevented intracellular Cd2+ accumulation in 20 µM (95.99 ± 9.93 vs 29.64 ± 5.08 ng/106 cells; P = 0.0008) or 50 µM Cd (179.78 ± 28.66 vs 141.62 ± 22.15 ng/106 cells; P = 0.003) exposed RAW 264.7 cells. Further investigation found that Cd promoted metallothioneins (MTs) and metal regulatory transcription factor 1 (MTF-1) expression in RAW 264.7 macrophages. Twenty µM Zn supplement dramatically enhanced MTs and MTF-1 levels in Cd-exposed RAW 264.7 macrophages. Intracellular Zn2+ chelation or MTF-1 gene silencing inhibited MTs synthesis in Cd-exposed RAW 264.7 macrophages, which was accompanied by the declined expression of MTF-1, indicating that regulation of Zn on MTs was partially achieved by MTF-1 mobilization. In conclusion, this study demonstrates the antagonism of Zn against Cd cytotoxicity in macrophages and reveals its antagonistic mechanism by preventing Cd2+ bioaccumulation and promoting MTs expression.

Cadmium accumulation and metallothionein gene expression in the liver of swamp eel (Monopterus albus) collected from the Mae Sot District, Tak Province, Thailand.

Cadmium (Cd) is produced mainly as a by-product of zinc mining. In Thailand, the largest zinc mine is located in the Mae Sot district, Tak Province. Samples of Monopterus albus were collected from paddy fields in 4 sites, three downstream and one upstream from the zinc mine. The upstream site was considered to be uncontaminated while the three downstream sites were considered to be contaminated with Cd. Studies on the accumulation level of cadmium were conducted on the liver of the fish using the atomic absorption spectrophotometer technique. The metallothionein (MT) gene expression level in the liver, as a potential biomarker for long-term Cd exposure in their natural habitat, was also assessed. The level of hepatic MT gene expression was performed by quantitative real-time PCR. The result showed that Cd accumulation in the liver was much higher in swamp eels collected from the downstream sites when compared to those collected from the upstream site. The hepatic MT level in the upstream site was 0.75-fold, while the other three downstream sites were 0.36-, 4.44- and 0.94-fold. There is no parallel correlation between hepatic cadmium levels and hepatic MT gene expression. This study then suggests that MT gene expression biomarkers might be not suitable for swamp eels with prolonged exposure to Cd.

Epigenetics, obesity and early-life cadmium or lead exposure.

Obesity is a complex and multifactorial disease, which likely comprises multiple subtypes. Emerging data have linked chemical exposures to obesity. As organismal response to environmental exposures includes altered gene expression, identifying the regulatory epigenetic changes involved would be key to understanding the path from exposure to phenotype and provide new tools for exposure detection and risk assessment. In this report, we summarize published data linking early-life exposure to the heavy metals, cadmium and lead, to obesity. We also discuss potential mechanisms, as well as the need for complete coverage in epigenetic screening to fully identify alterations. The keys to understanding how metal exposure contributes to obesity are improved assessment of exposure and comprehensive establishment of epigenetic profiles that may serve as markers for exposures.

Cellular mechanisms of cadmium-induced toxicity: a review.

Cadmium is a widespread toxic pollutant of occupational and environmental concern because of its diverse toxic effects: extremely protracted biological half-life (approximately 20-30 years in humans), low rate of excretion from the body and storage predominantly in soft tissues (primarily, liver and kidneys). It is an extremely toxic element of continuing concern because environmental levels have risen steadily due to continued worldwide anthropogenic mobilization. Cadmium is absorbed in significant quantities from cigarette smoke, food, water and air contamination and is known to have numerous undesirable effects in both humans and animals. Cadmium has a diversity of toxic effects including nephrotoxicity, carcinogenicity, teratogenicity and endocrine and reproductive toxicities. At the cellular level, cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Current evidence suggests that exposure to cadmium induces genomic instability through complex and multifactorial mechanisms. Most important seems to be cadmium interaction with DNA repair mechanism, generation of reactive oxygen species and induction of apoptosis. In this article, we have reviewed recent developments and findings on cadmium toxicology.

Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: comparison of uptake, distribution, metal content, and toxicity.

