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ArticleLiterature Review
Breast Cancer Frequency and Exposure to Cadmium: A Meta-Analysis and Systematic Review
Abstract
Background:
In this meta-analysis we review evidence suggesting that exposure to cadmium is a cause of breast cancer.
Materials and methods:
We conducted Medline/PubMed and Scopus searches using selected MeSH keywords to identify papers published from January 1, 1980 through January 1, 2013. Data were merged and summary mean differences were estimated using either a random-effects model or a fixed-effects model.
Results:
There were 13 studies including 978 exposed cases and 1,279 controls. There was no statistically significant difference in the frequencies of breast cancer between cadmium-exposed and control groups, and the summary estimate of mean difference was 0.71 (95%CI: 0.33-1.08). However, stratification showed that there were statistically significant differences in the frequencies of breast cancer between cadmium-exposed and control groups among Asian compared with Caucasian population, and the summary estimates of mean difference were 1.45 (95%CI: 0.62-2.28) vs. 0.25 (95%CI: -0.09-0.6), respectively. There was a difference in the frequencies of breast cancer between cadmium-exposed and control groups in peripheral venous blood sampling methods, and the summary estimate of mean difference was 1.41 (95%CI: 0.46-2.37).
Conclusions:
Data indicate that the frequencies of breast cancer might be an indicator of early genetic effects for cadmium-exposed populations. However, our meta-analysis was performed on population-based studies; meta-analysis based on individual data might provide more precise and reliable results. Therefore, it is necessary to construct an international database on genetic damage among populations exposed to cadmium that may contain all raw data of studies examining genetic toxicity.
... We speculated that these inconsistent results might due be to data detected from different race or by different biological materials. Rahim et al. pointed that the mean difference of cadmium levels between cancer patients and healthy controls was more significant in Asian population than in Caucasian (American) (Rahim et al. 2013). Our findings might provide further epidemiological evidence of the possible association between cadmium exposure and breast cancer in the general population. ...
... μg/L) , while much higher than those in other reports conducted in Canada, Lithuania, and USA (ranging from 0.032 to 1.09 μg/L) (Gallagher et al. 2010;Kotsopoulos et al. 2012;Strumylaite et al. 2008). Different nutritional behaviors between Chinese and Caucasian populations may lead to different exposure and risk of breast cancer related to heavy metal contaminations (Rahim et al. 2013). In the general population, the primary sources of cadmium are cigarette smoke, food, water, and ambient air (Jarup 2003). ...
... Nevertheless, Akerstrom et al. recently found a high correlation between urinary cadmium and BCLs for all participants and suggested that BCLs are a valid biomarker for cadmium body burden and cadmium exposure, at least in non-smokers (Akerstrom et al. 2013). Data from a meta-analysis of 13 studies including 978 exposed cases and 1279 controls showed that the mean difference between breast cancer patients and healthy controls was significantly more in the blood than in tissue and urine samples (Rahim et al. 2013). ...
Recently, there is increasing evidence indicating a link between cadmium exposure and human breast cancer. This study was aimed to explore the relationship between blood cadmium burden and the risk of breast cancer in Chaoshan women with no occupational exposure. Blood cadmium levels (BCLs) were determined in whole blood of 186 breast cancer cases and 139 controls. Basic clinical data and information of age, occupation, blood types, family cancer history, and disease history, as well as other demographic characteristics were collected from medical records. BCLs were detected by graphite-furnace atomizer absorption spectrophotometer (GFAAS). BCLs and proportions of BCLs over 3 μg/L between cases and controls were compared. The relationships between BCLs and breast cancer were explored by comparing BCL differences between/among different characteristics of investigated factors. In addition, BCLs within cases were also compared in relation to the disease clinical stages, tumor-node-metastasis (TNM) stages, and estrogen receptor (ER), progesterone receptor (PR), and Cerb-B2 expressions. The breast cancer patients had a higher median concentration of blood cadmium (2.28, interquartile range 1.57-3.15 μg/L) than the controls (1.77, 1.34-2.57 μg/L; P = 0.001). The proportion of BCLs over 3 μg/L was 2.35 times higher in the breast cancer cases than that of the controls after adjusting for age. Cadmium tends to accumulate in the human body with age and body mass index (BMI) but not associates with type of job, family history, disease history, and other investigated characters. With the increase of clinical stages and T and M stages, the BCLs in the breast cancer cases also increased. BCLs were positively associated with Cerb-B2 expression (r = 0.152, P = 0.038) but not significantly associated with ER and PR expressions. The data obtained show that cadmium concentration is significantly higher in blood of breast cancer patients in comparison to healthy controls. Cadmium seems to be a risk factor of breast cancer, and high cadmium exposure was observed in advanced stages of this disease, which indicates that it may promote the development of breast cancer.
... Earlier, Wu and colleagues performed a meta-analysis of observational studies and found no such association [72]. However, results obtained from other studies showed that cadmium concentration is significantly higher in the blood of breast cancer patients as compared to healthy controls [73,74]. ...
Trace elements are essentially required for various physiological and metabolic functions, and any disturbance in the trace elements homeostasis may result in the development of chronic diseases including breast cancer. Breast cancer is the most prevalent cancer type reported in women equally affecting both the high-income and low-income countries. This review therefore aimed to evaluate the impact of dietary trace element intake in relation to the incidence of breast cancer. We focused on five trace elements, thus emphasizing dietary selenium, zinc, iron, copper, and cadmium intake and risk of breast cancer. A systematic approach was applied to perform this review through entering a search term in PubMed and Scopus databases. A total of 24 articles were included after meeting the inclusion and exclusion criteria. Most of the studies regarding dietary iron intake showed a detrimental effect of increased dietary heme iron on breast cancer incidence risk. In addition, there is a limited evidence of high dietary intake of selenium and zinc to reduce the risk of breast cancer. Also, a few studies showed a relationship between high cadmium consumption and risk of breast cancer. More studies related to cadmium and copper exposure are needed to confirm this relationship. As a result, the findings of this review suggested that high dietary heme iron is a potential risk factor for breast cancer.
... High expression of CD109 antigen is associated with poor prognosis of soft tissue sarcoma (39), and CD109+ endothelial cells is a prognostic indicator for glioblastomas (40). It is of interest to note that cadmium exposure also has been discussed in the aetiology of several cancers (41,42). Nevertheless, CD109 now emerges as a new player in cadmium ADME, but this has to be replicated in an independent sample. ...
The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals.
Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project.
Analyses revealed 2 regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q4. The lead SNP in the 4q24 locus was rs13107325 (p value = 5.1 x 10(-11), beta=-0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (p value=2.2x10(-14), beta=-0.46). The SNP lies within an intronic region of SLC30A10, another transporter protein. Amongst other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (p=1.4 x 10(-10), beta=-1.2 and p=1.8 x 10(-9), beta=-1.8 respectively).
Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity.
© The Author 2015. Published by Oxford University Press.
... Experimental and environmental exposure to Cd revealed some effects of severe atrophy in the testes, loss of renal function, hepatic damage, respiratory and digestive system disorders, and anaemia. In addition, toxic effects on various cells include damage to the nucleus membrane and mitochondria crystals, chromatin condensation, and eventually cell death (Meeker et al., 2008;Rahim et al., 2013;Schwartz and Reis, 2000;Sarkar et al., 2013). ...
In this study, protective effects of lithium borate (LTB) on spermatogenesis as well as histopathological and immunohistochemical
findings of testes in experimentally induced acute Cadmium (Cd) toxicity in rats were determined. Twenty-eight male Wistar albino
rats, were used, weighing 200–220 g. Rats were randomly divided into 4 groups: Control, Cd, LTB, and LTB + Cd. Rats were anesthetized
with ketamine at the end of the sixth day, blood was taken from their hearts, and the rats were decapitated. Typically, the control and
LTB groups exhibited similar values. Compared with those observed for the control group, the sperm morphology (i.e. abnormal sperm
count) increased for the Cd group, while the FSH, LH, total testosterone levels, sperm motility, and density decreased in a statistically
significant manner. Clearly, no adverse effects of LTB on the sperm motility, density, and sperm morphology (i.e. abnormal sperm
count) were observed, but LTB decreased the negative effects of Cd toxicity. Abnormal disturbances in the head and tail areas of the
sperms increased; thus, the total abnormal sperm rate increases, leading to the decreased fertilization capacity. The histopathological
examination of testicular tissues revealed severe haemorrhage and hyperaemia in intertubular intervals, tubule atrophy, severe
degenerative and necrotic changes in spermatocytes, tubule wall thinning, and necrosis in basal germ cells. In immunohistochemically
Caspase-3, 8-OHdG, and COX-2 staining, changes in the control and LTB groups were not detected, while the Cd toxicity group
exhibited severe expression in the testis tissue. Histopathological and immunohistochemical changes were significantly decreased in the
LTB + Cd group compared to the Cd group. In conclusion, in this study it was determined that LTB has protective effects on Cd-induced
testicular toxicity in rats.
