Metabolomics in liver injury induced by dietary cadmium exposure and protective effect of calcium supplementation.

The purpose of the study was to explore the effect of calcium (Ca) supplementation on liver injury induced by cadmium (Cd) in rats and its potential metabolic mechanisms through metabolomics analysis. Seventy rats were randomly allotted into 7 groups, including a control group, 3 groups with different levels of Cd exposed (1, 5, and 50 mg Cd/kg diet), and 3 corresponding Ca supplement groups (4 g Ca/kg diet) based on the Cd exposed groups. Dietary intake was simulated by giving Cd or Cd+Ca in the diets of rats. After 13-week feeding, serum biochemical parameters and liver histopathology were examined. Then the metabolic analysis of rat liver tissues was performed by ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS). It was demonstrated that Ca supplementation could reverse the abnormal alterations in TG, TC, GSH, MDA induced by Cd exposure, as well as the hepatic pathological changes in rats. Furthermore, the metabolomics analysis of liver samples revealed several distinct regulatory pathways, including energy, amino acid, and lipid metabolic pathways. In conclusion, it showed that Ca supplementation had an ameliorative effect on liver injury induced by Cd exposure in rats, which may be related to the role of Ca in regulating multiple metabolic pathways.

Antioxidant and antigenotoxic potential of Morinda tinctoria Roxb. leaf extract succeeding cadmium exposure in Asian catfish, Pangasius sutchi.

The present study investigated the protective effect of methanolic leaf extract of Morinda tinctoria. Roxb (MEMT) (200 mg/kg) via feed in supplementation with standard compound silymarin (400 mg/kg). M. tinctoria (Roxb.) belonging to Rubiaceae, is an evergreen shrub indigenous to unfarmed lands of tropical countries. It is considered as an essential traditional medicine attributing for the potential antioxidant and anti-inflammatory properties. The enhancements of antioxidant and antigenotoxic status in different tissues of cadmium (Cd) intoxicated Pangasius sutchi were evaluated by using various antioxidant assays (superoxide dismutase (SOD) and catalase (CAT) and lipid peroxidation) in addition to micronuclei (MN), binuclei (BN) and comet assay. The cadmium toxicated fish showed a significant (p < 0.001) increase in lipid peroxidation (LPO) activities in liver, gills, muscle and kidney whereas significant (p < 0.001) decline were observed in superoxide dismutase (SOD) and catalase (CAT) contents in all fish tissues. The results also revealed that, Cd exposure induced the formation of genotoxic endpoints like MN, BN, notched nuclei, kidney shaped nuclei and DNA damage in the fish erythrocytes. Maximum of 26.8% MN frequencies and maximum of 66.74% tail DNA damage were observed on the 7th day of Cd exposure. A time-dependent significant increase (p < 0.001) in the frequencies of MN, BN and tail DNA damage were observed in all treated groups against the control which started to decline from 14th day onwards. There was a decline in the LPO content, frequencies of MN, BN and percentage of tail DNA in contrast to significant elevation in SOD and CAT content in all tissues due to the combined treatment of M. tinctoria feed and water borne Cd exposure. It can be concluded from our observations that, supplementation of M. tinctoria leaf extract through feed alone produced enhanced antioxidant and antigenotoxic status in cadmium treated fish by diminishing oxidative stress and genotoxicity effects in a time dependent manner.

Cadmium induces endoplasmic reticulum stress-mediated apoptosis in pig pancreas via the increase of Th1 cells.