The highly conserved human and mouse SLC39A8 gene encodes the divalent cation/bicarbonate symporter ZIP8 expressed ubiquitously in most cell types. Our bacterial artificial chromosome-transgenic BTZIP8-3 line has 3 additional copies of the Slc39a8 gene in addition to its constitutive diploid pair found in wild-type (WT) mice. In liver, kidney, lung, testis, gastrointestinal tract, and brain, BTZIP8-3 mice are known to express ∼2.5 times greater amounts of ZIP8, compared with WT mice. Herein we administered cadmium chloride (CdCl2) in drinking water (100 mg/L through week 2, 200 mg/L through week 4, 400 mg/L through week 8, 800 mg/L through week 12, and 1600 mg/L through week 20, when the experiment was concluded). We postulated that Cd uptake and distribution--and, therefore, toxicity in certain tissues--would be enhanced in BTZIP8-3, compared with WT mice. BTZIP8-3 and WT groups ingested comparable amounts of Cd. Compared with WT, BTZIP8-3 mice showed tissue specific: increases in Cd, zinc, and manganese content and decreases in calcium content. Both Cd-exposed BTZIP8-3 and WT were similar in lower urinary pH; increased plasma alanine and aspartate aminotransferase activities; elevated iron and copper content in liver, kidney, lung, and testis; and higher blood urea nitrogen and kidney weight. Histological changes in liver, kidney, lung, and testis were minimal. In summary, at the daily oral Cd exposures chosen for this study, 5 versus 2 Slc39a8 gene copies result in no differences in Cd toxicity but do cause differences in tissue-specific content of Cd, zinc, manganese, calcium, iron, and copper.

Cadmio: efectos sobre la salud. Respuesta celular y molecular / Cadmium: effects on health. Cellular and molecular response

El cadmio (Cd) es un metal que se encuentra principalmente en la corteza terrestre y siempre se presenta en combinación con el zinc. Es ampliamente utilizado en la industria. Se considera un contaminante y es liberado al ambiente como subproducto de la extracción de cobre, hierro y zinc. La exposición al Cd puede producir una variedad de efectos adversos tanto en el humano como en los animales. Una vez absorbido se acumula en el organismo por tiempos largos. Dependiendo de la dosis, fuente y tipo de exposición puede dañar varios órganos como el hígado, riñón, pulmón, hueso, testículos y placenta. Los seres humanos están expuestos al Cd principalmente a través de la ingesta de alimentos, del humo del cigarro, así como del agua y aire contaminados con el metal. La entrada de Cd a las células no es uniforme en todos los sistemas y puede ser mediada por transporte pasivo o activo, o por canales de calcio. Se considera que uno de los mecanismos de toxicidad de este metal es debido, en parte, a las especies reactivas de oxígeno, las cuales pueden actuar como segundos mensajeros y por tanto alterar diferentes vías de señalización. Por todo lo expuesto el objetivo de esta revisión es analizar los efectos del Cd sobre la salud, así como sobre la respuesta celular y molecular.

Cadmium (Cd) is a metal found in the earth´s crust, always as part of several, mainly zinc-rich, ores. Cd is considered as an environmental pollutant, it is widely used in the industry. It coexists with other metals and its release into the environment is carried out in parallel with the release of copper, iron and zinc. Cd is known to have numerous undesirable effects on health in both humans and animals. Once absorbed, it is effciently retained in the body, where it accumulates throughout life. Depending on the dose, source and type of exposure it could damage several organs as the liver, kidney, lung, bones, testes and placenta. Impor-tant sources of human intoxication are food, cigarette smoke as well as contaminated water and air. Cd cell uptake is not uniform across all systems. This could be mediated by passive or active transport, or via calcium channels. It is known that the toxicity produced by this metal is due, in part to reactive oxygen species, which could act as second messengers that may alter different signaling cascades. The aim of this review is to analyze the effects of Cd on health, as well as on cellular and molecular response.

A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2-microglobulin.