... Iron, another trace metal, is also associated with the development of genomic instability and liver, lung, and intestinal cancers in experimental rats [20]. Moreover, copper has reportedly been linked to genomic instability, which is related to breast cancer in rats [21], whereas cadmium is related to breast cancer in women worldwide [22]. Furthermore, aluminum chloride is being investigated for its potential relationship with neurological, hepatic, bone, and hematological conditions as well as with breast cancer [23][24][25][26][27]. Therefore, we assessed the genotoxic effects of aluminum concentration in Sprague Dawley rats and determined whether a link could be established with N-nitroso-N-methylurea (NMU)-induced breast cancer. ...
Recently, soluble forms of aluminum for human use or consumption have been determined to be potentially toxic due to their association with hepatic, neurological, hematological, neoplastic, and bone conditions. This study aims to assess the genotoxic effect of aluminum chloride on genomic instability associated with the onset of N-nitroso-N-methylurea (NMU)-induced breast cancer in Sprague Dawley rats. The dietary behavior of the rats was assessed, and the concentration of aluminum in the mammary glands was determined using atomic absorption spectroscopy. Genomic instability was determined in the histological sections of mammary glands stained with hematoxylin and eosin. Moreover, micronucleus in peripheral blood and comet assays were performed. The results of dietary behavior evaluation indicated no significant differences between the experimental treatments. However, aluminum concentration in breast tissues was high in the +2000Al/−NMU treatment. This experimental treatment caused moderate intraductal cell proliferation, lymph node hyperplasia, and serous gland adenoma. Furthermore, micronucleus and comet test results revealed that +2000Al/−NMU led to a genotoxic effect after a 10-day exposure and the damage was more evident after a 15-day exposure. Therefore, in conclusion, genomic instability is present and the experimental conditions assessed are not associated with breast cancer.
... The cadmium -metallothioneins complex dispersed to different organs and tissues, and is eventually reabsorbed in kidneys, so cadmium accumulates in tissues because of absence of mechanism for the excretion of it from the body (Rahim et al., 2013). ...
The present study aimed to assess the pisciculture status in Gaza strip. Field surveys and questionnaire interviews (n = 160) were applied to collect data concerning pisciculture sector. The present study revealed that five pisciculture projects ranging from 1200 to 5000 m2 are functioning in Gaza strip. Five farmed fish species; Oreochromis hybrids, Oreochromis niloticus, Sparus aurata, Mugil cephalus and Clarias gariepinus have been cultured. Beach wells are the main water source for most projects. The fish fry of Sparus aurata and the fish feedstuffs have been imported from the Palestinian teritories occupied. Marine fishes have been preferred by 42.5% of respondents over farmed ones due to health and taste standards. Most respondents (81.9%) confirmed the lack of marketing operations and electronic advertising of framed fishes. The findings pointed out that 98.1% of respondents confirmed certain challenges facing pisciculture in Gaza strip. Financial, technical, scientific, political and policy-making problems are functioning, with the fuel and electricity shortages are main problems. Two types of water samples were collected and analyzed for some physicochemical parameters. Concentrations of Cd, Cu, and Pb were determined in pond waters as well as in the white muscles of 40 samples of the three local farmed fish species: Oreochromis niloticus, Oreochromis hybrids, and Sparus aurata, using atomic absorption spectroscopy. pH, conc. of nitrate, nitrite and ammonia were ranging from 7.01-7.69, 11 - 41 mg/l, 0.11 - 0.17 mg/l, 0.1 - 0.19 mg/l respectively in all water samples and this values doesn’t exceed the international maximum standard limits. Electrical conductivity, alkalinity, total dissolved solids, hardness and chloride were ranging from 1743 - 55000 µs/cm, 147 - 360 mg/l, 1115 - 34100 mg/l, 100 - 7512 mg/l, 400 -19380 mg/l respectively and this values exceed the international maximum standard limits. The concentrations of both Cd and Pb in the water samples were ranging from 42.1 – 92.57, 48.5 – 96.2 µg/l respectively, and in fish samples were ranging from 0.59 – 2.08, 4.16 – 10.36 µg/g wet weight respectively, this values exceed the international maximum standard limits, compared with the concentration of copper which ranging from 109.7 – 183.2 µg/l in water and 0.08 – 1.41 µg/g wet weight in fish, this values doesn’t exceed the international maximum standard limits. Pisciculture projects are a promising sector in Gaza strip. Cooperation between the different parties regarding the fisheries resources including the pisciculture should be raised in a sustainable fashion.
Keywords: Pisciculture - farmed fish - heavy metals - challenges - Gaza strip - Palestine.
... As for the 146 genes, they were mainly involved in various metabolism process (digestion, cadmium ion, zinc ion and oxidation-reduction). Cadmium is a lustrous, silver-white, ductile, very malleable metal, and experimental evidences have confirmed cadmium carcinogenicity in multiple organs. 27 Two animal studies 28,29 indicated that Zn lacking caused tumorigenesis in rats' esophagus and fore stomach. An epidemiological study 30 found that high level of zinc may play a part in preventing gastric carcinogenesis. ...
Background:
Gastric cancer (GC) is the fourth most common cause of cancer- related deaths in the world and 5-year overall survival (OS) rate is less than 10%. So, it is urgent to identified novel diagnostic and prognostic biomarkers.
Methods:
Twelve GEO (Gene Expression Omnibus) datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between GC and normal tissues were screened and integrated using limma and RobustRankAggreg (RRA) packages in R software. Protein-protein interaction (PPI) network, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses for DEGs were conducted via STRING and DAVID, respectively. Moreover, Cox regression model was used to construct a gene prognosis signature.
Results:
Ten genes (COL1A1, CXCL8, COL3A1, SPP1, COL1A2, TIMP1, CXCL1, BGN, MMP3 and SERPINE1) were identified and might be highly related to GC. Further analysis showed high expression of CXCL8, COL3A1, CXCL1, MMP3 and SERPINE1, were significantly associated with late stage of GC. Lastly, we build a seven-gene prognosis signature (CYP19A1, SERPINE1, CGB5, CALCR, ASGR2, CYTL1 and ABCB5), which can give a good prediction of OS.
Conclusions:
Our article screened out key genes highly associating with GC's developments and prognosis, and it is useful for researcher to further understand GC's molecular basis and direct the synthesis medicine of GC.
... Exposures to As and Cd are strongly correlated with the incidence of various cancers, including prostate cancer 8 ; breast, lung, skin and pancreatic cancer [9][10][11][12][13][14][15] ; urinary tract and bladder cancer [16][17][18] ; and kidney cancer. 19 Notably, individuals who drank well water with an As concentration higher than 10 μg/L from birth and for more than 50 years are reported to have a significantly increased risk of urinary cancer. ...
Rationale:
Accumulating evidence has linked prolonged exposure to heavy metals to cancer occurrence in the urinary system. However, the specific biological mechanisms responsible for the association of heavy metals with the unusually high incidence of upper tract urothelial carcinoma in Taiwan are complex and incompletely understood.
Methods:
To elucidate the specific biological mechanism and identify molecular indicators of the unusually high association of upper tract urothelial carcinoma with heavy metal exposure, protein expression following the treatment of T24 human bladder carcinoma and RT4 human bladder papilloma cell line models with arsenic (As) and cadmium (Cd) were studied. Proteomic changes in these cell models were integrated with data from a human bladder cancer (BLCA) tissue proteome to identify possible protein indicators of heavy metal exposure.