Cadmium (Cd), an environmental pollutant, causes several adverse reactions in animals. High dose of Cd has serious cytotoxicities, including the induction of programmed cell necrosis, autophagy and apoptosis, which has aroused wide public concern. The balance of cytokine network is affected by Th1/Th2 balance which is closely related to immune response and the occurrence, development, treatment and outcome of various diseases. Cd can induce severe apoptosis, but the relationship between Cd induced apoptosis and Th1/Th2 balance has not been clarified. In this study, we established a pig Cd poisoning model, exposing to CdCl2 for 40 days (20 mg Cd/kg diet). Firstly, deviation of Th1/Th2 balance was observed by fluorescence staining, and apoptosis was observed by TUNEL staining. Then, real-time fluorescence quantitative analysis and Western blot were used to detect the expression of related proteins. The results show that Cd can interfere with the balance of Th1/Th2 and shift the balance towards Th1. In addition, through the experiments, we found that Cd exposure can increase the expression of glucose-regulated protein 94 (GRP94) and glucose-regulated protein 78 (GRP78), marker proteins of unfolded protein response (UPR). Cd exposure can increase the expression of pancreatic endoplasmic reticulum kinase (PERK), CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE-1), activating transcription factor 6 (ATF-6), cysteinyl aspartate specific proteinase (Caspase12), indicating the three branches (ATF6, PERK and IRE-1) of endoplasmic reticulum stress (ER-stress) were activated. Moreover, we found that the expression of pro-apoptosis genes in the downstream pathway of ER-stress increased. In summary, our results indicated that Cd exposure upregulated the expression of pro-apoptosis related genes and caused apoptosis via the activation of the ER-stress signaling pathways in pancreas cells. And these negative effects were correlated with the equilibrium drift of Th1/Th2, increase in the expression and secretion of Th1 cytokines.

Do Only Calcium and Vitamin D Matter? Micronutrients in the Diet of Inflammatory Bowel Diseases Patients and the Risk of Osteoporosis.

Osteoporosis is one of the most common extraintestinal complications among patients suffering from inflammatory bowel diseases. The role of vitamin D and calcium in the prevention of a decreased bone mineral density is well known, although other nutrients, including micronutrients, are also of extreme importance. Despite the fact that zinc, copper, selenium, iron, cadmium, silicon and fluorine have not been frequently discussed with regard to the prevention of osteoporosis, it is possible that a deficiency or excess of the abovementioned elements may affect bone mineralization. Additionally, the risk of malnutrition, which is common in patients with ulcerative colitis or Crohn's disease, as well as the composition of gut microbiota, may be associated with micronutrients status.

Analyzing dose dependency of antioxidant defense system in the cyanobacterium Nostoc muscorum Meg 1 chronically exposed to Cd2.

The aim of the present study was to analyze the dose dependency of oxidant-antioxidant homeostasis in Cd2+ exposed Nostoc muscorum Meg 1 cells. Quantification of percent DNA loss, protein oxidation and lipid peroxidation was carried out to assess Cd2+ induced ROS mediated damages to the organism. The countermeasures adopted by the cyanobacterium were also evaluated by computing various components of both enzymatic and non-enzymatic antioxidants. Exposure to different Cd2+ (0.1, 0.2, 0.3, 0.5, 1, 1.5, 2, 2.5, 3 ppm) doses showed substantial increase in ROS content in the ranges of 20-181% and 116-323% at the end of first and seventh day. The DNA damage, protein oxidation and lipid peroxidation were increased by 11-62%, 7-143% and 13-183% with increasing Cd2+ concentrations at the end of seven days. TEM images clearly showed damages to the cell wall, cell membrane and thylakoid organization at higher Cd2+ (0.5-3 ppm) concentrations. Cd2+ exposure up to 0.5 ppm registered increase in contents of antioxidative enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)) and in non-enzymatic antioxidants (glutathione, total thiol, phytochelatin and proline) indicating stimulation of ROS mitigating machinery. However, toxicity of Cd2+ was evident as at higher concentrations the cellular morphology and ultra-structures were negatively affected and the capacities of the cells to generate various antioxidant measures were highly compromised. The organism registered 96-98% sorption ability from a solution supplemented with 0.3 ppm Cd2+ and thus show realistic potential as Cd2+ bioremediator in wastewater treatment.

The Impact of a Polyphenol-Rich Extract from the Berries of Aronia melanocarpa L. on Collagen Metabolism in the Liver: A Study in an In Vivo Model of Human Environmental Exposure to Cadmium.

