The modifying effect of kidney function on the association of cadmium exposure with blood pressure and cardiovascular mortality: NHANES 1999-2010.

OBJECTIVE: We hypothesized that the associations of urinary Cd with blood pressure and cardiovascular disease (CVD) mortality may be modified by renal function. METHODS: We tested these hypotheses using data from the National Health and Nutrition Examination Survey (NHANES, 1999-2010). RESULTS: Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were positively associated with blood Cd. DBP was positively related to urinary Cd whereas SBP was inversely associated with urinary Cd. In the stratified analyses by level of eGFR, the associations between SBP and urinary Cd were not statistically significant among those with normal renal function and those with mildly reduced renal function whereas SBP significantly positively associated with urinary Cd among those with moderately or severely decreased renal function (p for trend, 0.0004). Renal function appeared to be a modifying factor of the association between urinary Cd and mortality. CVD mortality risks (p for trend, 0.04) were significantly increased with increasing urinary Cd with hazard ratios (HRs) (95% CIs) of 2.18 (0.68-7.01) for the highest quartile of urinary Cd compared to the lowest. The association between urinary Cd and CVD mortality became stronger in the stratified analyses by renal function and these associations became more consistent in those who never smoked. CONCLUSIONS: The inverse association between urinary Cd and blood pressure observed in previous studies may be due to lack of consideration of renal function as an effect modifier. The strength of the association between urinary Cd and CVD mortality may be underestimated without considering renal function.

Relevance of megalin receptor injury with nuclear factor-kappa B upregulation in acute kidney injury induced in rats.

Proximal tubule protein take-up is interceded by 2 receptors, megalin and cubilin. These receptors rescue an assortment of filtered ligands including fundamental vitamins and hormones. The objective of this study was to investigate the potential relation of megalin receptor injury with nuclear factor-kappa B (NF-κB) upregulation in acute kidney injury rat model. Twenty four rats were allocated into two groups: control group received saline, while the second group was intoxicated with cadmium chloride (2.4 mg Cd/kg/day i.p) for 30 days. Blood urea nitrogen, serum creatinine, tissue oxidant-antioxidant parameters (malondialdehyde [MDA] and reduced glutathione [GSH]) and expression levels for NF-κB, toll like receptor-2 (TLR2), toll like receptor-4 (TLR4), and megalin receptor were estimated. Noticeable downregulation of megalin receptor versus upregulation of NF-κB, TLR2, and TLR4 were observed in AKI rat model together with significant elevation in MDA as well as significant reduction in GSH. The study concluded that the oxidative stress in kidney tissue leads to megalin receptor damage, which indeed motivates upregulation of NF-κB through TLRs 2 and 4 pathways.

Rutin hydrate ameliorates cadmium chloride-induced spatial memory loss and neural apoptosis in rats by enhancing levels of acetylcholine, inhibiting JNK and ERK1/2 activation and activating mTOR signalling.

This study aimed at studying the potential neuroprotective effect of Rutin hydrate (RH) alone or in conjugation with α-tocopherol against cadmium chloride (CdCl2)-induced neurotoxicity and cognitive impairment in rats and to investigate the mechanisms of action. Rats intoxicated with CdCl2 were treated with the vehicle, RH, α-tocopherol or combined treatment were examined, and compared to control rats received vehicle or individual doses of either drug. Data confirmed that RH improves spatial memory function by increasing acetylcholine availability, boosting endogenous antioxidant potential, activating cell survival and inhibiting apoptotic pathways, an effect that is more effective when RH was conjugated with α-tocopherol. Mechanism of RH action includes activation of PP2A mediated inhibiting of ERK1/2 and JNK apoptotic pathways and inhibition of PTEN mediated activation of mTOR survival pathway. In conclusion, RH affords a potent neuroprotection against CdCl2-induced brain damage and memory dysfunction and co-administration of α-tocopherol enhances its activity.

Toxic effects of cadmium on tall fescue and different responses of the photosynthetic activities in the photosystem electron donor and acceptor sides.

Tall fescue (Festuca arundinacea Schreb) is a turf grass species which is widely used for rhizoremediation of organic contaminants and shows notable prospects in heavy metal phytoremediation. In this study, different concentrations of cadmium ion (Cd2+) were applied to study toxic effects of Cd2+ and responses of tall fescue by soilless culture. Tall fescue showed comparable high tolerance to Cd2+ as Indian mustard (Brassica juncea L.). Additionally, the treatment with high concentration of Cd2+ leaded to decreased chlorophyll contents, production of reactive oxygen species (ROS) and lipid peroxidation, as well as damage of cell membrane, necrosis and apoptosis in tall fescue roots, and toxicity of Cd2+ on physiologic properties of tall fescue has been well discussed. Moreover, in photosystem II electron donor side, electron transport from oxygen evolution complex (OEC) to Yz residue of D1 protein was inhibited under high Cd2+ treatments, which may be due to the Cd2+ induced ROS production and the replacement of Ca2+ in the core of OEC. In electron acceptor side, electron transport efficiency from quinone B to photosystem I acceptors increased under high Cd2+ treatments, which may be an important response for plants against Cd2+ toxicity and its mechanism needs our further study.