Results:
After mass spectrometry-based proteomic analysis and verification by Western blotting procedures, we identified 66 proteins that were up-regulated and 92 proteins that were down-regulated in RT4 cell extracts after treatment with As or Cd. 52 proteins were up-regulated and 136 proteins were down-regulated in T24 cell extracts after treatment with Cd. We further confirmed that down-expression of PML (promyelocytic leukemia) protein was sustained for at least 75 days after exposure of bladder cells to As. Dysregulation of these cellular proteins by As were associated with three biological pathways. Immunohistochemical analyses of paraffin-embedded BLCA tissue slides confirmed that PML protein expression was decreased in BLCA tumor cells compared with adjacent noncancerous epithelial cells.
Conclusions:
These data suggest that PML may play an important role in the pathogenesis of BLCA and may be an indicator of heavy metal exposure in bladder cells.
... Cadmium is able to produce malignant tumors in multiple organs following loge term and chronic exposure (Waalkes et al., 1999a(Waalkes et al., , 1999b. Besides experimental studies, epidemiological studies have also confirmed the potential cadmium carcinogenicity (Joseph, 2009;Cobanoglu et al., 2010;Rahim et al., 2013;Cheung et al., 2014). ...
Cancer, a serious public health problem in worldwide, results from an excessive and uncontrolled proliferation
of the body cells without obvious physiological demands of organs. The gastrointestinal tract, including the
esophagus, stomach and intestine, is a unique organ system. It has the highest cancer incidence and cancerrelated
mortality in the body and is influenceed by both genetic and environmental factors. Among the various
chemical elements recognized in the nature, some of them including zinc, iron, cobalt, and copper have essential
roles in the various biochemical and physiological processes, but only at low levels and others such as cadmium,
lead, mercury, arsenic, and nickel are considered as threats for human health especially with chronic exposure
at high levels. Cadmium, an environment contaminant, cannot be destroyed in nature. Through impairment
of vitamin D metabolism in the kidney it causes nephrotoxicity and subsequently bone metabolism impairment
and fragility. The major mechanisms involved in cadmium carcinogenesis could be related to the suppression of
gene expression, inhibition of DNA damage repair, inhibition of apoptosis, and induction of oxidative stress. In
addition, cadmium may act through aberrant DNA methylation. Cadmium affects multiple cellular processes,
including signal transduction pathways, cell proliferation, differentiation, and apoptosis. Down-regulation of
methyltransferases enzymes and reduction of DNA methylation have been stated as epigenetic effects of cadmium.
Furthermore, increasing intracellular free calcium ion levels induces neuronal apoptosis in addition to other
deleterious influence on the stability of the genome.
... Cadmium is able to produce malignant tumors in multiple organs following loge term and chronic exposure (Waalkes et al., 1999a(Waalkes et al., , 1999b. Besides experimental studies, epidemiological studies have also confirmed the potential cadmium carcinogenicity (Joseph, 2009;Cobanoglu et al., 2010;Rahim et al., 2013;Cheung et al., 2014). ...
Cancer, a serious public health problem in worldwide, results from an excessive and uncontrolled proliferation
of the body cells without obvious physiological demands of organs. The gastrointestinal tract, including the
esophagus, stomach and intestine, is a unique organ system. It has the highest cancer incidence and cancerrelated
mortality in the body and is influenceed by both genetic and environmental factors. Among the various
chemical elements recognized in the nature, some of them including zinc, iron, cobalt, and copper have essential
roles in the various biochemical and physiological processes, but only at low levels and others such as cadmium,
lead, mercury, arsenic, and nickel are considered as threats for human health especially with chronic exposure
at high levels. Cadmium, an environment contaminant, cannot be destroyed in nature. Through impairment
of vitamin D metabolism in the kidney it causes nephrotoxicity and subsequently bone metabolism impairment
and fragility. The major mechanisms involved in cadmium carcinogenesis could be related to the suppression of
gene expression, inhibition of DNA damage repair, inhibition of apoptosis, and induction of oxidative stress. In
addition, cadmium may act through aberrant DNA methylation. Cadmium affects multiple cellular processes,
including signal transduction pathways, cell proliferation, differentiation, and apoptosis. Down-regulation of
methyltransferases enzymes and reduction of DNA methylation have been stated as epigenetic effects of cadmium.
Furthermore, increasing intracellular free calcium ion levels induces neuronal apoptosis in addition to other
deleterious influence on the stability of the genome.
... Cadmium is able to produce malignant tumors in multiple organs following loge term and chronic exposure (Waalkes et al., 1999a(Waalkes et al., , 1999b. Besides experimental studies, epidemiological studies have also confirmed the potential cadmium carcinogenicity (Joseph, 2009;Cobanoglu et al., 2010;Rahim et al., 2013;Cheung et al., 2014). ...
Cancer, a serious public health problem in worldwide, results from an excessive and uncontrolled proliferation
of the body cells without obvious physiological demands of organs. The gastrointestinal tract, including the
esophagus, stomach and intestine, is a unique organ system. It has the highest cancer incidence and cancerrelated
mortality in the body and is influenceed by both genetic and environmental factors. Among the various
chemical elements recognized in the nature, some of them including zinc, iron, cobalt, and copper have essential
roles in the various biochemical and physiological processes, but only at low levels and others such as cadmium,
lead, mercury, arsenic, and nickel are considered as threats for human health especially with chronic exposure
at high levels. Cadmium, an environment contaminant, cannot be destroyed in nature. Through impairment
of vitamin D metabolism in the kidney it causes nephrotoxicity and subsequently bone metabolism impairment
and fragility. The major mechanisms involved in cadmium carcinogenesis could be related to the suppression of
gene expression, inhibition of DNA damage repair, inhibition of apoptosis, and induction of oxidative stress. In
addition, cadmium may act through aberrant DNA methylation. Cadmium affects multiple cellular processes,
including signal transduction pathways, cell proliferation, differentiation, and apoptosis. Down-regulation of
methyltransferases enzymes and reduction of DNA methylation have been stated as epigenetic effects of cadmium.
Furthermore, increasing intracellular free calcium ion levels induces neuronal apoptosis in addition to other
deleterious influence on the stability of the genome.
... In a recent meta-analysis on 13 studies including 978 exposed cases and 1,279 controls, several reviewed evidence suggesting that exposure to Cd is a cause of breast cancer. The results indicated that the frequencies of breast cancer were not significantly higher in the Cd-exposed group compared to the controls; thus, exposure to Cd could not significantly induce the breast cancer (113). ...
Breast cancer is a multifactorial disease and the most commonly diagnosed cancer in women. Traditional risk factors for breast cancer include reproductive status, genetic mutations, family history and lifestyle. However, increasing evidence has identified an association between breast cancer and occupational factors, including environmental stimuli. Epidemiological and experimental studies demonstrated that ionizing and non‑ionizing radiation exposure, night‑shift work, pesticides, polycyclic aromatic hydrocarbons and metals are defined environmental factors for breast cancer, particularly at young ages. However, the mechanisms by which occupational factors can promote breast cancer initiation and progression remains to be elucidated. Furthermore, the evaluation of occu‑ pational factors for breast cancer, particularly in the workplace, also remains to be explained. The present review summarizes the occupational risk factors and the associated mechanisms involved in breast cancer development, in order to highlight new environmental exposures that could be correlated to breast cancer and to provide new insights for breast cancer prevention in the occupational settings. Furthermore, this review suggests that there is a requirement to include, through multidisciplinary approaches, different occupational exposure risks among those associated with breast cancer development. Finally, the design of new epigenetic biomarkers may be useful to identify the workers that are more susceptible to develop breast cancer.
... In 2000, a meta-analysis showed that high exposure to cadmium may increase risk of pancreatic cancer [51]. Also, elevated levels of cadmium were found in breast cancer patients compared with those in the controls [52]. Nevertheless, environmental cadmium exposure at a lowlevel might be a risk factor for lung carcinoma [53]. ...
Cadmium is a heavy metal that has been suggested to be a carcinogen by evidence. A number of published studies have investigated the association between cadmium levels and prostate cancer, but the results were inconsistent. Thus, we conducted a meta-analysis to get a precise estimate of this subject. After a careful searching and screening, a total of 11 publications containing 14 separated studies were included. Based on a random-effect model, the pooled data showed that cadmium levels of prostate tissues (standard mean difference (SMD) = 3.17, 95 % confidence interval (CI) = 0.60-5.74, P < 0.05) and plasma (SMD = 4.07, 95 % CI = 2.01-6.13, P < 0.05) were significantly higher in prostate cancer patients than those in the healthy controls. No difference of hair and nail cadmium levels between the prostate cancer cases and the controls was found. The data suggested that cadmium exposure might exert an influence on the tumorigenesis of prostate tissues. Future investigations with large sample sizes are needed to verify the results.
