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Cadmium (Cd) is one of the heavy metal pollutants present in the environment due to human intervention. It is well known that Cd causes toxicological effects on various organs, including the testes. Morin hydrate is a plant-derived bioflavonoid with antioxidant, anti-inflammatory, and anti-stress properties. Thus, the question can be raised as to whether Morin has an effect on Cd-intoxication-induced testicular impairment. Therefore, the aim of this study was to investigate the role of Morin on Cd-mediated disruption of testicular activity. Mice were divided into three groups: group 1 served as the control group, group 2 was given Cd (10 mg/kg) orally for 35 days, and group 3 was given Cd and Morin hydrate (100 mg/kg) for 35 days. To validate the in vivo findings, an in vitro study on testicular explants was also performed. The results of the in vivo study showed that Cd-intoxicated mice had testicular disorganization, reduced circulating testosterone levels, decreased sperm density, and elevated oxidative stress and sperm abnormality. The expression of the germ cell proliferation marker, germ cell nuclear acidic protein (GCNA), and adipocytokine visfatin were also downregulated. It was observed that Morin hydrate upregulated testicular visfatin and GCNA expression in Cd-intoxicated mice, along with improvement in circulating testosterone, testicular histology, and sperm parameters. Furthermore, the in vitro study showed that Cd-mediated downregulation of testicular visfatin and GCNA expression, along with the suppressed secretion of testosterone from testicular explants, was normalized by Morin treatment, whereas visfatin expression was not. Overall, these data indicate that environmental cadmium exposure impairs testicular activity through downregulation of visfatin and GCNA expression, and Morin might play a protective role against Cd-induced testicular toxicity., (© 2023 Wiley Periodicals LLC.)

Cadmium (Cd) is an environmental pollutant known to pose a public health issue. The mechanism of Cd toxicity on the uterus, including the protective role of metallothionein (MT), is still not fully understood. The aim of the study was to evaluate the degree of MT-Cd binding in the uterus of rats exposed per os to Cd at daily doses of 0.09, 0.9, 1.8 and 4.5 mg Cd/kg b.w. for 90 days. To assess the permanence of the bond, the rats were observed over long observation periods: 90 and 180 days after termination of exposure. Additionally, uterine concentration of Zn, Cu, Ca, Mg was determined. Cd leads immediately after exposure to a max. 30-fold increase in the concentration of Cd in the uterus, with only small amounts being bound to MT. After 90 days following termination of exposure, and especially after 180 days, an increase in MT-Cd concentration was noted for the three highest doses; even so, the degree of Cd binding by MT was still small. Additionally, the accumulation of Cd in the uterus disturbs the homeostasis of determined essential elements, manifested by a significant increase in Cu concentration and a decrease in Zn, Mg and Ca, especially 180 days after termination of exposure. The obtained results indicate that MT has only a slight protective role in the uterus and that Cd ions may have harmful effects not related to MT: directly on the uterine tissue, and indirectly by disturbing the homeostasis of its essential elements.

Cadmium (Cd) is a toxic heavy metal that is widely present in the environment. Renal proximal tubule disorder is the main symptom of Cd chronic poisoning. Our previous study demonstrated that Cd inhibits the total activities of peroxisome proliferator-activated receptor (PPAR) transcription factors in human and rat proximal tubular cells. In this study, we investigated the involvement of PPAR in Cd renal toxicity using the HK-2 human proximal tubular cell line. Among PPAR isoform genes, only PPARD knockdown significantly showed resistance to Cd toxicity in HK-2 cells. The transcriptional activity of PPARδ was decreased not only by PPARD knockdown but also by Cd treatment. DNA microarray analysis showed that PPARD knockdown changed the expression of apoptosis-related genes in HK-2 cells. PPARD knockdown decreased apoptosis signals and caspase-3 activity induced by Cd treatment. PPARD knockdown did not affect the intracellular Cd level after Cd treatment. These results suggest that PPARδ plays a critical role in the modification of susceptibility to Cd renal toxicity and that the apoptosis pathway may be involved in PPARδ-related Cd toxicity.

Cadmium (Cd) is an environmental pollutant and pregnant women are especially susceptible to the effects of exposure to Cd. Our previous study found Cd can be accumulated in the placenta and causes fetal growth restriction (FGR) through damage the placental glucocorticoid barrier. Selenium (Se), as an essential micronutrient, can allivate Cd-induced toxicity. In this study, we aim to explore the protective mechanism of Se against Cd-induced the placental glucocorticoid barrier damage and FGR. Pregnant Sprague Dawley (SD) rats were exposed to CdCl 2 (1 mg/kg/day) and Na 2 SeO 3 (0.1-0.2-0.3 mg/kg/day) by gavage from gestational day (GD) 0 to GD 19. The results showed that reduced fetal weight, increased corticosterone concentrations in the maternal and fetal serum, and impaired placental labyrinth layer blood vessel development, appeared in pregnant rats after Cd exposure and improved after treated with Se. In cell experiments, we confirmed that Se reduces Cd-induced apoptosis. Moreover, Se can abolish Cd-induced 11β-HSD2 and specificity protein 1 (Sp1) decreasing in vivo and vitro. In human JEG-3 cells, the knockdown of Sp1 expression by small interfering RNA can suppressed the protective effect of Se on Cd-induced 11β-HSD2 decreasing. In general, our results demonstrated that Se is resistant to Cd-induced FGR through upregulating the placenta barrier via activation of the transcription factor Sp1., (© 2022 Wiley Periodicals LLC.)

Cadmium (Cd) is a toxic non-essential element, while calcium (Ca) is an essential element with high chemical similarity to Cd. Dietary intake is the major Cd exposure pathway for non-smokers. A multi-concentration dietary intervention experiment was designed to explore the optimum concentration of Ca in diet with obvious protective effects against the toxicity of livers and kidneys induced by Cd in mice. The mice were divided into six groups with different concentrations of Cd and Ca in their food: control-group (no Cd or Ca), Ca-group (100 g/kg Ca, without Cd), Cd-group (2 mg/kg Cd, without Ca), CaL+Cd-group (2 mg/kg Cd, 2 g/kg Ca), CaM+Cd-group (2 mg/kg Cd, 20 g/kg Ca) and CaH+Cd-group (2 mg/kg Cd, 100 g/kg Ca). The organ indexes, oxidative stress biomarkers, lesions and Cd concentrations were detected after a 30-day exposure period. Results showed that serum Aspartate Aminotransferase (AST) level in CaH+Cd-group was significantly lower than that in Cd-group, while close to that in control-group. The contents of Serum Blood Urea Nitrogen (BUN) in different groups showed the same trend. Concentrations of all oxidative stress biomarkers (GSH-Px, SOD, CAT, GSH and MDA) in CaH+Cd-group were close to the normal levels of control-group while significantly different from those in Cd-group. The only exception was the Malondialdehyde (MDA) levels in kidneys. This study suggests that Ca plays a protective role in relieving the Cd-induced toxicity of livers and kidneys and a concentration of 100 g/kg for Ca in diet showed the best protective effects. These findings could provide a clue for further studies concerning human diet intervention for Cd control., Competing Interests: The authors have declared that no competing interests exist.