This study examined whether a polyphenol-rich extract from the berries of Aronia melanocarpa L. (AE; chokeberries) may protect from the impact of cadmium (Cd) on the metabolism of collagen in the liver. The study was conducted in an experimental model (rats that were fed a diet containing 1 or 5 mg Cd/kg for 3-24 months) of human exposure to this xenobiotic during a lifetime. The concentration of total collagen and the expression of collagen types I and III at the mRNA and protein levels, as well as the concentrations of matrix metalloproteinases (MMP-1 and MMP-2) and their tissue inhibitors (TIMP-1 and TIMP-2), were assayed. The administration of Cd and/or AE had only a slight and temporary impact on the concentration of total collagen in the liver. The supplementation with AE significantly prevented Cd-mediated changes in the expression of collagen types I and III at the mRNA and protein levels and their ratio (collagen III/collagen I), as well as a rise in the concentrations of MMPs and TIMPs in this organ. The results allow the conclusion that the intake of chokeberry products in the case of Cd intoxication may be effective in prevention from this xenobiotic-induced disturbance in collagen homeostasis in the liver.

The Protection of Selenium Against Cadmium-Induced Mitochondrial Damage via the Cytochrome P450 in the Livers of Chicken.

Cadmium (Cd) is a heavy metal in natural environment and has extreme toxicity. Selenium (Se) has protective effect against heavy metal-induced injury or oxidative stress. Cytochrome P450 (CYP450) enzymes are a family of hemoproteins primarily responsible for detoxification functions. In order to investigate whether CYP450 is related to the damage of livers caused by Cd exposure, we chose forty-eight 28-day-old healthy Hailan cocks for four groups: control group, Se group, Cd group, and Se + Cd group. After 90-day treatment, euthanized for experiment. Based on an established subchronic Cd poisoning model in chicken, this experiment was designed to detect mitochondrial structure, malondialdehyde (MDA), glutathione (GSH), DNA and protein crosslink (DPC) and protein carbonyl (PCO) content, the CYP450 and b5 contents, the aminopyrine-N-demethylase (AND), erythromycin N-demethylase (ERND), aniline 4-hydroxylase (AH) and NADPH-cytochrome C reducatase (CR) activities, and mRNA expression level in the livers. The present results indicated that the MDA content, PCO content, and DPC index in Cd group were higher than those observed in other three groups. Most of the mitochondrial structure is incomplete in Cd group. The contents of CYP450 and b5 were decreased in Cd group. The activities of AND, ERND, AH, and CR got reduced after Cd exposure, as observed in CYP450 gene expression. Our results showed that CYP450 system was involved in the entire process of injury and protection. This research provides a comprehensive evaluation of the oxidative stress effects of Cd related to CYP450 in chicken.

Extract from Aronia melanocarpa L. Berries Prevents Cadmium-Induced Oxidative Stress in the Liver: A Study in A Rat Model of Low-Level and Moderate Lifetime Human Exposure to this Toxic Metal.

The study investigated, in a rat model of low-level and moderate environmental exposure to cadmium (Cd; 1 or 5 mg Cd/kg diet, respectively, for 3 to 24 months), whether the co-administration of 0.1% extract from Aronia melanocarpa L. berries (AE) may protect against oxidative stress in the liver and in this way mediate this organ status. The intoxication with Cd, dose- and duration-dependently, weakened the enzymatic antioxidative barrier, decreased the concentrations of reduced glutathione and total thiol groups, and increased the concentrations of oxidized glutathione, hydrogen peroxide, xanthine oxidase, and myeloperoxidase in this organ. These resulted in a decrease in the total antioxidative status, increase in the total oxidative status and development of oxidative stress (increased oxidative stress index and malondialdehyde concentration) and histopathological changes in the liver. The administration of AE at both levels of Cd treatment significantly improved the enzymatic and nonenzymatic antioxidative barrier, decreased pro-oxidant concentration, and protected from the development of oxidative stress in the liver and changes in its morphology, as well as normalized the serum activities of liver enzymes markers. In conclusion, consumption of aronia products may prevent Cd-induced destroying the oxidative/antioxidative balance and development of oxidative stress in the liver protecting against this organ damage.