... This was already observed in the meta-analysis of Wu et al. (2015) including pre-and postmenopausal women and heterogeneity was explained by the differences in adjustment factors considered in the two European studies. In a metaanalysis on breast cancer (all women) and exposure (from all sources) to Cd estimated by using different sampling methods (including hair, urine, tissue and peripheral venous blood), higher frequencies of breast cancer were observed among Cd exposed Asians compared with Caucasian population (Rahim et al., 2013). We investigated if heterogeneity could be due to ethnicity differences by combining studies with Caucasian populations (USA and European) but heterogeneity was not reduced (meta-RR: 1.02; 95% CI: 0.87-1.19; ...
Background:
With tobacco smoking, diet is the main source of cadmium (Cd) exposure in the general population. The carcinogenic and estrogenic activities of Cd make it a contaminant of potential concern for hormone-dependent cancers including breast cancer. Postmenopausal women represent the most appropriate population to investigate the possible impact of exogenous factors with potential estrogenic activity on breast cancer as, after menopause, their estrogenic influence is predominant.
Objectives:
We systematically reviewed available studies on the association between dietary exposure to Cd and breast cancer focusing on postmenopausal women. A meta-analysis combining the risk estimators was performed and potential sources of between studies heterogeneity were traced.
Methods:
Studies were searched from MEDLINE through 31 January 2015 and from the reference lists of relevant publications. Six eligible studies published between 2012 and 2014 were identified and relative risk estimates were extracted. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect models. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for study design, geographic location, use of hormone replacement therapy (HRT), tumor estrogen receptor status (ER+ or ER-), progesterone receptor status (PGR+ or PGR-), body mass index (BMI), smoker status, zinc or iron intake.
Results:
No statistically significant increased risk of breast cancer was observed when all studies were combined (mRR=1.03; 95% confidence interval [CI]: 0.89-1.19). Several sources of heterogeneity and inconsistency were identified, including smoker status, HRT use, BMI, zinc and iron intake. Inconsistency was also strongly reduced when only considering ER-, PGR-, tumors subgroups from USA and from Japan. The risks were, however, not substantially modified after stratifications. No evidence of publication bias was found.
Conclusion:
The present study does not provide support for the hypothesis that dietary exposure to Cd increases the risk of breast cancer in postmenopausal women. Misclassification in dietary Cd assessment in primary studies could have biased the results towards a finding of no association.
Background
Diet is the primary way cadmium (Cd) enters the body in those without occupational exposure and who do not inhabit Cd-polluted regions. Findings on the relationship between dietary Cd exposure and breast cancer (BC) risk have been inconsistent; a meta-analysis has supported this association but 2 recent cohort studies showed inconsistent results. Hence, we performed an updated meta-analysis to re-evaluate the association between dietary Cd exposure and BC risk.
Heavy metals are known to disrupt important physiological processes in living cells, and have been responsible for various pathological conditions with possible contributions to cancer development. Food contamination have been identified as one of the ways humans are exposed to heavy metals. In developing countries like Nigeria, the regulatory framework for enforcing compliance with globally acceptable exposure to deleterious contaminants is poor. In the current study, thirteen samples of cured meat products of diverse origin marketed in South-west Nigeria were evaluated for lead, cadmium, chromium and nickel contents using the atomic absorption spectroscopy technique. All the samples analysed contained cadmium between 0.35 and 1.20 ppm, levels considered higher than acceptable limits in consumable products. Lead, chromium and nickel were not detected in any of the samples. As known cumulative poisons, there is the need for stringent regulatory control of these heavy metals in cured meat products imported into or produced indigenously in the country in order to minimize the risks to public health.
Occupational factors can lead to breast cancer, though the relationship between these variables is not well established. The objective of this study was to search the relevant literature for information on the association between breast cancer and exposure to occupational risk factors. For that purpose, electronic databases were searched using the following keywords: breast cancer and occupational exposures. A total of 40 articles published in the 10-year period from 2009 to 2019 were included in this review. Workers exposed to metals such as cadmium, chemical products, radiation and night work were more susceptible to breast cancer. The findings showed significant evidence to support an association between breast cancer and some chemical products, ionizing radiation and night work. However, most studies have difficulty establishing a causal relationship between these variables, pointing to the need for further investigation of these issues.
Endocrine disruptors (EDs) are pollutants that alter the endocrine system and are involved in carcinogenesis. EDs have multiple and complex levels of action. They can affect the synthesis, release and transport of natural hormones. In target tissues, EDs can reduce or increase the effects of natural hormones on their receptors and change signaling cascades. When ED exposure happens at critical periods of life, from embryo to puberty, they can act at doses considered safe for an adult. Furthermore, their epigenetic effects can also influence the cancer risk of future generations. The cancer mechanisms of known EDs are hereby reviewed, There are thousands of newly introduced substances whose potential endocrine-disrupting and cancer effects are completely unknown. Although there are still gaps in our knowledge, these data support the urgent need for health and environmental policies aimed at protecting the public and in particular, the developing fetus and women of reproductive age.
Laser-induced breakdown spectroscopy (LIBS) is a fast, relatively simple and precise alternative technique to measure heavy metal concentrations in solid, liquid and gaseous materials with limits of detection compatible with the recommended values for soil and water quality criteria. In this paper, a conventional LIBS apparatus has been used for the quantitative analysis of cadmium (Cd) in a landfill leachate under controlled atmospheric and reduced pressure (100 Torr) conditions. LIBS analysis was performed using a background correction and the sum of the areas above the three Cd transitions peaks (Cd II at 214.44 nm; Cd II at 226.50 nm and Cd I at 228.80 nm). Under reduced pressure the linear correlation of the calibration curve increased from 0.96 to 0.99, with respect to the atmospheric pressure. The limit of detection for Cd improved by a factor of 5, from 5 to 1 mg kg⁻¹, and the concentrations measured by LIBS were assessed by complementary induced coupled plasma-optical emission spectroscopy (ICP-OES). These results indicated that LIBS under controlled atmosphere can be recommended for the analytical quantification of Cd in landfill leachates.
Background:
To evaluate association of lung cancer with arsenic and cadmium levels measured in tumor tissue.
Materials and methods:
Ninety-five patients with lung cancer tumor tissue obtained surgically were included in this study. Arsenic and cadmium levels were measured and levels of metals were compared among types of lung cancer and with reference to patient data.
Results:
The histopathologic diagnoses of the 95 cases were SCC, 49, adenocarcinoma, 28, large cell, 11 and SCLC, 1. Mean tumor arsenic and cadmium levels were 149.3±129.1μg/kg and 276.3±219.3μg/kg, respectively. Cadmium levels were significantly associated with smoking (p=0.02), histopathologic type (p=0.005), and TNM staging (r=0.325; p=0.001), although arsenic was not related to any parameter (p>0.05). There was no relation between metal levels and mortality (p>0.05).
Conclusions:
We found a significant association between tumor cadmium levels of patients with lung cancer and smoking, histopathologic type and staging, although there was no relation with arsenic levels.