We examined, in a rat model of moderate environmental human exposure to cadmium (Cd), whether the enhanced intake of zinc (Zn) may protect against Cd-caused destroying the oxidative/antioxidative balance and its consequences in the brain. The intoxication with Cd (5 mg/L, 6 months) weakened the enzymatic (superoxide dismutase, glutathione peroxidase, catalase) and non-enzymatic (total thiol groups, reduced glutathione) antioxidative barrier decreasing the total antioxidative status and increased the concentrations of pro-oxidants (hydrogen peroxide, myeloperoxidase) in this organ and its total oxidative status. These resulted in the development of oxidative stress and oxidative modifications of lipids and proteins. The co-administration of Zn (30 and 60 mg/L enhancing this element intake by 79% and 151%, respectively) importantly protected against Cd accumulation in the brain tissue and this xenobiotic-induced development of oxidative stress and oxidative damage to lipids and proteins. Moreover, this bioelement also prevented Cd-mediated oxidative stress evaluated in the serum. The favorable effect of Zn was caused by its independent action and interaction with Cd. Concluding, the enhancement of Zn intake under oral exposure to Cd may prevent the oxidative/antioxidative imbalance and oxidative stress in the brain and thus protect against injury of cellular macromolecules in the nervous system.

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., (Copyright © 2020. Published by Elsevier B.V.)

Cadmium (Cd), a substance with one of the most critical health hazard indices, can cause damage to both the blood and kidneys and accumulates in the body at last. The present work studied the toxicological effects of Cd and the therapeutic effects of metallothionein (MT) and vitamin E (VE) on the trunk kidney and blood of freshwater grass carp (Ctenopharyngodon idellus). Grass carp were divided into three groups: Cd + phosphate-buffered saline (PBS) group, Cd + VE group, and the Cd + MT group. Fish were injected with CdCl 2 on the first day and then VE, MT, or PBS was administered 4 days post-injection. Fish not injected with Cd were used as a negative control. The blood and trunk kidney amassed Cd and suffered severe damage in the forms of organ toxicity cytotoxicity, and immunotoxicity. However, the MT reduced the Cd content in the trunk kidney and blood and partially stabilized the damaged organs. Treatment with VE, however, only demonstrated weaker protection against on Cd-induced toxicity. The results indicate that exogenous MT may play an essential role in restoring homeostasis of the Cd-poisoned urinary and circulatory system and that it may help eliminate Cd in aquatic animals.

Heavy metal pollution has become an important issue threatening human health and the liver is a very important metabolic organ. Here, we use label-free Raman confocal imaging to study the alterations of the liver tissue after cadmium pollution. Raman imaging has been performed on 100μmx100μm liver tissues to study the distribution of important macromolecules and the average Raman spectrum of the entire region has been used to characterize and quantize the change of biochemical compositions in liver tissue. The poisoned livers displayed a significant decrease in the intensity of 748 cm -1 , 1128 cm -1 and 1585 cm -1 bands of cytochrome C, in comparison to the control. The collagen peak at 1082 cm -1 is significantly higher than that of control, suggesting the increasing fibrosis of Cd liver tissues. To confirm the results, we selected a 30μmx15μm liver cell area for high-resolution Raman imaging. We observed a substantial increase of lipids and proteins at specific points of hepatocytes. The confocal Raman imaging of liver tissues provided a unique tool to better understand disease-induced changes in the biochemical phenotype of primary liver tissues. Our study provides valuable references as in vitro models for studying Cd accumulation and toxicity in human liver., (Copyright © 2019. Published by Elsevier B.V.)

Toxic heavy metal cadmium wildly pollutes the environment and threats the human health. Effective treatment of cadmium-induced toxicity and organ damage is an important issue. Cadmium causes organ damage through inducing oxidative stress. Our previous study also found oleic acid (OA) synthesis-related gene can confer resistance to cadmium and alleviate cadmium-induced stress in yeast. However, its alleviation mechanism on cadmium stress especially in animals is still unclear. In this study, the alleviative effects of OA on cadmium and cadmium-induced oxidative stress in rats were investigated. Oral administration of 10, 20, and 30 mg/kg/day OA can significantly increase the survival rate of rats intraperitoneally injected with 30 mg/kg/day cadmium continuously for 7 days. Similar to ascorbic acid (AA), OA can significantly reduce the cadmium-induced lipid peroxidation in multiple organs of rats. The investigation of OA on superoxide dismutase (SOD) activity showed that OA increased the SOD activity of cadmium-treated rat organs. More important, OA reduced the level of superoxide radical O 2- of cadmium-treated rat organs. And OA exhibited a strong DPPH radicals scavenging activity at dose of 10, 20 and 30 mg/mL, which may contributed to alleviating cadmium-induced oxidative stress. This study revealed that OA could significantly alleviate cadmium stress via reducing cadmium-induced lipid peroxidation and SOD activity inhibition through its radicals scavenging activity.

Treatment modalities for kidney disease caused by long-term exposure to heavy metals, such as cadmium (Cd), are limited. Often, chronic, long-term environmental exposure to heavy metal is not recognized in the early stages; therefore, chelation therapy is not an effective option. Extracellular vesicles (EVs) derived from stem cells have been demonstrated to reduce disease pathology in both acute and chronic kidney disease models. To test the ability of EVs derived from human bone marrow mesenchymal stem cells (hBM-MSCs) to treat Cd damage, we generated a Cd-exposed medaka model. This model develops heavy metal-induced cell damage in various organs and tissues, and shows decreased overall survival. Intravenous injection of highly purified EVs from hBM-MSCs repaired the damage to apical and basolateral membranes and mitochondria of kidney proximal tubules, glomerular podocytes, bone deformation, and improved survival. Our system also serves as a model with which to study age- and sex-dependent cell injuries of organs caused by various agents and diseases. The beneficial effects of EVs on the tissue repair process, as shown in our novel Cd-exposed medaka model, may open new broad avenues for interventional strategies., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The article solves a current task concerning a substantiated use of acetylation phenotype as susceptibility biomarker to unfavourable effect of chemical substances in scientific studies. Objective: to study a combined effect of sodium nitrate and cadmium chloride on the prooxidant-antioxidant balance of the blood, liver and functional state of the central nervous system in young rats with different acetylation type. The experimental studies were performed on immature male rats 1,5-month of age. The experimental animals were divided into two groups according to the amount of general sulfadimine excreted with urine: "rapid" and "slow" acetylators. 2 subgroups were differentiated in every group: I - control animals, II - animals subjected to administration of cadmium chloride and sodium nitrate. Administration of sodium nitrate and cadmium chloride to animals in the doses 1/15 DL50 and 1/150 DL50 respectively during 14 days found that at the young age "slow" acetylation type is susceptibility marker, and the criteria of a harmful effect in them are the following: 25% increase protein peroxide oxidation in the blood plasma, 34% and 30% increase of average molecular peptides and ceruloplasmin respectively, and 6,7 times increase of methemoglobin (hemiglobin) concentration. Nitrate-cadmium intoxication caused inhibition of the integral behavioural activity both in slow and rapid acetylators. Disturbed behavioural activity in young animals with "slow" acetylation type under conditions of subacute effect of sodium nitrate and cadmium chloride is caused mainly by an increased content of liver lipoperoxidation secondary products and less - by the levels of average molecular peptides and ceruloplasmin in the blood plasma, and in "rapid" acetylators - by increased products of oxidation-modification proteins.