The effect of tannic acid on bone mechanical and geometric properties, bone density, and trabecular histomorphometry as well as the morphology of articular and growth cartilages in rats co-exposed to cadmium and lead is dose dependent.

Cadmium (Cd) and lead (Pb) are toxic elements that accumulate to the largest extent in bones. Rats were used to investigate whether tannic acid (TA; 0.5%, 1.0%, 1.5%. 2.0%, or 2.5%) would have a protective effect on the structure and properties of bones in the case of exposure to Cd and Pb (diet: 7 mg Cd/kg and 50 mg Pb/kg) for 6 weeks. The effects of administration of TA in Cd- and Pb-poisoned rats on bone characteristics and the morphology of articular and growth cartilages were determined. All the rats administered Cd and Pb had an enhanced Cd and Pb concentration in blood plasma and bone and reduced bone Ca content irrespective of the TA administration. Cd and Pb alone reduced the mechanical endurance and histomorphometric parameters of trabecular bone and the thickness of the growth plate and articular cartilage. Tannic acid improved cancellous bone parameters in the rat exposed to Cd and Pb. A diet rich in TA improved articular cartilage constituents in heavy metal-poisoned rats. These results suggest that alimentary TA supplementation can counteract in a dose-dependent manner some of the destructive changes evoked by Cd and Pb possibly by reducing the exposure.

Neurotoxicity of Metal Mixtures.

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.

Curcumin attenuates memory deficits and the impairment of cholinergic and purinergic signaling in rats chronically exposed to cadmium.

This study investigated the protective effect of curcumin on memory loss and on the alteration of acetylcholinesterase and ectonucleotidases activities in rats exposed chronically to cadmium (Cd). Rats received Cd (1 mg/kg) and curcumin (30, 60, or 90 mg/kg) by oral gavage 5 days a week for 3 months. The animals were divided into eight groups: vehicle (saline/oil), saline/curcumin 30 mg/kg, saline/curcumin 60 mg/kg, saline/curcumin 90 mg/kg, Cd/oil, Cd/curcumin 30 mg/kg, Cd/curcumin 60 mg/kg, and Cd/curcumin 90 mg/kg. Curcumin prevented the decrease in the step-down latency induced by Cd. In cerebral cortex synaptosomes, Cd-exposed rats showed an increase in acetylcholinesterase and NTPDase (ATP and ADP as substrates) activities and a decrease in the 5'-nucleotidase activity. Curcumin was not able to prevent the effect of Cd on acetylcholinesterase activity, but it prevented the effects caused by Cd on NTPDase (ATP and ADP as substrate) and 5'-nucleotidase activities. Increased acetylcholinesterase activity was observed in different brain structures, whole blood and lymphocytes of the Cd-treated group. In addition, Cd increased lipid peroxidation in different brain structures. Higher doses of curcumin were more effective in preventing these effects. These findings show that curcumin prevented the Cd-mediated memory impairment, demonstrating that this compound has a neuroprotective role and is capable of modulating acetylcholinesterase, NTPDase, and 5'-nucleotidase activities. Finally, it highlights the possibility of using curcumin as an adjuvant against toxicological conditions involving Cd exposure. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 70-83, 2017.

Grape seed proanthocyanidins protects against cadmium induced oxidative pancreatitis in rats by attenuating oxidative stress, inflammation and apoptosis via Nrf-2/HO-1 signaling.

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, IL1ß 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.

Acute exposure to cadmium induces prolonged neutrophilia along with delayed induction of granulocyte colony-stimulating factor in the livers of mice.

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.

Protective effects of grape seed extract on cadmium-induced testicular damage, apoptosis, and endothelial nitric oxide synthases expression in rats.

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 influence of zinc on the blood serum of cadmium-treated rats through the rheological properties.

The blood rheological properties serve as an important indicator for the early detection of many diseases. This study aimed to investigate the influence of zinc (Zn) on blood serum of cadmium (Cd) intoxication-treated male rats through the rheological properties. The rheological parameters were measured in serum of control, Cd, and Cd+Zn groups at wide range of shear rates (225-1875 s(-1)). The rat blood serum showed a non-significant change in cadmium-treated rats' %torque and shear stress at the lower shear rates (200-600 s(-1)) while a significant increase was observed at the higher shear rates (650-1875 s(-1)) compared with the control. The rat blood serum viscosity increased significantly in the Cd-treated group at each shear rate compared with the control. The viscosity and shear rate exhibited a non-Newtonian behavior for all groups. The increase in blood serum viscosity in Cd-treated male rats might be attributed to destruction or changes in the non-clotting proteins, and other blood serum components. In Cd+Zn-treated rats, the rat blood serum viscosity values returned nearer to the control values at each shear rate. Our results confirmed that Zn displaced Cd or compete with the binding sites for Cd uptake.

Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood­Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice [corrected].

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) -ß3, 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-ß3, 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.

Noninvasive Biomarker Candidates for Cadmium-Induced Nephrotoxicity by 2DE/MALDI-TOF-MS and SILAC/LC-MS Proteomic Analyses.

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.

Preeclampsia induced by cadmium in rats is related to abnormal local glucocorticoid synthesis in placenta.

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 chloride toxicity revisited: effect on certain andrological, endocrinological and biochemical parameters of adult male rabbits.

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.

Chronic cadmium treatment induces tubular nephropathy and osteomalacic osteopenia in ovariectomized cynomolgus monkeys.

In an attempt to establish a primate model of chronic cadmium toxicosis, we ovariectomized cynomolgus monkeys and treated them with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed normocytic-normochromic anemia. The cadmium treatment resulted in increases of urinary enzyme activity indicative of renal tubular degeneration. Histopathology of the kidney revealed renal proximal tubular atrophy accompanied by interstitial fibrosis. Decreased bone mineral density was evident in the trabecular and cortical zones of the lumbar vertebra and femur, with osteoid accumulation around the trabeculae and Haversian canals. Iron deposition at the mineralization front and osteoclasts hyperplasia were indicative of impairment of bone mineralization and an increase of resorption. Blood inorganic phosphorus and 1α,25(OH)2 vitamin D3 levels decreased and urinary deoxypyridinoline level increased in cadmium-treated animals. The renal and bone lesions closely resemble those of itai-itai disease patients, the most severe case of cadmium toxicosis in terms of clinical chemistry and histopathology. Thus, ovariectomized monkeys chronically exposed to cadmium can serve as a primate itai-itai disease model, which is beneficial for developing novel therapeutic methods, investigating the mechanisms of the renal and bone lesions, and establishing more clearly defined criteria for diagnosing the disease.

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.

The hypothalamic-pituitary-gonadal axis is target of cadmium toxicity. An update of recent studies and potential therapeutic approaches.

This review presents an overview of neuroendocrine disruption induced by cadmium on the hypothalamic-pituitary-gonadal (HHG) axis. This review focuses on a number of hypotheses: (1) the HHG axis is a physiological target on cadmium toxicity; (2) cadmium could induce chronotoxicity on this neuroendocrine axis by disrupting the daily pattern of the HHG axis activity; (3) cadmium exposure throughout life could contribute to the oxidative stress and the circadian rhythms disruption induced by aging on the HHG; and (4) cadmium induces oxidative stress in the HHG axis so antioxidants could prevent or reduce cadmium toxicity in this system. Cadmium disrupts the regulatory mechanisms of this physiological axis, by altering neurotransmitters involved in this regulation at the hypothalamic level, altering gonadotropin hormone secretion, and by affecting testicular or ovarian structure and activity. These effects are age-dependent and they could be related to the circadian rhythms of this physiological axis. Several antioxidant agents could have a protective action against the neuroendocrine toxicity of cadmium on the reproductive system. A comprehensive view of the physiological axis may provide a better understanding about the neuroendocrine toxicity of cadmium on the reproductive system, so this perspective is recommended for undertaking further studies.

Combined effects of estrogen deficiency and cadmium exposure on calcified hard tissues: animal model relating to itai-itai disease in postmenopausal women.

Using ovariectomized rats as a model of postmenopausal women, we studied the effects of estrogen (Es) deficiency and in combination with cadmium (Cd) exposure on the calcified hard tissues related to the development of itai-itai disease. Es deficiency suppressed the synthesis of carbonic anhydrase required for the crystal nucleation process, causing the crystal structure defects in the tooth enamel. Regarding the combined effects of Es deficiency and Cd exposure on the bone, in which rats were given drinking water containing Cd ions, soft X-ray radiography revealed a development of labyrinthine pattern in the calvaria, and micro-computed tomography demonstrated the declining trabecular architecture of the tibia, suggesting Cd-induced osteoporotic change. Further, electron microscopy showed the increase of amorphous minerals in the calvaria. In conclusion, the combined effects of Es deficiency and Cd exposure can be responsible for accelerating the declining bone strength together with the crystal structure defects resulting in the preferential occurrence of itai-itai disease in postmenopausal women.(Communicated by Tatsuo SUDA, M.J.A.).

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers.

PURPOSE: Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect. METHODS: Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (µ-Alb), beta-2-microglobulin (ß2-MG), retinol binding protein (RBP), N-acetyl-ß-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey. RESULTS AND CONCLUSIONS: The median Cd-B, Cd-U, Pb-B were: 0.8 µg/l (IQR = 0.5, 1.2), 0.5 µg/g creatinine (IQR = 0.3, 0.8) and 158.5 µg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥ 75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥ 75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., µ-Alb and ß2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.