Studies on quantitative soil contamination due to heavy metals were carried out in Katedan Industrial Development Area (KIDA), south of Hyderabad, Andhra Pradesh, India under the Indo-Norwegian Institutional Cooperation Programme. The study area falls under a semi-arid type of climate and consists of granites and pegmatite of igneous origin belonging to the Archaean age. There are about 300 industries dealing with dyeing, edible oil production, battery manufacturing, metal plating, chemicals, etc. Most of the industries discharge their untreated effluents either on open land or into ditches. Solid waste from industries is randomly dumped along roads and open grounds. Soil samples were collected throughout the industrial area and from downstream residential areas and were analysed by X-ray Fluo-rescence Spectrometer for fourteen trace metals and ten major oxides. The analytical data shows very high concentrations of lead, chromium, nickel, zinc, arsenic and cadmium through out the industrial area. The random dumping of hazardous waste in the industrial area could be the main cause of the soil contamination spreading by rainwater and wind. In the residential areas the local dumping is expected to be the main source as it is difficult to foresee that rain and wind can transport the contaminants from the industrial area. If emission to air by the smokestacks is significant, this may contribute to considerable spreading of contaminants like As, Cd and Pb throughout the area. A comparison of the results with the Canadian Soil Quality Guidelines (SQGL) show that most of the industrial area is heavily contaminat-ed by As, Pb and Zn and local areas by Cr, Cu and Ni. The residential area is also contaminated by As and some small areas by Cr, Cu, Pb and Zn. The Cd contamination is detected over large area but it is not exceeding the SQGL value. Natural background values of As and Cr exceed the SQGL values and contribute significantly to the contamination in the residential area. However, the availability is consid-erably less than anthropogenic contaminants and must therefore be assessed differently. The pre-and post-monsoon sampling over two hydrological cycles in 2002 and 2003 indicate that the As, Cd and Pb contaminants are more mobile and may expect to reach the groundwater. The other contaminants seem to be much more stable. The contamination is especially serious in the industrial area as it is housing Environ Monit Assess a large permanent residing population. The study not only aims at determining the natural background levels of trace elements as a guide for future pollution monitoring but also focuses on the pollution vulnera-bility of the watershed. A plan of action for remedia-tion is recommended.
Breast cancer (BC) is linked to estrogen exposure. Estradiol (E 2) stimulates BC cells proliferation by binding the estrogen receptor (ER). Hormone-related cancers have been linked to estrogenic environmental contaminants. Cadmium (Cd) a toxic pollutant, acts as estrogens in BC cells. Purpose of our study was to evaluate whether Cd regulates MCF-7 cell proliferation by activating ERK1/2, Akt and PDGFR kinases. Cd increased cell proliferation and the ER-antagonist ICI 182,780 blunted it. To characterize an ER-dependent mechanism, ER/ expression was evaluated. Cd decreased ER expression, but not ER. Cd also increased ERK1/2, Akt and PDGFR phosphorylation while ICI blocked it. Since stimulation of phosphorylation was slower than expected, c-fos and c-jun proto-oncogenes, and PDGFA were analyzed. Cd rapidly increased c-jun, c-fos and PDGFA expression. Cells were also co-incubated with the Cd and specific kinases inhibitors, which blocked the Cd-stimulated proliferation. In conclusion, our results indicate that Cd increases BC cell proliferation in vitro by stimulating Akt, ERK1/2 and PDGFR kinases activity likely by activating c-fos, c-jun and PDGFA by an ER-dependent mechanism.
Non-occupational exposure to cadmium has been suspected to be a risk factor for breast cancer. The present study examined the association between urinary cadmium level and the risk of breast cancer in a case-control study among Japanese women. Cases were 153 women newly diagnosed and histologically confirmed with breast cancer at a general hospital in Gifu, Japan. A total of 431 controls individually matched to cases by age, menopausal status, and the period of urine sampling were selected from those who attended a breast cancer mass screening at this hospital. Urinary cadmium levels were measured using spot urine samples. Spot urine samples were collected from cases after surgery but before any cancer therapy. For controls, spot urine samples were obtained at the date of the screening visit. Information on known or suggested breast cancer risk factors was obtained by a self-administered questionnaire. The odds ratios (ORs) and 95 % confidence intervals (CIs) of breast cancer according to the tertile of the creatinine-adjusted cadmium level were calculated using conditional logistic regression models. Women in the highest tertile of the creatinine-adjusted cadmium level (>2.620 μg/g) had significantly elevated OR of breast cancer relative to those in the lowest tertile (<1.674 μg/g) after controlling for covariates [OR = 6.05, (95 % CI 2.90, 12.62)]. The trend of increase in risk with increasing cadmium level was also statistically significant [OR = 1.67, (95 % CI 1.39, 2.01) for every 1.0 μg/g increase in urinary cadmium level, P-trend <0.01]. These data suggested that exposure to cadmium was associated with a risk of breast cancer in Japanese women.
Cadmium has been hypothesized to be a pancreatic carcinogen. We test the hypothesis that cadmium exposure is a risk factor for pancreatic cancer with a population-based case-control study sampled from a population with persistently high rates of pancreatic cancer (south Louisiana). We tested potential dietary and nondietary sources of cadmium for their association with urinary cadmium concentrations which reflect long-term exposure to cadmium due to the accumulation of cadmium in the kidney cortex. Increasing urinary cadmium concentrations were significantly associated with an increasing risk of pancreatic cancer (2nd quartile OR = 3.34, 3rd = 5.58, 4th = 7.70; test for trend
P
≤
0.0001
)
. Potential sources of cadmium exposure, as documented in the scientific literature, found to be statistically significantly associated with increased risk of pancreatic cancer included working as a plumber, pipefitter or welder (OR = 5.88) and high consumption levels of red meat (4th quartile OR = 6.18) and grains (4th quartile OR = 3.38). Current cigarette smoking, at least 80 pack years of smoking, occupational exposure to cadmium and paints, working in a shipyard, and high consumption of grains were found to be statistically significantly associated with increased concentrations of urinary cadmium. This study provides epidemiologic evidence that cadmium is a potential human pancreatic carcinogen.
Experimental data convincingly propose the toxic metal cadmium as a prostate carcinogen. Cadmium is widely dispersed into the environment and, consequently, food is contaminated.
A population-based cohort of 41 089 Swedish men aged 45-79 years was followed prospectively from 1998 through 2009 to assess the association between food frequency questionnaire-based estimates of dietary cadmium exposure (at baseline, 1998) and incidence of prostate cancer (3085 cases, of which 894 were localised and 794 advanced) and through 2008 for prostate cancer mortality (326 fatal cases).
Mean dietary cadmium exposure was 19 μg per day±s.d. 3.7. Multivariable-adjusted dietary cadmium exposure was positively associated with overall prostate cancer, comparing extreme tertiles; rate ratio (RR) 1.13 (95% confidence interval (CI): 1.03-1.24). For subtypes of prostate cancer, the RR was 1.29 (95% CI: 1.08-1.53) for localised, 1.05 (95% CI: 0.87-1.25) for advanced, and 1.14 (95% CI: 0.86-1.51) for fatal cases. No statistically significant difference was observed in the multivariable-adjusted risk estimates between tumour subtypes (P(heterogeneity)=0.27). For localised prostate cancer, RR was 1.55 (1.16-2.08) among men with a small waist circumference and RR 1.45 (1.15, 1.83) among ever smokers.
Our findings provide support that dietary cadmium exposure may have a role in prostate cancer development.
Few studies have evaluated the role of micronutrients or trace elements in breast cancer development among BRCA1 mutation carriers. To investigate a possible role of dietary and environmental exposures on cancer risk, we undertook an exploratory study, using a matched case-control design (n = 48 cases and 96 controls), to evaluate the relationships between plasma levels of 14 micronutrients and breast cancer risk among BRCA1 mutation carriers in Poland.
We estimated the univariate odds ratios (OR) and 95 % confidence intervals (CI) for breast cancer associated with plasma levels for each of 14 micronutrients.
Of the 14 analytes quantified, significant differences between cases and controls were seen for two (iron and retinol; p = 0.009 and p = 0.03, respectively). Women in the highest tertile of plasma iron had a 57 % lower risk, compared with those in the lowest quartile (OR = 0.43; 95 % CI 0.18-1.04; p for trend = 0.06). Increasing antimony levels were associated with an increased risk of breast cancer (p for trend = 0.05). Women in the highest tertile had a 2.43-fold increase in breast cancer risk compared with women in the lowest tertile (OR = 2.43; 95 % CI 1.00-5.91).
This study provides some preliminary evidence regarding a role of diet, specifically iron and antimony, in the etiology of BRCA1-associated breast cancer. Prospective studies are necessary to confirm these findings.
The aim of the study was to estimate the association between dietary intake of cadmium, a carcinogenic heavy metal, and risk of invasive postmenopausal breast cancer.
Study subjects were 30,543 postmenopausal women in the VITamins And Lifestyle (VITAL) cohort who completed a food frequency questionnaire (FFQ) at baseline (2000-2002). Dietary cadmium consumption was estimated by combining FFQ responses with US Food and Drug Administration data on food cadmium content. Incidence of invasive breast cancer was ascertained through linkage of the cohort to the western Washington Surveillance, Epidemiology, and End Results cancer registry through 31 December 2009. Cox regression was applied to estimate adjusted hazard ratios (aHRs) and 95 % confidence intervals (CIs) for breast cancer with increasing dietary cadmium intake, adjusted for total energy intake, smoking history, consumption of vegetables, potatoes, and whole grains, multivitamin use, education, race, body mass index, physical activity, age at first birth, postmenopausal hormone use, and mammography.