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 Cd 2+ accumulation in 20 μM (95.99 ± 9.93 vs 29.64 ± 5.08 ng/10 6 cells; P = 0.0008) or 50 μM Cd (179.78 ± 28.66 vs 141.62 ± 22.15 ng/10 6 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 Zn 2+ 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 Cd 2+ bioaccumulation and promoting MTs expression.

Quantum dots (QDs) have widespread application in many fields such as medicine and electronics. The need for understanding the potentially harmful side effects of these materials becomes clear. In this study, the toxicity of cadmium telluride quantum dots (CdTe-QDs) and bulk Cd 2+ has been investigated and compared by applying metabolomics methods. The datasets were 1 H-NMR data from mice plasma which had been taken from four groups of mice in different time intervals. Then, the data were analyzed by applying chemometrics methods and the metabolites were found from Human Metabolome Database (HMDB). The results showed the significant change in the level of some metabolites especially estrogenic steroids in different groups with different amounts of received Cd. The findings also indicated that steroid hormone biosynthesis, lysine biosynthesis and taurine and hypotaurine metabolism are the most affected pathways by CdTe-QDs especially in estrogenic steroids. The over-representation analysis indicated that endoplasmic reticulum, gonads, and hepatocytes are most affected. Since the pattern of metabolite alteration of CdTe-QDs with equivalent Cd 2+ was similar to those of CdCl 2 , it was postulated that beside Cd 2+ effects, the toxicity of CdTe-QDs is associated with other factors.

Objective: To investigate the effects of cadmium exposure on cardiovascular system of occupational workers. Methods: Cross-sectional study was applied to 992 workers in a nickel-cadmium battery plant in November, 2011, of which 749 were cadmium exposed workers and 243 were controls without cadmium and other expose. Urinary cadmium、electrocardiogram (ECG) and blood pressure were examined simultaneously among 992 workers. The risk factors of ECG abnormality rate and hypertension rate were analyzed by Logistic regression. Results: The level of urinary cadmium in cadmium exposed workers was significantly higher than controls (8.89±4.00 vs 1.34±1.18 μg/g creatinine, P <0.01) . Urinary cadmium level in women was significantly higher than men in both exposure and control group ( P <0.05) . According to the group of working years, Urinary cadmium level raised with the increase of working years (F=28.272, P <0.001) . The ECG abnormality rate and hypertension rate of cadmium exposed workers were higher than that of control group, the differences were all statistically significant ( P <0.01) . The abnormal rate of ECG and the hypertension rate increased with the prolonging of working years and demonstrated dose-response relationship. With the increase of urinary cadmium level, the abnormal rate of ECG and hypertension rate raised ( OR =1.11, P <0.01) and ( OR =1.15, P <0.01) respectively. Conclusion: Occupational cadmium exposure increased the abnormal rate of ECG and blood pressure and therefore damaged cardiovascular system of workers. This study provided base data for protecting health of cadmium exposed workers.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates a cluster of oxidative stress-inducible genes in cells. Here, we aimed to investigate whether trehalose (Tre) protects primary rat proximal tubular (rPT) cells against cadmium (Cd)-induced oxidative stress via Nrf2 antioxidant pathway. Data showed that Tre treatment inhibited Nrf2 nuclear translocation and restored the decline in Kelch-like ECH-associated protein 1 (Keap1) protein level in Cd-exposed rPT cells. Moreover, Cd-activated Nrf2 target genes, including phase II detoxifying enzymes, that is, NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1, direct antioxidant proteins, that is, glutathione peroxidase, superoxide dismutase, catalase, and glutathione biosynthesis-related proteins, that is, glutamatecysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase, were all downregulated by co-treatment with Tre. Collectively, these findings demonstrate that Tre treatment alleviates Cd-induced oxidative stress in rPT cells by inhibiting the Nrf2-Keap1 signaling pathway., (© 2017 Wiley Periodicals, Inc.)

Cadmium (Cd) is an environmental contaminant that exhibits renal toxicity. The target transcription factors involved in Cd renal toxicity are still unknown. In this study, we demonstrated that Cd decreased the activity of the ARNT transcription factor, and knockdown of ARNT significantly decreased the viability of human proximal tubular HK-2 cells. Microarray analysis in ARNT knockdown cells revealed a decrease in the expression of a number of genes, including a known apoptosis inhibitor, BIRC3, whose gene and protein expression level was also decreased by Cd treatment. Although the BIRC family consists of 8 members, Cd suppressed only BIRC3 gene expression. BIRC3 is known to suppress apoptosis through the inhibition effect on caspase-3. Knockdown of BIRC3 by siRNA as well as Cd treatment increased the level of active caspase-3. Moreover, knockdown of BIRC3 not only triggered cell toxicity and apoptosis but also strengthened Cd toxicity in HK-2 cells. Meanwhile, the activation of caspase-3 by suppression of BIRC3 gene expression was mostly specific to Cd and to proximal tubular cells. These results suggest that Cd induces apoptosis through the inhibition of ARNT-regulated BIRC3 in human proximal tubular cells.

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.

In the present work, protective effect of tetrahydrocurcumin (THC) against oxidative damages in cadmium (Cd)-induced toxicity in rats was evaluated. Cd is an important environmental and industrial toxicant that affects almost all the organs, especially liver. Liver is the major organ responsible for the metabolism and the primary target for many toxic chemicals and drugs. Effect of THC, the curcumin-derived polyphenolic compound on Cd-induced oxidative stress and hepatic damage was evaluated using male albino Wistar rats. In Cd-administered rats (5 mg/kg body weight (b.w.), orally for 4 weeks), activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) were significantly increased in serum with the elevated level of bilirubin. Red blood cells (RBC), haemoglobin contents and haematocrit values were also significantly decreased in Cd-treated rats. In addition, the levels of lipid peroxidation markers like thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LHP), protein carbonyl contents (PCC) and conjugated dienes (CD) were significantly increased followed by the significant decrease in the levels of reduced glutathione (GSH), total sulphydryl groups (TSH), ascorbic acid (vitamin C) and vitamin E in liver of Cd-administered rats. Oral administration of THC (20, 40 and 80 mg/kg b.w.) followed by Cd for 4 weeks showed a significant restoration of the above changes to near normal. Histopathological changes observed in Cd intoxicated hepatic tissues were minimized on treatment with THC. This study suggests that THC at the dose of 80 mg/kg b.w. effectively subdues the Cd-induced toxicity and controls the free radical-induced liver damage in rats.