The Antagonistic Effect of Selenium on Cadmium-Induced Damage and mRNA Levels of Selenoprotein Genes and Inflammatory Factors in Chicken Kidney Tissue.

Selenium (Se) is a necessary trace mineral in the diet of humans and animals. Cadmium (Cd) is a toxic heavy metal that can damage animal organs, especially the kidneys. Antagonistic interactions between Se and Cd have been reported in previous studies. However, little is known about the effects of Se against Cd toxicity and on the mRNA levels of 25 selenoprotein genes and inflammatory factors in chicken kidneys. In the current study, we fed chickens with a Se-treated, Cd-treated, or Se/Cd treated diet for 90 days. We then analyzed the mRNA expression of inflammatory factors (including prostaglandin E synthase (PTGES), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2)) and 25 selenoprotein genes (Gpx1, Gpx2, Gpx3, Gpx4, Txnrd1, Txnrd2, Txnrd3, Dio1, Dio2, Dio3, SPS2, Sepp1, SelPb, Sep15, Selh, Seli, Selm, Selo, Sels, Sepx1, Selu, Selk, Selw, Seln, Selt). The results demonstrated that Cd exposure increased the Cd content in the chicken kidneys, renal tubular epithelial cells underwent denaturation and necrosis, and the tubules became narrow or disappeared. However, Se supplementation reduced the Cd content in chicken kidneys and induced normal development of renal tubular epithelial cells. In addition, we also observed that Se alleviated the Cd-induced increase in the mRNA levels of inflammatory factors and ameliorated the Cd-induced downtrend in the mRNA levels of 25 selenoprotein genes in chicken kidneys.

Early-Life Exposure to Cadmium Triggers Distinct Zn-Dependent Protein Expression Patterns and Impairs Brain Development.

The objective of this study was to determine if the brain development impairment induced by early-life exposure to cadmium (Cd) could result from changes in the expression pattern of distinct zinc (Zn)-dependent proteins. For this purpose, adult female rats receiving either tap water, Cd, Zn, or Cd + Zn in their drinking water during gestation and lactation periods were used. After birth, the male offspring were screened for locomotors and sensorial defects. At postnatal day 21 (PND 21), the male pups were sacrificed and their brains, liver, and plasma were taken for chemical, biochemical, and molecular analyses. Our results show that exposure to Cd significantly increased the metal accumulation and decreased Zn concentrations in the brain of male pups from Cd-treated mothers. Besides, Cd exposure reduced significantly the locomotor activity of the offspring in open-field test, the body weight, and the cranio-caudal length at PND21. Insulin-like growth factor-I (IGF-1) levels in the plasma and liver were also decreased in male pups from Cd-treated mothers. Cd-induced brain development disruption was accompanied by a significant increase of the superoxide dismutase (SOD) activity, induction of the metallothionein (MT) synthesis, and, at the molecular level, by an upregulation of Zrt-,Irt-related protein 6 (ZIP6) gene and a significant downregulation of the expression of the Zn transporter 3 (ZnT3) and brain-derived neurotrophic factor (BDNF) genes in the brain. No significant changes on the expression of genes encoding other Zn-dependent proteins and factors such as ZnT1, ZIP12, NF-κB, and Zif268. Interestingly, Zn supplementation provided a total or partial correction of the changes induced by the Cd exposure. These data indicated that changes in expression of ZnT3 and ZIP6 as well as alteration of other transcription factors, such as BDNF, or Zn-dependent proteins, such as SOD and MTs, in response to Cd exposure might be an underlying mechanism of Cd-induced brain development impairment.

Ameliorative Effects of Selenium on Cadmium-Induced Injury in the Chicken Ovary: Mechanisms of Oxidative Stress and Endoplasmic Reticulum Stress in Cadmium-Induced Apoptosis.