Vegetables and grains together contributed an average of 66 % of estimated dietary cadmium. During a mean of 7.5 years of follow-up, 1,026 invasive postmenopausal breast cancers were identified. Among 899 cases with complete covariate information, no evidence of an association between dietary cadmium intake and breast cancer risk was observed (aHR (95 % CI), highest to lowest quartile cadmium: 1.00 (0.72-1.41), p (trend) = 0.95). No evidence was found for interactions between dietary cadmium and breast cancer risk factors, smoking habits, or total intake of calcium, iron, or zinc from diet, supplements, and multivitamins.
This study does not support the hypothesis that dietary cadmium intake is a risk factor for breast cancer. However, non-differential measurement error in the estimate of cadmium intake is likely the most important factor that could have obscured an association.
Cadmium is a known human lung carcinogen, although some studies indicate a link between cadmium exposure and human breast cancer. The objective of this study was to assess cadmium concentration in breast tissue samples of patients with breast cancer and benign breast tumor.
MATERIAL AND METHODS
The concentration of cadmium was determined in breast tissue samples of 21 breast cancer and 19 benign tumor patients. Two samples of breast tissue from each patient, i.e. tumor and normal tissue close to tumor, were taken for the analysis. Cadmium was determined by atomic absorption spectrometry (Perkin-Elmer, Zeeman 3030).
RESULTS
In patients with breast cancer, the mean cadmium concentration was 33.1 ng/g (95% CI, 21.9-44.4) in malignant breast tissue and 10.4 ng/g (95% CI, 5.6-15.2) in normal breast tissue (P=0.002). In patients with benign tumor, the corresponding values were 17.5 ng/g (95% CI, 8.4-26.5) and 11.8 ng/g (95% CI, 5.1-18.5) (P=0.3144). There was a statistically significant difference in cadmium concentration between malignant and benign breast tissues (P=0.009).
CONCLUSION
The data obtained show that cadmium concentration is significantly higher in malignant breast tissue as compared with normal breast tissue of the same women or benign breast tissue. Further studies are necessary to determine the association between cadmium concentration in malignant breast tissue and estrogen receptor level, and smoking.
This prospective study was designed to compare the hair levels of 36 elements in 52 patients with stage III breast cancer to those of an equal number of healthy individuals. Principal component and cluster analysis were used for source of identification and apportionment of heavy metals and trace elements in these two groups. A higher average level of iron was found in samples from patients while controls had higher levels of calcium. Both patients and controls had elevated levels of tin, magnesium, zinc, and sodium. Almost all element values in cancer patients showed higher dispersion and asymmetry than in healthy controls. Between the two groups, there were statistically significant differences in the concentrations of silver, arsenic, gold, boron, barium, beryllium, calcium, cadmium, cerium, cobalt, cesium, gadolinium, manganese, nickel, lead, antimony, scandium, selenium, and zinc (p < 0.05). Strong positive correlations were found between lead and gold (r = 0.785) in the cancer group and between palladium and cobalt (r = 0.945) in the healthy individuals. Our results show that there are distinct patterns of heavy metals and trace elements in the hair of breast cancer patients in comparison to healthy controls. These results could be of significance in the diagnosis of breast cancer.
Breast cancer is the most prevalent women's cancer, with an age-adjusted incidence of 122.9 per 100,000 US women. Cadmium, a ubiquitous carcinogenic pollutant with multiple biological effects, has been reported to be associated with breast cancer in one US regional case-control study. We examined the association of breast cancer with urinary cadmium (UCd), in a case-control sample of women living on Long Island (LI), NY (100 with breast cancer and 98 without), a region with an especially high rate of breast cancer (142.7 per 100,000 in Suffolk County) and in a representative sample of US women (NHANES 1999-2008, 92 with breast cancer and 2,884 without). In a multivariable logistic model, both samples showed a significant trend for increased odds of breast cancer across increasing UCd quartiles (NHANES, p=0.039 and LI, p=0.023). Compared to those in the lowest quartile, LI women in the highest quartile had increased risk for breast cancer (OR=2.69; 95% CI=1.07, 6.78) and US women in the two highest quartiles had increased risk (OR=2.50; 95% CI=1.11, 5.63 and OR=2.22; 95% CI=.89, 5.52, respectively). Further research is warranted on the impact of environmental cadmium on breast cancer risk in specific populations and on identifying the underlying molecular mechanisms.
The study aimed to determine and compare cadmium (Cd) concentration in different biological media of breast cancer and benign breast tumor patients. Concentration of Cd was determined in breast tissue, urine, and blood of 57 breast cancer and 51 benign tumor patients. Two samples of breast tissue from each patient, i.e., tumor and healthy tissue were taken for the analysis. Cd in biological media was determined by atomic absorption spectrometry (Perkin-Elmer, Zeeman 3030). The mean Cd concentration in breast cancer patients was 0.053 μg/g (95% confidence intervals, CI 0.042-0.065) for tumor sample and 0.02 μg/g (95% CI 0.014-0.026) for healthy breast tissue sample (P < 0.001). In benign tumor patients, the figures were as follows: 0.037 μg/g (95% CI 0.023-0.051) and 0.032 μg/g (95% CI 0.018-0.047) (P > 0.05). Cd content in malignant tumor significantly differed from that in benign tumor (P < 0.01). Cancer patients with positive estrogen receptors (ERs) had significantly greater concentration of breast tissue Cd compared to patients with negative ERs (P = 0.035). Adjusted for creatinine, Cd in urine was significantly higher in cancer patients than in controls (P < 0.001). In cancer patients, a positive Spearman's correlation was found between Cd in tumor and healthy breast tissue, blood (r = 0.44 and r = 0.39, respectively, P < 0.01). Correlation between Cd in urine of cancer patients and number of cigarettes smoked during lifetime was suggestive (r = 0.59, P = 0.075). The data obtained show higher concentration of cadmium in breast tumor and urine of cancer patients and support a possible relationship between cadmium and breast cancer.
This study aims at investigating the blood level of Cu, Zn, Se, and Cd in breast cancer patients and the association between such level and the frequency of micronucleated lymphocytes. Fifty stage I breast cancer patients were recruited for this study at the time of diagnosis and before receiving any treatment or surgery. The control group consisted of 150 normal females matched to the patients for age (± 5 years). The whole blood level of Cu, Zn, Se, and Cd was determined using spectrophotometry. The frequency of micronucleated lymphocytes in the blood was determined using the cytokinesis-block micronucleus assay. The level of Cu, Zn, and Se was significantly lower (p = 0.0006, <0.0001, and <0.0001, respectively) in breast cancer patients, as compared to controls. The level of Cd was significantly (p < 0.0001) higher in the patients, as compared to controls. The frequency of lymphocytes with one micronucleus was significantly (p < 0.0001) higher in the patients, as compared to controls. In breast cancer patients, the frequency of micronucleated lymphocytes showed different associations with different levels of these trace elements. High Cd, low Zn, low Se, and both high and low Cu levels were significantly associated with micronucleus formation in lymphocytes. A similar association was found in the normal control group only in relation to high Se and Cd levels. Breast cancer patients seem to have abnormal levels of Cu, Zn, Se, and Cd, and such abnormality is associated with micronucleus formation in lymphocytes.
Studies on the association between prostate cancer and cadmium exposure have yielded conflicting results. This study explored cadmium burden on the risk and phenotype of prostate cancer in men with no evident environmental exposure.
Hospital-based 261 prostate cancer cases and 267 controls with benign diseases were recruited from four hospitals in Taiwan. Demographic, dietary and lifestyle data were collected by standardized questionnaires. Blood cadmium (BCd) and creatinine-adjusted urine cadmium (CAUCd) levels were measured for each participant. Statistical analyses measured the prostate cancer risk associated with BCd and CAUCd separately, controlling for age, smoking and institution. BCd and CAUCd levels within cases were compared in relation to the disease stage and the Gleason score.