Cadmium (Cd), a non-essential metal, stealthily enters the cells by utilizing the essential metal importing pathways. The zinc transporters Zip8, Zip14, and divalent metal transporter 1 (Dmt1) are now emerging as several important metal transporters involved in cellular Cd incorporation and their expressions have been shown to be down-regulated in several Cd-resistant (CdR) cell lines, however, the involvement of these transporters during the development of Cd-resistance in lung cells is unclear. In this study, we therefore check the expression of these metal transporters in our previously established rat lung epithelial cells (LECs) and show that the level of Zip8 is progressively silenced when LECs are adapted to increasing concentrations of CdCl2 (from 1 to 20 μM). Subsequent measurement of the cellular Cd content indicated that CdR LECs exhibit a marked decrease of Cd accumulation, possibly due to the loss of Zip8 expression. We investigate the possibility that epigenetic silencing of the Zip8 gene by DNA hypermethylation is involved in the down-regulation of Zip8 expression. CdR LECs show a higher mRNA level of DNA methyltransferase 3b (Dnmt3b) than parental cells. Treatment of CdR LECs with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferases, reverted the expression of Zip8 and sensitivity to Cd in these cells, indicating the critical role of Zip8 for Cd import. Taken together, our results demonstrate that the progressive silencing of Zip8 expression is involved in the acquisition of resistance against Cd in lung cells, representing an adaptive survival mechanism that resists Cd-induced cytotoxicity., (© The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Changes in the intracellular thiol-disulfide balance are considered major determinants in the redox status/signaling of the cell. Cellular signaling is very sensitive to both exogenous and intracellular redox status and respond to many exogenous pro-oxidative or oxidative stresses. Redox status has dual effects on upstream signaling systems and downstream transcription factors. Redox signaling pathways use reactive oxygen species (ROS) to transfer signals from different sources to the nucleus to regulate such functions as growth, differentiation, proliferation, and apoptosis. Mitogen-activated protein kinases are activated by numerous cellular stresses and ligand-receptor bindings. An imbalance in the oxidant/antioxidant system, either resulting from excessive ROS/reactive nitrogen species production and/or antioxidant system impairment, leads to oxidative stress. Glutathione (GSH) is known to play a critical role in the cellular defense against unregulated oxidative stress in mammalian cells and involvement of large molecular antioxidants include classical antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Cadmium (Cd), a potent toxic heavy metal, is a widespread environmental contaminant. It is known to cause renal dysfunction, hepatic toxicity, genotoxicity, and apoptotic effects depending on the dose, route, and duration of exposure. This review examines the signaling pathways and mechanisms of activation of transcription factors by Cd-induced oxidative stress thus representing an important basis for understanding the mechanisms of Cd effect on the cells., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The glial cells are positioned to be the first cells of the brain parenchyma to face molecules crossing the blood-brain barrier with a relevant neuroprotective role from cytotoxic action of heavy metals on the nervous system. Cadmium is a highly toxic metal and its levels in the environment are increasing due to industrial activities. This element can pass the blood-brain barrier and have neurotoxic activity. For this reason we have studied the effects of cadmium on the glial architecture in the lizard Podarcis siculus, a significant bioindicator of chemical exposure due to its persistence in a variety of habitats. The study was performed on two groups of lizards. The first group of P. siculus was exposed to an acute treatment by a single i.p. injection (2 mg/kg-BW) of CdCl2 and sacrificed after 2, 7 and 16 days. The second one was used as control. The histology of the brain was studied by Hematoxylin/Eosin and Cresyl/Violet stains while the glial structures were analyzed by immunodetection of the glial fibrillary acidic protein (GFAP), the most widely accepted marker for astroglial cells. Evident morphological alterations of the brain were observed at 7 and 16 days from the injection, when we revealed also a decrease of the GFAP-immunopositive structures in particular in the rhombencephalic ventricle, telencephalon and optic tectum. These results show that in the lizards an acute exposure to cadmium provokes morphological cellular alterations in the brain but also a decrement of the expression of GFAP marker with possible consequent damage of glial cells functions.

The paraoxonases (PONs) are a three-gene family which includes PON1, PON2, and PON3. PON1 and PON3 are synthesized primarily in the liver and a portion is secreted in the plasma, where they are associated with high-density lipoproteins (HDLs), while PON2 is an intracellular enzyme, expressed in most tissues and organs, including the brain. PON1 received its name from its ability to hydrolyze paraoxon, the active metabolite of the organophosphorus (OP) insecticide parathion, and also more efficiently hydrolyzes the active metabolites of several other OPs. PON2 and PON3 do not have OP-esterase activity, but all PONs are lactonases and are capable of hydrolyzing a variety of lactones, including certain drugs, endogenous compounds, and quorum-sensing signals of pathogenic bacteria. In addition, all PONs exert potent antioxidant effects. PONs play important roles in cardiovascular diseases and other oxidative stress-related diseases, modulate susceptibility to infection, and may provide neuroprotection (PON2). Hence, significant attention has been devoted to their modulation by a variety of dietary, pharmacological, lifestyle, or environmental factors. A number of metals have been shown in in vitro, animal, and human studies to mostly negatively modulate expression of PONs, particularly PON1, the most studied in this regard. In addition, different levels of expression of PONs may affect susceptibility to toxicity and neurotoxicity of metals due to their aforementioned antioxidant properties.

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

Acute exposure to cadmium (Cd), a toxic heavy metal, causes systemic inflammation characterized by neutrophilia. To elucidate the mechanism of neutrophilia induced by Cd, we investigated the induction of granulocyte colony-stimulating factor (G-CSF), which regulates neutrophil production, in mice with acute Cd toxicity, and compared it with mice injected with lipopolysaccharide (LPS) as an inducer of general inflammatory responses. We injected BALB/c mice with Cd at 2.5 mg/kg i.p. or LPS at 0.5 mg/kg i.p. and sampled the peripheral blood and organs at time points up to 24 h. In Cd-treated mice, the peripheral neutrophil count increased steadily up to 24 h, whereas LPS-treated mice showed a more rapid increase with a peak at 12 h. The serum G-CSF level increased gradually to reach a plateau at 12-18 h in Cd-treated mice, but LPS-treated mice showed a marked increase, reaching a peak at 2-3 h. A gradual elevation of G-CSF mRNA expression up to 24 h was detected by real-time PCR in the livers of Cd-treated mice, but in LPS-treated mice its highest expression was observed in the liver with a rapid increase at 2 h. By in situ hybridization using G-CSF RNA probes, hepatic Kupffer cells were identified as G-CSF-producing cells in the liver. These results indicated that Cd has a characteristic effect of delayed induction of G-CSF in the liver, causing systemic inflammation accompanied by prolonged neutrophilia.

Antagonistic effects of selenium (Se) in cadmium (Cd)-induced toxicity have been frequently reported in previous studies. However, little was known about the interactions of Se and Cd on ion profiles in the brains of poultry. The aim of this study was to investigate the interaction between Se and Cd in the ion profile of the chicken brain. In the present study, a total of 128 laying hens were fed a Se-, Cd-, or Se + Cd-supplemented diet for 90 days. Levels of 28 ions were detected in chicken brains using ICP-MS. We found that Cd exposure significantly increased the content of Cd in the brain; furthermore, the content of lithium (Li), stannum (Sn), and stibium (Sb) increased, but the content of kalium (K) decreased. The content of Se in the brain was not altered by Se supplementation; however, Se reduced the concentrations of Sn and Sb, which in contrast were increased by Cd exposure. Complex interactions between ions were analyzed by principal component analysis, and both positive and negative correlations between different ions were found after prolonged exposure to Se and Cd. These findings suggest that Se and Cd supplementation influences the ion profiles in the chicken brain, and moreover, Se may have an antagonistic effect under longer exposure to Cd.