Despite the well-established toxicity of cadmium (Cd) to animals and the ameliorative effects of selenium (Se), some specific mechanisms in the chicken ovary are not yet clarified. To explore the mechanism by which the toxicity effect of Cd is induced and explore the effect of supranutritional Se on Cd toxicity in female bird reproduction, forty-eight 50-day-old Isa Brown female chickens were divided randomly into four groups. Group I (control group) was fed the basic diet containing 0.2 mg/kg Se. Group II (Se-treated group) was fed the basic diet supplemented with sodium selenite (Na2SeO3), and the total Se content was 2 mg/kg. Group III (Se + Cd-treated group) was fed the basic diet supplemented with Na2SeO3; the total Se content was 2 mg/kg, and it was supplemented with 150 mg/kg cadmium chloride (CdCl2). Group IV (Cd-treated group) was with the basic diet supplemented with 150 mg/kg CdCl2. The Cd, estradiol (E2), and progestogen (P4) contents changed after subchronic Cd exposure in chicken ovarian tissue; subsequently, oxidative stress occurred and activated the endoplasmic reticulum (ER) pathway to induce apoptosis. Further, Se decreased the accumulation of Cd in ovarian tissue, increased the E2 and P4 contents, alleviated oxidative stress, and reduced apoptosis via the ER stress pathway. The present results demonstrated that Cd could induce apoptosis via the ER stress pathway in chicken ovarian tissue and that Se had a significant antagonistic effect. These results are potentially valuable for finding a strategy to prevent Cd poisoning.

Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function.

Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium-induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats.

Intake of Boron, Cadmium, and Molybdenum enhances rat thyroid cell transformation.

BACKGROUND: Epidemiologic data in volcanic areas suggest that environmental factors might be involved in the increase of thyroid cancer (TC) incidence. Recent reports indicate that several heavy metals and metalloids are increased in volcanic areas. This study aims to evaluate the combined effect of three of these elements Boron (B), Cadmium (Cd), and Molybdenum (Mo) - all increased in the volcanic area of Mt. Etna, in Italy - on thyroid tumorigenesis in the rat. METHODS: Female Wistar rats prone to develop thyroid tumors by low-iodine diet and methimazole treatment received ad libitum drinking water supplemented with B, Cd, and Mo at concentrations in the range found in the urine samples of residents of the volcanic area. At 5 and 10 months animals were euthanized, and their thyroid analysed. Statistical analysis was performed with a 2-way unpaired t-test. RESULTS: No toxic effect of the three elements on the growth of the animals was observed. A significant increase of histological features of transformation was observed in thyroid follicular cells of rats treated with B, Cd, and Mo compared with those of control group. These abnormalities were associated with decreased iodine content in the thyroid. CONCLUSIONS: This study provides the evidence that slightly increased environmental concentrations of B, Cd, and Mo can accelerate the appearance of transformation marks in the thyroid gland of hypothyroid rats.

Protective effect of low dose intra-articular cadmium on inflammation and joint destruction in arthritis.

Synovium hyperplasia characterizes joint diseases, such as rheumatoid arthritis (RA). The cytotoxic effect of low-dose Cadmium (Cd) was tested in vitro and ex vivo on synoviocytes, the mesenchymal key effector cells of inflammation and proliferation in arthritis. The anti-inflammatory and anti-proliferative effects of Cd were tested in vivo by intra-articular injection in the adjuvant induced arthritis rat joints, where the clinical scores and the consequences of arthritis were evaluated. Cell death through apoptosis was highly induced by Cd in inflammatory synoviocytes (80% reduction of cell viability, p < 0.01). TNF plus IL-17 cytokine combination induced a two-fold increase of Cd cell content by enhancing the ZIP-8 importer and the MT-1 homeostasis regulator expression. Addition of Cd reduced IL-6 production in TNF plus IL-17-activated synoviocytes (up to 83%, p < 0.05) and in ex-vivo synovium biopsies (up to 94%, p < 0.01). Cd-injection in rat joints improved arthritis, reducing clinical scores (arthritic score reduced from 4 to 2, p < 0.01), inflammatory cell recruitment (up to 50%, p < 0.01) and protecting from bone/cartilage destruction. This proof of concept study is supported by the limited Cd spread in body reservoirs, with low-dose Cd providing a safe risk/benefit ratio, without toxic effects on other cell types and organs.