High family income, low beef intake, low dairy product consumption and positive family history were independently associated with the prostate carcinogenesis. There was no difference in BCd levels between cases and controls (median, 0.88 versus 0.87 microg/l, p = 0.45). Cases had lower CAUCd levels than controls (median, 0.94 versus 1.40 microg/g creatinine, p = 0.001). However, cases with higher BCd and CAUCd levels tended to be at more advanced stages and to have higher Gleason scores. The prostate cancer cases with Gleason scores of > or = 8 had an odds ratio of 2.89 (95% confidence interval 1.25-6.70), compared with patients with scores of 2-6.
Higher CAUCd and BCd levels may be associated with advanced cancer phenotypes, but there was only a tenuous association between cadmium and prostate cancer.
Little is known about the etiology of pancreatic cancer, which is an important cause of cancer mortality in developed countries. We hypothesize that exposure to cadmium is a cause of pancreatic cancer. Cadmium is a nonessential metal that is known to accumulate in the human pancreas. The major risk factors for pancreatic cancer (increasing age, cigarette smoking, residence in Louisiana, and occupations involving exposure to metalworking and pesticides) are all associated with increased exposure to cadmium. Our meta-analysis of cohorts with high exposure to cadmium is also consistent with an increased risk of pancreatic cancer (standardized mortality ratio = 166; 95% confidence interval, 98-280; P = 0.059). Cadmium can cause the transdifferentiation of pancreatic cells, increases in the synthesis of pancreatic DNA, and increases in oncogene activation. Thus, cadmium is a plausible pancreatic carcinogen. The cadmium hypothesis provides a coherent explanation for much of the descriptive epidemiology of pancreatic cancer and suggests new avenues for analytical research.
Consolidation of epidemiological data on pancreatic cancer and worksite exposures.
Publications during 1969-98 were surveyed. Studies without verified exposures were excluded. Meta-analyses were conducted on data from 92 studies covering 161 populations, with results for 23 agents or groups of agents. With a standard format, five epidemiologists extracted risk estimates and variables of the structure and quality of each study. The extracted data were centrally checked. Random meta-models were applied.
Based on 20 populations, exposure to chlorinated hydrocarbon (CHC) solvents and related compounds was associated with a meta-risk ratio (MRR) of 1.4 (95% confidence interval (95% CI) 1.0 to 1.8). Nickel and nickel compounds were considered in four populations (1.9; 1.2 to 3.2). Excesses were found also for chromium and chromium compounds (1.4; 0.9 to 2.3), polycyclic aromatic hydrocarbons (PAHs) (1.5; 0.9 to 2.5), organochlorine insecticides (1.5; 0.6 to 3.7), silica dust (1.4; 0.9 to 2.0), and aliphatic and alicyclic hydrocarbon solvents (1.3; 0.8 to 2.8). Evidence on pancreatic carcinogenicity was weak or non-positive for the following agents: acrylonitrile (1.1; 0.0 to 6.2); arsenic (1.0; 0.6 to 1.5); asbestos (1.1; 0.9 to 1.5); diesel engine exhaust (1.0; 0.9 to 1.3); electromagnetic fields (1.1; 0.8 to 1.4); formaldehyde (0. 8; 0.5 to 1.0); flour dust (1.1; 0.3 to 3.2); cadmium and cadmium compounds (0.7; 0.4 to 1.4); gasoline (1.0; 0.8 to 1.2); herbicides (1.0; 0.8 to 1.3); iron and iron compounds (1.3; 0.7 to 2.5); lead and lead compounds (1.1; 0.8 to 1.5); man-made vitreous fibres (1.0; 0.6 to 1.6); oil mist (0.9; 0.8 to 1.0); and wood dust (1.1; 0.9 to 2.5). The occupational aetiological fraction of pancreatic cancer was estimated at 12%. In a subpopulation exposed to CHC solvents and related compounds, it was 29%; to chromium and chromium compounds, 23%; to nickel and nickel compounds, 47%; to insecticides, 33%; and to PAHs, 33%.
Occupational exposures may increase risk of pancreatic cancer. High quality studies are called for on interactions between occupational, environmental, and lifestyle factors as well as interactions between genes and the environment.
Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by post-replication mismatch repair (MMR). Inactivation of both mutation-avoidance systems results in extremely high mutability that can lead to error catastrophe. High mutability and the likelihood of cancer can be caused by mutations and epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Identifying such factors has important implications for understanding the role of the environment in genome stability. We found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicate that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, cadmium inhibited at least one step leading to mismatch removal. Together, our data show that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system.
It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.
Cadmium is a toxic environmental pollutant that has worrisome estrogenic effects in cell culture. New data from rats show that cadmium can act as an estrogen mimic in the whole animal, inducing conditions ranging from uterine hyperplasia to early onset of puberty.
High levels of transition metals such as iron, nickel, chromium, copper, and lead are closely related to free radical generation, lipid peroxidation, formation of DNA strand breaks, and tumor growth in cellular systems. In order to determine the correlation to malignant growth in humans, we investigated the accumulation of heavy metals in 20 breast cancer biopsies and compared the findings to the levels found in 8 healthy biopsies.
The concentration of transition metals in breast cancer and control biopsies was assessed by a standardized Atomic Absorption Spectrofotometry technique with acidic hydrolysis for sample preparation. Additionally, heavy metal analysis in control biopsies was also performed with an Inductive Coupled Plasma--Mass Spectroscopy technique. For statistical analysis of the results, the Mann-Whitney U Test was applied.
A highly significant accumulation of iron (p<0.0001), nickel (p<0.00005), chromium (p<0.00005), zinc (p<0.00001), cadmium (p<0.005), mercury (p<0.005), and lead (p< 0.05) was found in the cancer samples when compared to the control group. Copper and silver showed no significant differences to the control group, whereas tin, gold, and palladium were not detectable in any biopsies.
The data suggest that pathological accumulation of transition metals in breast tissue may be closely related to the malignant growth process.
The molecular mechanisms of carcinogenesis by cadmium were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with cadmium chloride were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in the present study. The proto-oncogenes c-fos and c-jun were overexpressed in 100% (10 out of 10) of the cell lines, while a statistically significant overexpression of c-myc was observed in 40% (4 out of 10) of the cell lines. Analysis of tumor cells stained with fluorescent dyes specific for reactive oxygen species revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by treating the cells with superoxide dismutase, catalase, and 1,2-bis(o-aminophenoxy)ethane-N,N,N*,N*-tetra acetoxy methyl ester (BAPTA/ AM), which are scavengers of superoxide anion, hydrogen peroxide, and calcium, respectively. This confirmed that the overexpression of the proto-oncogenes in the tumor cells required elevated intracellular levels of reactive oxygen species and calcium. In addition to the scavengers of reactive oxygen species and calcium, inhibitors specific for transcription (actinomycin D), protein kinase C (RO-31-8220), and MAP kinase (PD 98059) also blocked the cadmium-induced overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/ c-3T3 cells to 20 mM cadmium chloride for 1 h caused elevated intracellular levels of superoxide anion, hydrogen peroxide, and calcium, with corresponding increases in the expression levels of c-fos, c-jun, and c-myc. As in the case of the tumor cells, treating the nontransformed cells with the various modulators prior to their exposure to cadmium chloride resulted in inhibition in the expression of the proto-oncogenes. Based on these data, we conclude that the cadmium-induced overexpression of cellular protooncogenes is mediated by the elevation of intracellular levels of superoxide anion, hydrogen peroxide, and calcium. Further, the cadmium-induced overexpression of the proto-oncogenes is dependent on transcriptional activation as well as on pathways involving
The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic. These metals have been extensively studied and their effects on human health regularly reviewed by international bodies such as the WHO. Heavy metals have been used by humans for thousands of years. Although several adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues, and is even increasing in some parts of the world, in particular in less developed countries, though emissions have declined in most developed countries over the last 100 years. Cadmium compounds are currently mainly used in re-chargeable nickel-cadmium batteries. Cadmium emissions have increased dramatically during the 20th century, one reason being that cadmium-containing products are rarely re-cycled, but often dumped together with household waste. Cigarette smoking is a major source of cadmium exposure. In non-smokers, food is the most important source of cadmium exposure. Recent data indicate that adverse health effects of cadmium exposure may occur at lower exposure levels than previously anticipated, primarily in the form of kidney damage but possibly also bone effects and fractures. Many individuals in Europe already exceed these exposure levels and the margin is very narrow for large groups. Therefore, measures should be taken to reduce cadmium exposure in the general population in order to minimize the risk of adverse health effects. The general population is primarily exposed to mercury via food, fish being a major source of methyl mercury exposure, and dental amalgam. The general population does not face a significant health risk from methyl mercury, although certain groups with high fish consumption may attain blood levels associated with a low risk of neurological damage to adults. Since there is a risk to the fetus in particular, pregnant women should avoid a high intake of certain fish, such as shark, swordfish and tuna; fish (such as pike, walleye and bass) taken from polluted fresh waters should especially be avoided. There has been a debate on the safety of dental amalgams and claims have been made that mercury from amalgam may cause a variety of diseases. However, there are no studies so far that have been able to show any associations between amalgam fillings and ill health. The general population is exposed to lead from air and food in roughly equal proportions. During the last century, lead emissions to ambient air have caused considerable pollution, mainly due to lead emissions from petrol. Children are particularly susceptible to lead exposure due to high gastrointestinal uptake and the permeable blood-brain barrier. Blood levels in children should be reduced below the levels so far considered acceptable, recent data indicating that there may be neurotoxic effects of lead at lower levels of exposure than previously anticipated. Although lead in petrol has dramatically decreased over the last decades, thereby reducing environmental exposure, phasing out any remaining uses of lead additives in motor fuels should be encouraged. The use of lead-based paints should be abandoned, and lead should not be used in food containers. In particular, the public should be aware of glazed food containers, which may leach lead into food. Exposure to arsenic is mainly via intake of food and drinking water, food being the most important source in most populations. Long-term exposure to arsenic in drinking-water is mainly related to increased risks of skin cancer, but also some other cancers, as well as other skin lesions such as hyperkeratosis and pigmentation changes. Occupational exposure to arsenic, primarily by inhalation, is causally associated with lung cancer. Clear exposure-response relationships and high risks have been observed.