The aim of this study was to investigate microstructure and ultrastructure alterations in the pallium of immature mice exposed to cadmium. Forty immature mice were randomly divided into control, 1/100 LD 50 (1.87 mg/kg, low), 1/50 LD 50 (3.74 mg/kg, medium), and 1/25 LD 50 (7.48 mg/kg, high) dose groups. After oral cadmium exposure for 40 days, the pallium of mice was obtained for microstructure and ultrastructure studies. The results showed that both microstructure and ultrastructure alterations of the pallium were observed in all treated mice and the most obvious alterations were in the high dose group. Microstructural analysis showed seriously congested capillary in the pia mater of the pallium in the high cadmium group. Meanwhile, vacuolar degenerate or karyopyknosis presented in some neurocytes, capillary quantity, and the number of apoptotic cells increased, some neurocytes became hypertrophy, the pia mater separated from the cortex, and local hemorrhage and accompanied inflammatory cell infiltration were also observed. Ultrastructural analysis showed that rough endoplasmic reticulum was expanded, heterochromatin marginalized, perinuclear space distinctly broadened, swelling and vacuolization mitochondria appeared, synapse was swelling, presynaptic and postsynaptic membranes presented fusion, and most of mitochondrial cristae were ambiguous. The results indicated that cadmium exposure for 40 days induced dose-dependent microstructure and ultrastructure alterations in pallium of immature mice.

This study aims to evaluate the protective effect of grape seed proanthocyanidin extract (GSPE) on cadmium (Cd)-induced testicular apoptosis, endothelial nitric oxide synthases (eNOS) expression, and toxicity in rats. A total of 24 male Wistar rats were divided into four groups, namely, control, Cd (2.5 mg/kg), Cd + GSPE (100 mg/kg/day), and GSPE. Spermatogenesis and mean seminiferous tubule diameter were significantly decreased in the Cd groups. Furthermore, the GSPE-treated animals showed an improved histological appearance in the Cd group. The immunoreactivity of eNOS and the number of apoptotic cells were increased in Cd group. Our data indicate a significant reduction of terminal deoxynucleotide transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling staining and a decrease in the expression of eNOS in the testes tissue of the Cd group treated with GSPE therapy. Therefore, our results suggest that GSPE acts as a potent protective agent against Cd-induced testicular toxicity in rats., (© The Author(s) 2015.)

The present study was conducted to assess the effects of Cd exposure on estrogen signaling in the zebrafish brain, as well as the potential protective role of Zn against Cd-induced toxicity. For this purpose, the effects on transcriptional activation of the estrogen receptors (ERs), aromatase B (Aro-B) protein expression and molecular expression of related genes were examined in vivo using wild-type and transgenic zebrafish embryos. For in vitro studies, an ER-negative glial cell line (U251MG) transfected with different zebrafish ER subtypes (ERα, ERβ1 and ERβ2) was also used. Embryos were exposed either to estradiol (E2 ), Cd, E2 +Cd or E2 +Cd+Zn for 72 h and cells were exposed to the same treatments for 30 h. Our results show that E2 treatment promoted the transcriptional activation of ERs and increased Aro-B expression, at both the protein and mRNA levels. Although exposure to Cd, does not affect the studied parameters when administered alone, it significantly abolished the E2 -stimulated transcriptional response of the reporter gene for the three ER subtypes in U251-MG cells, and clearly inhibited the E2 induction of Aro-B in radial glial cells of zebrafish embryos. These inhibitory effects were accompanied by a significant downregulation of the expression of esr1, esr2a, esr2b and cyp19a1b genes compared to the E2 -treated group used as a positive control. Zn administration during simultaneous exposure to E2 and Cd strongly stimulated zebrafish ERs transactivation and increased Aro-B protein expression, whereas mRNA levels of the three ERs as well as the cyp19a1b remained unchanged in comparison with Cd-treated embryos. In conclusion, our results clearly demonstrate that Cd acts as a potent anti-estrogen in vivo and in vitro, and that Cd-induced E2 antagonism can be reversed, at the protein level, by Zn supplement. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The present study has been designed and carried out to explore the role of grape seed proanthocyanidins (GSP) in the pancreas of cadmium (Cd)-induced cellular oxidative stress-mediated toxicity in rats. Four groups of healthy rats were given oral doses of Cd (5-mg/kg BW) and to identify the possible mechanism of action of GSP 100-mg/kg BW was selected and was given 90 min before Cd intoxication. The causative molecular and cellular mechanism of Cd was determined using various biochemical assays, histology, western blotting and ELISA. Cd intoxication revealed increased levels of proinflammatory cytokines (TNF-α, IL1β and IFN-γ), reduced levels of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2 and GLUT-4) along with the enhanced levels of signaling molecules of apoptosis (cleaved Caspase-12/9/8/3) in the pancreas of Cd-intoxicated rats. Results suggested that the treatment with GSP reduced blood glucose level, increased plasma insulin and mitigated oxidative stress-related markers. GSP protects pancreatic tissue by attenuated inflammatory responses and inhibited apoptosis. This uniqueness and absence of any detectable adverse effect of GSP proposes the possibility of using it as an effective protector in the oxidative stress-mediated pancreatic dysfunction in rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This study aimed to examine the protective effects of ginger (G) on the genetic response induced by cadmium (Cd) and immunohistochemical expression of Caspase3 and MKI67 in the kidney and liver of rabbits. Male rabbits were divided into three groups; each group contains 10 animals: group (C) received basic diet and tap water for 12 weeks, the second group (Cd) received 200 mg/kg b.w CdCl2 in water for 12 weeks, group (Cd + G) was given 200 mg/kg b.w CdCl2 in water and 400 mg ginger/kg b.w in food for 12 weeks. Cd administration increased the activity of mRNA expression of the examined apoptotic (Caspase3), proliferation (MKI67), proto-oncogene (C-fos), and antioxidant (GST), while decreased the expression of anti-apoptotic (Bcl2). Ginger counteracted the effects of Cd in (Cd + G) group and downregulated the previously upregulated genes under Cd administration appeared in (Cd) group. The immunohistochemical expression of Caspase3 and MKI67 in the liver and kidney cells of the (C) group was shown very faint to negative reactions, strong staining in hepatocytes and the tubular epithelium in cadmium-treated group, while slight staining in some hepatocytes and tubular epithelium in co-administration with ginger in (Cd + G) group. In conclusion, ginger administration showed a protective effect against cadmium toxicity.

Background: Parsley was employed as an experimental probe to prevent the behavioral, biochemical and morphological changes in the brain tissue of the albino mice following chronic cadmium (Cd) administration., Methods: Non-anesthetized adult male mice were given parsley juice (Petroselinum crispum, Apiaceae) daily by gastric intubation at doses of 10 and 20 g/kg/day. The animals were divided into six groups: Group A, mice were exposed to saline; Groups B and C, were given low and high doses of parsley juice, respectively; Group D, mice were exposed to Cd; Groups E and F, were exposed to Cd and concomitantly given low and high doses of parsley, respectively., Results: Cd intoxication can cause behavioral abnormalities, biochemical and histopathological disturbances in treated mice. Parsley juice has significantly improved the Cd-associated behavioral changes, reduced the elevation of lipid peroxidation and normalized the Cd effect on reduced glutathione and peroxidase activities in the brain of treated mice. Histological data have supported these foundations whereas Cd treatment has induced neuronal degeneration, chromatolysis and pyknosis in the cerebrum, cerebellum and medulla oblongata., Conclusion: The low dose (5 g/kg/day) of parsley exhibited beneficial effects in reducing the deleterious changes associated with Cd treatment on the behavior, neurotransmitters level, oxidative stress and brain neurons of the Cd-treated mice.