Effects of different doses of cadmium on secondary metabolites and gene expression in Artemisia annua L.

This study aims to elucidate the underlying molecular mechanisms of artemisinin accumulation induced by Cd. The effects of different Cd concentrations (0, 20, 60, and 120 µmol/L) on the biosynthesis of Artemisia annua L. were examined. Intermediate and end products were quantified by HPLC-ESI-MS/MS analysis. The expression of key biosynthesis enzymes was also determined by qRT-PCR. The results showed that the application of treatment with 60 and 120 µmol/L Cd for 3 days significantly improved the biosynthesis of artemisinic acid, arteannuin B, and artemisinin. The concentrations of artemisinic acid, arteannuin B, and artemisinin in the 120 µmol/L Cd-treated group were 2.26, 102.08, and 33.63 times higher than those in the control group, respectively. The concentrations of arteannuin B and artemisinin in 60 µmol/L Cd-treated leaves were 61.10 and 26.40 times higher than those in the control group, respectively. The relative expression levels of HMGR, FPS, ADS, CYP71AV1, DBR2, ALDH1, and DXR were up-regulated in the 120 µmol/L Cd-treated group because of increased contents of artemisinic metabolites after 3 days of treatment. Hence, appropriate doses of Cd can increase the concentrations of artemisinic metabolites at a certain time point by up-regulating the relative expression levels of key enzyme genes involved in artemisinin biosynthesis.

The potential protective effect of green, black, red and white tea infusions against adverse effect of cadmium and lead during chronic exposure - A rat model study.

The protective effect of green (GT), black (BT), red (RT) and white (WT) tea infusions on the lungs, brains, hearts, livers and kidneys of adult Wistar rats exposed to Cd (7 mg/kg) and Pb (50 m/kg) was studied. The degree of reduction in the absorption of Cd and Pb in the organs compared to control group and the activity of SOD, CAT and GPx as well as GSH level was evaluated. It was determined that tea significant reduced the accumulation of Cd in the tissues. A significant reduction in the accumulation of Pb was recorded in the brain (WT), liver (GT, WT) and kidneys (BT, GT, RT, WT). A significant increase was observed in the activity of SOD, CAT and GPx in the organs of all rats from tea groups. It was found that the results obtained in rats receiving black, red and white tea were overall not worse than those recorded for rats receiving green tea. The obtained results suggest that drinking tea could be an effective method of reducing the adverse effect of environmental Cd and Pb pollution on the human body.

The lack of protective effects of tea supplementation on liver and jejunal epithelium in adult rats exposed to cadmium and lead.

Adult rats at the age of 12 weeks were divided into the control group and groups supplemented with green (GT), black (BT), red (RT), or white (WT) tea extracts. The diet (except that for the control) was mixed with 7 mg Cd/kg and 50 mg Pb/kg. The experiment lasted 12 weeks. Basal haematology and plasma biochemical parameters as well as the histomorphometrical parameters of jejunal epithelium and liver were determined. The lowest body mass was found in the RT and WT groups. Some functional (increased plasma ALT and AST, and the de Ritis coefficient) and structural changes in the liver (slight fatty degenerative changes, an increase in the intercellular space) were evident irrespective of the type of tea in the Cd and Pb poisoned rats. This toxic effect was visible especially in rats drinking black or red tea. However, the rats had no elevated LDH and ALT activities. The highest content of Cd and Pb in the liver and blood plasma was found in rats drinking red tea. Based on the results obtained, it is clear that long-term exposure of adult rats with a mature intestinal barrier to Cd and Pb contamination, under higher exposure conditions than the current estimates of weekly exposure of the general population to Cd and Pb through diet, causes a toxic effect, especially in the liver, and can change the structure of intestinal mucosa, irrespective of tea administration.

Metabolomics analysis and biomarker identification for brains of rats exposed subchronically to the mixtures of low-dose cadmium and chlorpyrifos.