OBJECTIVES: Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage. METHODS: In a cross-sectional study N=512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd=2.67 µg/L], moderately [U-Cd=4.23 µg/L] and highly [U-Cd=9.13 µg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary ß2-microglobulin (UB2M) by ELISA. RESULTS: Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend=0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p=0.001) and UB2M concentrations (p=0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (ß=1.2, 95% CI 0.72-1.6) compared to GG carriers (ß=0.30, 95% CI 0.15-0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (ß=0.55, 95% CI 0.27-0.84) compared to GG carriers (ß=0.018, 95% CI -0.79-0.11). CONCLUSIONS: MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels.

Effects of chronic cadmium poisoning on Zn, Cu, Fe, Ca, and metallothionein in liver and kidney of rats.

An experiment was conducted to invest effects of chronic cadmium poisoning on Zn, Cu, Fe, Ca, and metallothionein gene expression and protein synthesis in liver and kidney in rats. Forty rats, 6 weeks old, were randomly allocated into two groups. A group was given CdCl(2) (1 mg/KgCd(2+)) by intraperitoneal injection once a day. The other group was treated with normal saline in the same way. Liver and kidney were collected for analysis at the end of the third week. Results showed that Cd exposure increased Cd (P<0.01) and Zn (P<0.01) content both in liver and kidney. Fe and Ca concentration had a considerable increase in kidney (P<0.01), while both had different degree reduction in liver. Discrepancies between MT mRNA and protein were observed in liver and kidney. In liver, both MT mRNA and protein had a significant increase (P<0.01), while in kidney, only MT gene increase was checked. Meanwhile, the expression levels of MT-1 mRNA and MT-2 mRNA were distinct between liver and kidney. The present study indicated that changes in tissue Cd and Zn levels tended to reflect MT mRNA expression, but bear no clear relationship with MT protein. There did not have a strict dose-dependent relationship among Cd content, MT gene expression, and MT protein synthesis. What is more, changes of Zn, Fe, Cu, and Ca had a certain interaction with both MT mRNA and protein.

Rising environmental cadmium levels in developing countries: threat to genome stability and health.

Cadmium (Cd) is a ubiquitous environmental pollutant of increasing worldwide concern. It is thought to be of greater concern to rapidly industrializing developing countries because of the increasing pace of industrial activities in these countries with increasing consumption and release into the environment. Traditionally, health concerns in exposed human populations have revolved around the association of Cd with bone disease, emphysema and possibly hypertension. Accumulating evidence suggest that Cd is involved in the disruption of many genomic processes, the mechanisms of which are being gradually understood. Changes in DNA Methylation may be induced by cadmium leading to epigenetic alterations. Additionally, though Cd is not thought to induce reactive oxygen species (ROS) directly because it is not capable of accepting or donating electrons under physiological conditions, 8-hydroxy deoxyguanosine (8-OHdG) (a marker of oxidative stress to DNA and a risk factor for cancer among others) has been shown to be elevated in the DNA of testes from rats treated with cadmium chloride, at least in part because Cd inhibits DNA repair mechanisms.  Cadmium is also a metabolic antagonist to Zinc (Zn), an important micronutrient involved in numerous molecular activities. This antagonism alters the physiological stoichiometric relationship between Cd and Zn leading to high Cd/Zn ratio, one consequence of which is high error rate and lack of efficient DNA repair systems leading to high mutation and genome instability culminating in many carcinogenic states, particularly prostate carcinogenesis. Cadmium has also been shown to replace Zn in the tumor suppressor protein, p53 thereby impairing p53's DNA binding activity and associated repair processes. The expression of the p53 protein is significantly depressed by cadmium. Although the rising level of Cd in the environment is widely acknowledged, the occult threat it poses to genome stability largely through inhibition of normal DNA damage repair, oxidative stress and apoptosis and health is poorly recognized. This paper examines the involvement of Cd in the molecular pathways of human disease, providing insight for the prevention of genome instability and associated disease susceptibility particularly cancer across populations through micronutrient intervention, aiding upregulation of the antioxidant defense and DNA repair systems.

Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats.