Protein array technology is a powerful platform for the simultaneous determination of the expression levels of a number of proteins as well as post-translational modifications such as phosphorylation. Here, we screen and report for the first time, the dominant signaling cascades and apoptotic mediators during the course of cadmium (Cd)-induced cytotoxicity in human bronchial epithelial cells (BEAS-2B) by antibody array analyses. Proteins from control and Cd-treated cells were captured on Proteome Profiler™ Arrays for the parallel determination of the relative levels of protein phosphorylation and proteins associated with apoptosis. Our results indicated that the p38 MAPK- and JNK-related signal transduction pathways were dramatically activated by Cd treatment. Cd potently stimulates the phosphorylations of p38α (MAPK14), JNK1/2 (MAPK8/9), and JUN; while the phosphorylations of Akt1, ERK1/2 (MAPK3/1), GSK3β, and mTOR were suppressed. Moreover, there was an induction of proapoptotic protein BAX, release of cytochrome c (CYCS) from mitochondria, activation of caspase-3/9 (CASP3/9); as well as decreased expression of cell cycle checkpoint proteins (TP53, p21, and p27) and several inhibitors of apoptosis proteins (IAPs) [including cIAP-1/2 (BIRC2/3), XIAP (BIRC4), and survivin (BIRC5)]. Pretreatment of cells with the thiol antioxidant glutathione or p38 MAPK/JNK inhibitors before Cd treatment effectively abrogated ROS activation of p38 MAPK/JNK pathways and apoptosis-related proteins. Taken together, our results demonstrate that Cd causes oxidative stress-induced apoptosis; and the p38 MAPK/JNK and mitochondrial pathways are more importantly participated for signal transduction and the induction of apoptosis in Cd-exposed human lung cells.

The aim of this study was to investigate if purple carrot extract is able to protect against the noxious activities induced by cadmium exposure in multiple organs of rats. For this purpose, histopathological analysis, genotoxicity and oxidative status were investigated in this setting. A total of twenty Wistar rats weighing 250g on the average, and 8 weeks age were distributed into four groups (n=5), as follows: Control group (non-treated group, CTRL); Cadmium group (Cd) and Purple carrot extract groups at 400mg/L or 800mg/L. Histopathological analysis revealed that liver from animals treated with purple carrot extract improved tissue degeneration induced by cadmium intoxication. Genetic damage was reduced in blood and hepatocytes as depicted by comet and micronucleus assays in animals treated with purple carrot extract. SOD-CuZn and cytocrome C gene expression increased in groups treated with purple carrot extract. Purple carrot extract also reduced the 8OHdG levels in liver cells when compared to cadmium group. Taken together, our results demonstrate that purple carrot extract is able to protect against cadmium intoxication by means of reducing tissue regeneration, genotoxicity and oxidative stress in multiple organs of Wistar rats., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, Cd treated and Cd treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to Cd injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after Cd exposure. Rats intoxicated with Cd for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and catalase in the frontal cortex tissue. Administration of QE with Cd significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the Cd group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after Cd exposure in rats., (© The Author(s) 2013.)

Cadmium (Cd) is one of the most dangerous occupational and environmental toxins. The objective of the present study is to examine the potential prophylactic effects of phytic acid (PA) on thyroid hormones of male rats intoxicated with Cd. The male albino rats were divided into five groups: group I (control) was fed with the basal diet, group II was intoxicated with Cd in drinking water, groups III, IV, and V were intoxicated with Cd in drinking water and fed with the diet containing 3.5, 7, and 10 g of PA/kg, respectively. The results indicated that the serum calcium, iron (Fe), and total Fe binding capacity levels and serum T3 and T4 in Cd-treated rats of group II were decreased when compared with the control group, while PA-administered groups with Cd showed a significant improvement when compared with the Cd-treated rats only. Serum thyroid stimulating hormone (TSH) level was significantly increased in Cd-treated rats compared with the control group, while the addition of PA in diet decreased the high levels of TSH. These results indicated a prophylactic effect of PA against Cd-induced toxicity in rats., (© The Author(s) 2013.)

Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -β3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-β3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Cadmium (Cd(2+)) is a major environmental pollutant that induces cytotoxicity by heavy-metal accumulation. Prolonged Cd(2+) exposure leads to cell damage by oxidative stress mainly in the kidneys, a critical organ for detoxification. To identify reliable on invasive protein biomarkers for Cd(2+)-induced nephrotoxicity, we performed 2-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization time of flight mass spectra and stable isotope labeling by amino acids in cell culture/liquid chromatography-mass spectrometry analyses using conditioned media (CM) of HK-2 human kidney epithelial cells treated with CdCl2. Here, we identified heat shock cognate 71 kDa protein isoform1 (HSPA8) and α-enolase (ENO1) as potential biomarker candidates for the evaluation of Cd(2+)-induced nephrotoxicity. Treatment with CdCl2 increased the protein level of HSPA8 in CM and lysates of HK-2 cells. The mRNA level of HSPA8 was also increased by CdCl2 treatment, indicating transcriptional regulation. The level of ENO1 was increased in CM, but not in lysates of CdCl2-treated HK-2 cells. CdCl2 did not affect the mRNA level of ENO1. We provide evidence that the increases of HSPA8 and ENO1 in CM were due to Cd(2+)-induced cell death through oxidative stress. The increases of HSPA8 and ENO1 levels were also detected in CM of HK-2 cells treated with other nephrotoxic agents, such as HgCl2, NaAsO2, cisplatin, amphotericin B, and cyclosporine A. Urine and kidney tissues of CdCl2-treated rats showed increased levels of HSPA8. Taken together, this study identified HSPA8 and ENO1 as noninvasive biomarker candidates by 2 comparative proteomic analyses. These new biomarker candidates may have potential as alternatives to traditional biomarkers for the efficient and sensitive assessment of nephrotoxicity., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The aim of this study was to estimate the reference level of cadmium in rice as the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for various renal effects by applying an updated hybrid approach. The participants were 1120 men and 1274 women aged 50 years or older who lived in the environmentally exposed Kakehashi river basin for at least 30 years. As indicators of renal dysfunction, glucose, protein, aminonitrogen, metallothionein and β(2) -microgrobulin in urine were measured. Cadmium concentration was determined for rice samples stored in warehouses of the farmers in all of the polluted hamlets. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at a zero exposure set at 5%. The obtained BMDLs were 0.39 (aminonitrogen), 0.26 (metallothionein), 0.25 (β(2) -microgrobulin) mg kg(-1) in men and 0.44 (glucose), 0.32 (protein), 0.33 (aminonitrogen), 0.28 (metallothionein) and 0.24 (β(2) -microgrobulin) mg kg(-1) in women. The lowest BMDL was 0.25 and 0.24 mg kg(-1) (β(2) -microgrobulin) in men and women respectively. These values were lower than the maximum level (0.4 mg kg(-1)) determined by the Codex Alimentarius Commission, indicating that these BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure., (Copyright © 2014 John Wiley & Sons, Ltd.)