Cadmium (Cd) and chlorpyrifos (CPF) are widespread harmful environmental pollutants with neurotoxicity to mammals. Although the exposure to Cd and CPF at the same time may pose a significant risk to human health, the subchronic combined neurotoxicity of these two chemicals at low levels in the brain is poorly understood. In this study, we treated rats with three doses (low, middle, and high) of Cd, CPF, or their mixture for 90 days. No obvious symptom was observed in the treated animals except those treated with high-dose CPF. Histological results showed that middle and high doses of the chemicals caused neuronal cell damage in brains. GC-MS-based metabonomics analysis revealed that energy and amino acid metabolism were disturbed in the brains of rats exposed to the two chemicals and their combinations even at low doses. We further identified the unique brain metabolite biomarkers for rats treated with Cd, CPF, or both. Two amino acids, tyrosine and l-leucine, were identified as the biomarkers for Cd and CPF treatment, respectively. In addition, a set of five unique biomarkers (1,2-propanediol-1-phosphate, d-gluconic acid, 9H-purine, serine, and 2-ketoisovaleric acid) was identified for the mixtures of Cd and CPF. Therefore, the metabolomics analysis is more sensitive than regular clinical observation and pathological examination for detecting the neurotoxicity of the individual and combined Cd and CPF at low levels. Overall, these results identified the unique biomarkers for Cd and CPF exposure, which provide new insights into the mechanism of their joint toxicity.

Effects of Dietary Cadmium and Boron Supplementation on Performance, Eggshell Quality and Mineral Concentrations of Bone in Laying Hens.

This study was conducted to determine the effects of supplementation of different levels of cadmium and boron on performance, eggshell quality, and mineral concentrations of bone in layer diets. In this trial, a total of 144 layer chickens, 21 weeks old, were randomly divided into 12 experimental groups. In each experimental group, there were four replicates, and in each of the replicates, there were three hens. Experimental diets consisted of all possible combinations of four levels of added cadmium (0, 5, 15, and 45 mg/kg) and three levels of added boron (0, 60, and 120 mg/kg) to the basal diet. Added cadmium (15 or 45 mg/kg) had a significant adverse effect on performance parameters (P < 0.01). Eggshell thickness increased with the addition of 5 mg/kg level of cadmium to the diet (P < 0.01). Tibia cadmium content increased with the addition of cadmium and boron in the diet (P < 0.01). However, tibia boron content decreased with the supplementation of cadmium (P < 0.01). These results indicate that the addition of boron to the diet did not prevent adverse effect of cadmium on performance and eggshell quality, or accumulation of cadmium in bone.

Dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal women: a prospective cohort study.

PURPOSE: Cadmium is a human lung carcinogen and possesses estrogen-like activity. This combination of carcinogenic and estrogenic activity makes cadmium a contaminant of high concern for hormone-related cancers. Diet and smoking are the main sources of cadmium exposure. The aim of this study was to investigate the association between dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal woman. METHODS: We estimated dietary cadmium intake in the Diet, Cancer and Health cohort at enrolment 1993-97. The estimates were based on food frequency questionnaires and cadmium contents in all foods. Among 23,815 postmenopausal women we identified 1390 breast, 192 endometrial, and 146 ovarian cancer cases from enrolment through December 31, 2010 using the Danish Cancer Registry. Cox regression was used to analyse the association between dietary cadmium intake and cancer risk. RESULTS: Mean dietary cadmium intake was 14 µg/day. Cadmium was not associated with breast cancer, incidence rate ratio (IRR) = 0.99, 95% confidence interval (CI): 0.87-1.13 per 10 µg higher dietary cadmium intake/day; endometrial cancer, IRR = 1.08, 95% CI: 0.76-1.53; or ovarian cancer, IRR = 1.15, 95% CI: 0.78-1.70. We found a positive association between cadmium and endometrial cancer for the women with BMI<25 (IRR = 1.50, 95% CI: 0.94-2.39), whereas an inverse association was seen for the women with BMI≥25 (IRR = 0.69, 95% CI: 0.42-1.12); p value for interaction = 0.02. CONCLUSIONS: Our study does not indicate that our estimated dietary cadmium intake is associated with hormone-related cancers in women.