We have previously reported that inbred Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced testicular toxicity compared with inbred Fischer 344 (F344) rats. The present study was to elucidate the genetic background of resistance to Cd-induced testicular toxicity in WI rats. The genetic analysis of susceptibility to Cd-induced testicular toxicity was conducted by using Cd-resistant WI and Cd-sensitive F344 strains as the parental rats and by using the testicular hemoglobin level as the indicator. In the frequency distribution of testicular hemoglobin levels in parental, first filial (F(1)) and second filial (F(2)) rats treated with Cd at a dose of 2.0 mg/kg, F(1) rats had testicular hemoglobin levels intermediate to WI and F344 rats, and F(2) rats segregated into three groups of low, intermediate, and high phenotypes at the expected ratio. Furthermore, the backcross progeny between WI and F(1) or between F344 and F(1) segregated into two groups with the expected ratio. Based on a simple Mendelian genetic analysis, these segregation patterns lead us to conclude that two codominant alleles at a gene locus are responsible for the susceptibility to Cd-induced testicular toxicity in rats. This is the first report for the genetic analysis of susceptibility to Cd-induced testicular toxicity in inbred rat strains.

Attenuation of cadmium-induced testicular injury in metallothionein-III null mice.

AIMS: In order to evaluate the role of metallothionein (MT)-III in cadmium (Cd)-induced testicular toxicity, we examined the sensitivity of MT-III null mice to severe testicular injury caused by Cd. MAIN METHODS: Male MT-III null mice, MT-I/II null mice and wild-type mice were given a subcutaneous injection of CdCl(2) (15µmol/kg). The testis was collected from each mouse at 6, 12 and 24h after Cd administration. KEY FINDINGS: Testicular hemorrhages by evaluating morphology, hemoglobin content and histological parameters in the 3 types of mice were elevated by Cd injection in a time-dependent manner. The degree of hemorrhage in Cd-injected MT-I/II null mice was similar to that in the wild-type mice. In contrast, hemorrhage in the MT-III null mice was attenuated compared with that in wild-type mice and MT-I/II null mice. Cd levels, MT-I and MT-II mRNA levels and Cd-binding molecules in the testis were similar between MT-III null mice and wild-type mice. In microarray analysis, high expression of purine-nucleoside phosphorylase 2 (Pnp2), retinal degeneration 3 (Rd3), and cadherin-like 24 (Cdh24) was revealed in the testis of MT-III null mice under normal or Cd-treated conditions. SIGNIFICANCE: MT-III null mice were found to show attenuation of Cd-induced severe testicular toxicity. These results suggest the lack of MT-III contributes to protection of testis from Cd. In addition, regulation of Pnp2, Rd3, and Cdh24 mRNA levels may involve the sensitivity of MT-III null mice to Cd.

Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure.

The incidence of serious poisoning caused by occupational cadmium exposure has declined over the past four decades due to improvements in the work environment. However, long-term low-level exposure to cadmium needs to be addressed. For workers in industries that handle cadmium, it is necessary to consider the daily cadmium intake from contaminated foods such as cereals and rice in addition to the occupational exposure, since workers might be exposed to higher levels of cadmium from a combination of these sources. Cadmium accumulates in the renal cortex by the long-term exposure along with increased concentrations of metallothionein, an important protein for protection from cadmium toxicity. However, some individuals have lower metallothionein levels despite increased cadmium accumulation in the kidneys. This article describes the strategy method for analyzing individual susceptibility to cadmium toxicity and genetic polymorphisms of metallothionein, with reference to the current status of occupational cadmium exposure.

Protective effects of Chlorella vulgaris on liver toxicity in cadmium-administered rats.

The biochemical mechanisms of Chlorella vulgaris protection against cadmium (Cd)-induced liver toxicity were investigated in male Sprague-Dawley rats (5 weeks of age, weighing 90-110 g). Forty rats were randomly divided into one control and three groups treated with 10 ppm Cd: one Cd without Chlorella (Cd-0C), one Cd with 5% Chlorella (Cd-5C), and one Cd with 10% Chlorella (Cd-10C) groups. The rats had free access to water and diet for 8 weeks. Body weight gain and relative liver weight were significantly lower in the Cd-0C group than in Cd-5C and Cd-10C groups. Rats in the Cd-0C group had significantly higher hepatic concentrations of Cd and metallothioneins (MTs) than in the Cd-5C or Cd-10C group. The hepatic MT I/II mRNA was expressed in all experimental rats. MT II was more expressed in the Cd-5C and Cd-10C groups than in the Cd-0C group. Morphologically, a higher level of congestion and vacuolation was observed in the livers of the Cd-0C group compared to those of the Cd-5C and Cd-10C groups. Therefore, this study suggests that C. vulgaris has a protective effect against Cd-induced liver damage by reducing Cd accumulation and stimulating the expression of MT II in liver. However, the details of the mechanism of C. vulgaris on liver toxicity remains to be clarified by further studies.