Alpha-lipoic acid (α-LA) is an important antioxidant that is capable of regenerating other antioxidants, such as glutathione (GSH). In the present study, we examined the protective effects of α-LA against the oxidative stress and cytotoxicity induced by cadmium in human hepatoma cell lines (HepG2) and investigated if the process was mediated through regenerating GSH. Our results showed that after exposure to 25 μM cadmium for 16 h, there was a significant decrease in the cell viability and glutathione levels and a significant increase in lipid peroxidation (p<0.01) compared with untreated cells. The presence of α-LA significantly attenuated cadmium-induced cytotoxicity and lipid peroxidation, and reversed cellular GSH levels compared with cadmium-treated cells (p<0.05). Compared with the cells treated with cadmium, co-treatment with α-LA and cadmium significantly increased the activities of γ-glutamylcysteine ligase (γ-GCL), the rate limiting enzyme in GSH biosynthesis and the mRNA and the protein levels of γ-GCL catalytic subunit (GCLC) and a modifier subunit (GCLM). In conclusion, our results indicated that α-LA is an effective agent to reduce the oxidative stress and cytotoxicity induced by cadmium by regenerating GSH levels through increasing the activities and the expressions of γ-GCL.

The Mimosa (Mimosa caesalpiniifolia) is a plant native from South America; it is used in the traditional medicine systems for treating bacterial, fungal, parasitic and inflammatory conditions. The aim of this study was to evaluate the antigenotoxic and antioxidant activities induced by mimosa (M. caesalpiniifolia) in multiple rodent organs subjected to intoxication with cadmium chloride. A total of 40 Wistar rats (8 weeks old, 250 g) were distributed into eight groups (n = 5), as follows: Control group (non-treated group, CTRL); Cadmium exposed group (Cd); cadmium exposure and treated with extract at 62.5 mg/kg/day; cadmium exposure and treated with extract at 125 mg/kg/day; cadmium exposure and treated with extract at 250 mg/kg/day; cadmium exposure and treated with ethyl acetate fraction at 62.5 mg/kg/day. For evaluating the toxicogenetic potential of mimosa, two groups were included in the study being treated with extract at 250 mg/kg/day and acetate fraction of mimosa at 62 mg/kg/day, only. Extract of mimosa at concentrations of 62.5 and 125 mg decreased DNA damage in animals intoxicated with cadmium when compared to cadmium group. In a similar manner, treatment with ethyl acetate fraction of mimosa at 62.5 mg concentration in animals previously exposed to cadmium reduced genetic damage in peripheral blood cells. In a similar manner, the treatment with ethyl acetate fraction reduced DNA damage in liver cells. Oxidative DNA damage was reduced to animals exposed to cadmium and treated with 125 mg of extract as well as those intoxicated to cadmium and treated with 62.5 of acetate fraction of mimosa. Taken together, our results indicate that mimosa prevents genotoxicity induced by cadmium exposure in liver and peripheral blood cells of rats as a result of antioxidant activity.

Background: Cadmium (Cd) is a major environmental pollutant that causes multiple adverse health effects in humans and animals. In this study, we investigated Cd-mediated toxic effects in rats during pregnancy and endocrine intervention in the placenta., Methods: We exposed pregnant rats to intraperitoneal Cd (CdCl2) at various doses (0, 0.25, and 0.5 mg/kg BW/day) from days 5 to 19 of pregnancy and evaluated the maternal-placental-fetal parameters linked to preeclampsia. We measured the corticosterone level in rat serum and placental tissue by sensitive ELISA and also analyzed the expression of glucocorticoid synthesis enzymes in the placenta., Results: Key features of preeclampsia (PE), including hypertension, proteinuria, glomerular endotheliosis, placental abnormalities and small fetal size, appeared in pregnant rats after injection with 0.5 mg/kg BW/day Cd. The placental corticosterone production and maternal and fetal plasma corticosterone levels were increased in rats treated with 0.5 mg/kg BW/day Cd (P <0.01). The expression of 21-hydroxylase (CYP21) and 11beta-hydroxylase (CYP11B1), enzymes essential for corticosteroid synthesis, were increased in Cd-exposed placenta (P <0.01). 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), a dominant negative regulator of local glucocorticoid levels, was decreased in Cd-exposed placenta (P <0.01)., Conclusions: Our study demonstrates for the first time that changes in placental glucocorticoid synthesis induced by Cd exposure during pregnancy could contribute to preeclamptic conditions in rats.

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.

Arsenic and cadmium are toxic metals of environmental significance with harmful effects on man. To study the toxicological and biochemical effects of arsenic/cadmium in mammals a combined metallomic and metabolomic approach has been developed, complemented with the measurement of biochemical parameters in blood and histopathological evaluation of liver injury in mice Mus musculus under exposure to both xenobiotics. Size-exclusion chromatography (SEC) was combined with affinity chromatography (AF) and ICP-MS detection using species unspecific isotopic dilution analysis (SUID) to characterize the biological effects of As/Cd on selenium containing proteins in the bloodstream of exposed mice. On the other hand, both direct infusion mass spectrometry (DIMS) and gas chromatography-mass spectrometry (GC-MS) provided information about changes in metabolites caused by metals. The results show that As/Cd exposure produces interactions in the distribution of both toxics between organs and plasma of mice and antagonistic interactions with selenium containing proteins in the bloodstream. Interplay with essential metabolic pathways, such as energy metabolism and breakdown of membrane phospholipids were observed, which are more pronounced under As/Cd exposure. In addition, heavy metal and metalloid causes differential liver injury, manifested by steatosis (non-alcoholic fatty liver disease, NAFLD) and infiltration of blood cells into the space of Disse., Biological Significance: This work presents new contributions in the study of arsenic/cadmium interactions in mice Mus musculus under controlled exposure. With the combination of metallomic and metabolomic approaches the traffic of As and Cd from liver to kidney by means of blood was observed and excretion of As (as arsenic metabolites) or Cd (as MTCd) is inhibited with the simultaneous administration of As/Cd, and these toxic elements have important influence in the levels of seleno-proteins in the plasma. In addition, the metabolomic approach reveals inhibition of different metabolic cycles such as tricarboxylic acid and phospholipid degradation that causes membrane damage and apoptosis that is histopathologically confirmed. This article is part of a Special Issue entitled: Environmental and structural proteomics., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cadmium (Cd) is an environmental and industrial pollutant that can induce a broad spectrum of toxicological effects that affect various organs in humans and experimental animals. This study aims to investigate the effect of betaine supplementation on cadmium-induced oxidative impairment in rat kidney. The animals were divided into four groups (n=10 per group): control, cadmium, betaine and betaine+cadmium (1) saline control group; (2) cadmium group in which cadmium chloride (CdCl2) was given orally at a daily dose of 5 mg/kg body weight for four weeks; (3) betaine group, in which betaine was given to rats at a dose of 250 mg/kg/day, orally via gavage for six weeks; (4) cadmium+betaine group in which betaine was given at a dose of 250 mg/kg/day, orally via gavage for two weeks prior to cadmium administration and concurrently during cadmium administration for four weeks. Cadmium nephrotoxicity was indicated by elevated blood urea nitrogen (BUN) and serum creatinine levels. Kidneys from cadmium-treated rats showed an increase in lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS) concentration and reductions in total antioxidant status (TAS), reduced glutathione (GSH) content, glutathione peroxidase (GSH-Px) activity, superoxide dismutase concentration (SOD) and catalase activity. Caspase-3 activity, a marker of DNA damage was also elevated in renal tissues of cadmium-treated rats. Pre-treatment of rats with betaine substantially attenuated the increase in BUN and serum creatinine levels. Betaine also inhibited the increase in TBARS concentration and reversed the cadmium-induced depletion in total antioxidant status, GSH, GSH-Px, SOD and catalase concentrations in renal tissues. Renal caspase-3 activity was also reduced with betaine supplementation. These data emphasize the importance of oxidative stress and caspase signaling cascade in cadmium nephrotoxicity and suggest that betaine pretreatment reduces severity of cadmium nephrotoxicity probably via antioxidant action and suppression of apoptosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background & Aims: Cadmium (Cd) is a widespread environmental contaminant that causes both renal tubulopathy and osteomalacia. Osteomalacia is thought to be a result of renal tubulopathy, but there are few studies about the histopathological relationship between the two pathoses. Therefore, in the present study, we examined specimens from cases of itai-itai disease (IID), the most severe form of chronic cadmium poisoning, to evaluate the relationship between them., Methods: We analyzed kidney and bone specimens of 61 IID cases and the data regarding Cd concentration in kidney and bone. Tubulopathy was graded on the basis of a three-step scale (mild, moderate, and severe) using the following three items: the degree of proximal tubular defluxion, thickness of renal cortex, and weight of the kidney. Osteomalacia was evaluated using the relative osteoid volume (ROV)., Results: There were 15 cases of mild, 19 cases of moderate, and 27 cases of severe tubulopathy. The average ROV was 24.9 ± 2.0%. ROV tended to increase as tubulopathy advanced in severity, and ROV was significantly higher in cases with severe tubulopathy than those with mild or moderate tubulopathy. ROV had a negative correlation with Cd concentration in the kidney but no correlation with that in the bone., Conclusions: Our results suggest that the development of osteomalacia was related to the development of tubulopathy.