Molecular responses during cadmium-induced stress in Daphnia magna: integration of differential gene expression with higher-level effects.

DNA microarrays offer great potential in revealing insight into mechanistic toxicity of contaminants. The aim of the present study was (i) to gain insight in concentration- and time-dependent cadmium-induced molecular responses by using a customized Daphnia magna microarray, and (ii) to compare the gene expression profiles with effects at higher levels of biological organization (e.g. total energy budget and growth). Daphnids were exposed to three cadmium concentrations (nominal value of 10, 50, 100microg/l) for two time intervals (48 and 96h). In general, dynamic expression patterns were obtained with a clear increase of gene expression changes at higher concentrations and longer exposure duration. Microarray analysis revealed cadmium affected molecular pathways associated with processes such as digestion, oxygen transport, cuticula metabolism and embryo development. These effects were compared with higher-level effects (energy budgets and growth). For instance, next to reduced energy budgets due to a decline in lipid, carbohydrate and protein content, we found an up-regulated expression of genes related to digestive processes (e.g. alpha-esterase, cellulase, alpha-amylase). Furthermore, cadmium affected the expression of genes coding for proteins involved in molecular pathways associated with immune response, stress response, cell adhesion, visual perception and signal transduction in the present study.

Short-interfering RNA-mediated silencing of thioredoxin reductase 1 alters the sensitivity of HeLa cells toward cadmium.

The mammalian thioredoxin reductase (TrxR) is a selenocysteine-containing flavoprotein that regulates the thioredoxin system, one of the major systems that maintain the intracellular redox balance. We previously reported that cytosolic TrxR (TrxR1), one of three mammalian TrxR isozymes, was induced by treatment with cadmium. In the present study, to study the role of cadmium-induced TrxR1 in cellular defense, we silenced the expression of TrxR1 in HeLa cells by using small interfering RNA and examined the effect of TrxR1 silencing on the sensitivity of the cells toward cadmium. We found that the gene silencing of TrxR1 had a dual effect on cadmium-induced cell death, depending on the concentration of cadmium. The TrxR1 silencing increased the sensitivity toward a low dose (less than 10 microM) of cadmium but decreased the sensitivity toward a high dose of cadmium. These results suggested that TrxR1 might play an important role in the cellular defense system against cadmium in two ways. TrxR1 might rescue the cells from a low dose of cadmium-induced moderate injury, while it might promote the death of cells severely injured by a high dose of cadmium.

Arsenic and mercury tolerance and cadmium sensitivity in Arabidopsis plants expressing bacterial gamma-glutamylcysteine synthetase.

Cysteine sulfhydryl-rich peptide thiols are believed to play important roles in the detoxification of many heavy metals and metalloids such as arsenic, mercury, and cadmium in plants. The gamma-glutamylcysteine synthetase (gamma-ECS) catalyzes the synthesis of the dipeptidethiol gamma-glu-cys (gamma-EC), the first step in the biosynthesis of phytochelatins (PCs). Arabidopsis thaliana, engineered to express the bacterial gamma-ECS gene under control of a strong constitutive actin regulatory sequence (A2), expressed gamma-ECS at levels approaching 0.1% of total protein. In response to arsenic, mercury, and cadmium stresses, the levels of gamma-EC and its derivatives, glutathione (GSH) and PCs, were increased in the A2::ECS transgenic plants to three- to 20-fold higher concentrations than the increases that occurred in wild-type (WT). Compared to cadmium and mercury treatments, arsenic treatment most significantly increased levels of gamma-EC and PCs in both the A2::ECS transgenic and WT plants. The A2::ECS transgenic plants were highly resistant to arsenic and weakly resistant to mercury. Although exposure to cadmium produced three- to fivefold increases in levels of gamma-EC-related peptides in the A2::ECS lines, these plants were significantly more sensitive to Cd(II) than WT and trace levels of Cd(II) blocked resistance to arsenic and mercury. A few possible mechanisms for gamma-ECS-enhanced arsenic and mercury resistance and cadmium hypersensitivity are discussed.

Mitochondrial DNA deletion of proximal tubules is the result of itai-itai disease.

BACKGROUND: The pathogenesis of itai-itai disease continues to be controversial, although cadmium (Cd) poisoning which arises via polluted water and rice in Japan is likely involved. Until recently, however, a well-defined animal model for Cd intoxication was not available. An animal model for itai-itai disease was produced in rats by low-dose Cd treatment, intraperitoneally for a period of 70-80 weeks. Osteomalacia followed the renal damage. RESULTS: A gene deletion in the mitochondrial DNA was found in the mitochondria of the proximal tubule cells of rats with chronic Cd intoxication, as was shown by the increased smaller PCR product seen by gel electrophoresis in one DNA region, where ATPase and cytochrome oxidase genes are located. However, the PCR product was different from that seen with a gene deletion associated with aging: del4834bp. Renal damage from Cd intoxication initially caused mitochondrial dysfunction indicated by the disturbance in reabsorption in the proximal tubules and decreased amounts of ATP, ATPase, and cytochrome oxidase with gradually progressing tubular proteinuria, and, finally, chronic renal failure with tubulointerstitial damage throughout the renal cortex. These gave rise to osteomalacia, subsequently. CONCLUSION: We concluded that in Cd poisoning, a mitochondrial gene deletion in the mitochondria of the proximal tubule cells was the primary event for the pathogenesis of osteomalacia in itai-itai disease.

No relationship exists between itai-itai disease and TA repeat polymorphisms of the estrogen receptor alpha gene.

Itai-itai (ouch-ouch) disease is a syndrome accompanied by bone mineral disorders that may be related to oral cadmium exposure. Itai-itai predominantly affects postmenopausal women with a history of multiple childbirth. In a previous study we have examined the genotype distributions of PvuII and XbaI restriction fragment length polymorphisms of the estrogen receptor alpha (ER alpha) gene in patients with itai-itai disease and compared them with those of controls. However, no significant differences were shown between the genotype distributions of the patients and controls. In the present study, we determined the TA repeat polymorphisms of the patients and controls. The distributions of the patients were: HH 25.0%, HL 50.0%, and LL 25.0%; where HH includes two alleles with a high number of TA repeats (TA> or =16), HL includes one high number allele and one low number allele (TA< or =15), and LL includes two alleles with a low number of TA repeats. These patients' distributions were not significantly different from those of the controls. Although our sample number was limited, we concluded that a polymorphism variant of the ER alpha gene is not a predisposing factor for itai-itai disease.

A systematic review of cytogenetic studies conducted in human populations exposed to cadmium compounds.

BACKGROUND: Exposure to cadmium fumes or dusts has been associated with an increased risk of lung cancer and the characterisation of the genotoxic potential of cadmium compounds is, among other possible mechanisms, an important element in the assessment of the carcinogenic hazard of the element. While there is some evidence that in experimental systems, cadmium compounds may exert genotoxic effects, the results of the epidemiological studies having examined cytogenetic endpoints in humans exposed to cadmium appear conflicting. Therefore, a systematic review was undertaken to assess whether a cytogenetic effect of cadmium exposure is supported by the studies with the strongest design. METHODS: The relevant literature was identified through several databases and assessed with a check-list by two reviewers. Causes of heterogeneity between studies were looked for. Results were extracted and the strength of the evidence was evaluated with causality criteria. RESULTS: No studies met the criteria for being considered as very convincing. Several factors were identified that could explain contradictory findings (small sample size, selection bias, insufficient characterisation of exposure, lack of consideration of confounders) but their actual impact could not be conclusively assessed with the published information. Importantly, it should be recognised that the absence of a clear mechanism for the cytogenetic action of cadmium compounds did not allow to select the most appropriate endpoint to be examined. CONCLUSIONS: No clear association between cadmium exposure and cytogenetic endpoint appeared but no definite conclusion can be drawn from the existing studies in humans. Future research efforts should mainly focus on experimental studies to understand how cadmium compounds could produce genotoxic/carcinogenic effects, in order to target the most relevant endpoint to be examined in humans.