The present study was devised to assess the effects of cadmium chloride (CdCl(2)) administration on certain andrological, endocrinological and biochemical alterations in adult male rabbits (n=24). The animals were assigned to control (n=8) and experimental (n=16) group. Experimental group was orally administered with 1.5 mg/kg body weight of CdCl(2). The trials were carried out for a total of 5 weeks and blood sampling was carried out on weekly basis. A gradual decrease was noticed for body weight in the experimental group from week 1 to 5, being significantly lower in week 4 and 5 (P<0.05). A similar decremented trend was noticed for serum testosterone level being significantly lower in experimental group in week 4 and 5 (P<0.001). Significantly lower values were noticed for prolactin in experimental group in week 4 and 5 (P<0.05), than in the control. On the contrary, serum cortisol level showed a gradual increase in experimental group, from week 1 to 5, being significantly higher in week 4 and 5 (P<0.05). Regarding the biochemical attributes, all the parameters under study revealed a gradually ascending trend. Statistical significance was, however, achieved in varying weeks and at varying levels. The total protein and albumin were significantly higher in week 4 and 5 (P<0.01); alanine aminotransferase in week 2 (P<0.01), 3 (P<0.001), 4 (P<0.01) and 5 (P<0.001); aspartate aminotransferase in week 1, 2, 3, 4 and 5 (P<0.01); and alkaline phosphatase in week 1, 2 (P<0.01), 3, 4 and 5 (P<0.0001), respectively. Overall mortality rate in experimental group was 68.75 (11/16). In a nutshell, Cd exposure results in adverse effects on all physiological parameters of body and may lead to lethal consequences.

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.

Environmental exposure to pollutants such as heavy metal(s) is responsible for various altered physiological functions which are detrimental for health. The gut microbiota is critical for intestinal homeostasis but its role on xenobiotic handling is not fully understood, especially when continuous sub-chronic exposure is addressed. We first confirmed the essential role of the intestinal microbiome to limit heavy metal body burden by using germ-free mice following 6-weeks oral exposure. Significant increases of cadmium and lead absorption and dissemination in blood and target organs were measured in germ-free mice when compared with conventional specific pathogen free (SPF) mice. Besides the "barrier" function of the luminal microbiota, this may involve specific host-genes such as metallothioneins, which are differentially expressed in the gastrointestinal tract of each group of mice. Considering genes relevant for divalent metal transporters and oxidative pathways, significant differences in basal gene expression were measured between control and germ-free mice. Moreover, the magnitude of induction of these genes upon stimulation by heavy metals varied greatly depending on the dose and type of metal as well as the microbial status of the animal. Collectively, these data illustrate the complex host-microbes interplay occurring with environmental pollutants inside the gut., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Chronic exposure to low cadmium (Cd) levels produces urinary excretion of low molecular weight proteins, which is considered the critical effect of Cd exposure. However, the mechanisms involved in Cd-induced proteinuria are not entirely clear. Therefore, the present study was designed to evaluate the possible role of megalin and cubilin (important endocytic receptors in proximal tubule cells) and angiotensin II type 1 (AT1) receptor on Cd-induced microalbuminuria., Methods: Four groups of female Wistar rats were studied. Control (CT) group, vehicle-treated rats; LOS group, rats treated with losartan (an AT1 antagonist) from weeks 5 to 8 (10 mg/kg/day by gavage); Cd group, rats subchronically exposed to Cd (3 mg/kg/day by gavage) during 8 weeks, and Cd + LOS group, rats treated with Cd for 8 weeks and LOS from weeks 5-8. Kidney Cd content, glomerular function (evaluated by creatinine clearance and plasma creatinine), kidney injury and tubular function (evaluated by Kim-1 expression, urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and glucose, and microalbuminuria), oxidative stress (measured by lipid peroxidation and NAD(P)H oxidase activity), mRNA levels of megalin, expressions of megalin and cubilin (by confocal microscopy) and AT1 receptor (by Western blot), were measured in the different experimental groups. Data were analyzed by one-way ANOVA or Kruskal-Wallis test using GraphPad Prism 5 software (Version 5.00). P < 0.05 was considered statistically significant., Results: Administration of Cd (Cd and Cd + LOS groups) increased renal Cd content. LOS-treatment decreased Cd-induced microalbuminuria without changes in: plasma creatinine, creatinine clearance, urinary NAG and glucose, oxidative stress, mRNA levels of megalin and cubilin, neither protein expression of megalin nor AT1 receptor, in the different experimental groups studied. However, Cd exposure did induce the expression of the tubular injury marker Kim-1 and decreased cubilin protein levels in proximal tubule cells whereas LOS-treatment restored cubilin levels and suppressed Kim-1 expression., Conclusion: LOS treatment decreased microalbuminuria induced by Cd apparently through a cubilin receptor-dependent mechanism but independent of megalin.