Objectives—Consolidation of epidemiological data on pancreatic cancer and worksite exposures. Methods—Publications during 1969‐98 were surveyed. Studies without verified exposures were excluded. Meta-analyses were conducted on data from 92 studies covering 161 populations, with results for 23 agents or groups of agents. With a standard format, five epidemiologists extracted risk estimates and variables of the structure and quality of each study. The extracted data were centrally checked. Random meta-models were applied. Results—Based on 20 populations, exposure to chlorinated hydrocarbon (CHC) solvents and related compounds was associated with a meta-risk ratio (MRR) of 1.4 (95% confidence interval (95% CI) 1.0 to 1.8). Nickel and nickel compounds were considered in four populations (1.9; 1.2 to 3.2). Excesses were found also for chromium and chromium compounds (1.4; 0.9 to 2.3), polycyclic aromatic hydrocarbons (PAHs) (1.5; 0.9 to 2.5), organochlorine insecticides (1.5; 0.6 to 3.7), silica dust (1.4; 0.9 to 2.0), and aliphatic and alicyclic hydrocarbon solvents (1.3; 0.8 to 2.8). Evidence on pancreatic carcinogenicity was weak or non-positive for the following agents: acrylonitrile (1.1; 0.0 to 6.2); arsenic (1.0; 0.6 to 1.5); asbestos (1.1; 0.9 to 1.5); diesel engine exhaust (1.0; 0.9 to 1.3); electromagnetic fields (1.1; 0.8 to 1.4); formaldehyde (0.8; 0.5 to 1.0); flour dust (1.1; 0.3 to 3.2); cadmium and cadmium compounds (0.7; 0.4 to 1.4); gasoline (1.0; 0.8 to 1.2); herbicides (1.0; 0.8 to 1.3); iron and iron compounds (1.3; 0.7 to 2.5); lead and lead compounds (1.1; 0.8 to 1.5); man-made vitreous fibres (1.0; 0.6 to 1.6); oil mist (0.9; 0.8 to 1.0); and wood dust (1.1; 0.9 to 2.5). The occupational aetiological fraction of pancreatic cancer was estimated at 12%. In a subpopulation exposed to CHC solvents and related compounds, it was 29%; to chromium and chromium compounds, 23%; to nickel and nickel compounds, 47%; to insecticides, 33%; and to PAHs, 33%. Conclusion—Occupational exposures may increase risk of pancreatic cancer. High quality studies are called for on interactions between occupational, environmental, and lifestyle factors as well as interactions between genes and the environment. (Occup Environ Med 2000;57:316‐324)
Cadmium occurs naturally in the environment and as an anthropogenic pollutant. Exposure to low concentrations of cadmium is inevitable and may produce toxic effects. Another important aspect of cadmium toxicity is its interaction, often antagonistic, with essential elements such as selenium. The aim of this study was to highlight the risks of long-term exposure to low cadmium concentrations, using a scientific and chemical approach and hares (Lepus europaeus Pallas) as model organisms in a field study. Two study areas were monitored. Levels of cadmium and selenium were quantified in the organs of hares, the expression of metallothioneins I + II and the products of lipid peroxidation were determined. The median cadmium concentrations (wet weight) in the muscle, liver, kidney and brain of hares from an exposed group ranged from 0.033 to 0.037, 0.763 to 1.054, 3.090 to 16.594 and 0.016 to 0.087µg g(-1) , respectively; whereas, the median selenium concentrations (wet weight) ranged from 0.100 to 0.108, 0.153 to 0.332, 0.677 to 0.701 and 0.078 to 0.116µg g(-1) , respectively. Expression of the metallothioneins I + II proteins was observed in tissues. Lipid peroxidation (LPO) levels, measured as malondialdehyde (MDA) equivalents, increased with the cadmium concentration. Further research on long-term exposure to low concentrations of cadmium in the environment is needed. Copyright © 2013 John Wiley & Sons, Ltd.
The detrimental health effects of cadmium (Cd) were first described in the mid 19th century. As part of industrial developments, increasing usage of Cd has led to widespread contamination of the environment that threatens human health, particularly today. Rather than acute, lethal exposures, the real challenge in the 21st century in a global setting seems to be chronic low Cd exposure (CLCE), mainly from dietary sources. Ubiquity of Cd makes it a serious environmental health problem that needs to be thoroughly assessed because it already affects or will affect large proportions of the world's population. CLCE is a health problem that affects increasingly organ toxicity, especially nephrotoxicity, without a known threshold, implying that there is currently no safe limit for CLCE. In this chapter, we summarize current knowledge on the sources of Cd in the environment, describe the entry pathways for Cd into mammalian organisms, sum up the major organs targeted by acute or chronic Cd exposure and review the impact of Cd on organ function and human health. We also aim to put early pioneering studies on Cd poisoning into perspective in the context of recent ground-breaking prospective long-term population studies, which link CLCE to leading causes of diseases in modern societies - cancer, diabetes, and cardiovascular diseases, and of state-of-the-art studies detailing cellular and molecular mechanisms of acute and chronic Cd toxicity.
Metallothioneins (MTs) are low-molecular-mass cysteine-rich proteins with the ability to bind mono- and divalent metal ions with the electron configuration d
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in form of metal-thiolate clusters. MTs are thought, among others, to play a role in the homeostasis of essential Zn(II) and Cu(I) ions. Besides these metal ions also Cd(II) can be bound to certain MTs in vivo, giving rise to the perception that another physiological role of MTs is in the detoxification of heavy metal ions. Substitution of the spectroscopically silent Zn(II) ions in metalloproteins by Cd(II) proved to be an indispensable tool to probe the Zn(II) sites in vitro. In this review, methods applied in the studies of structural and chemical properties of Cd-MTs are presented. The first section focuses on the physical basis of spectroscopic techniques such as electronic absorption, circular dichroism (CD), magnetic CD, X-ray absorption, and perturbed angular correlation of γ-rays spectroscopy, as well as mass spectrometry, and their applications to Cd-MTs from different organisms. The following is devoted to the discussion of metal binding affinities of Cd-MTs, cluster dynamics, the reactivity of bound Cd(II) ions with metal ion chelators and of thiolate ligands with alkylating and oxidizing agents. Finally, a brief summary of the known three-dimensional structures of Cd-MTs, determined almost exclusively by multinuclear NMR techniques, is presented. Besides Cd-MTs, the described methods can also be applied to the study of metal binding sites in other metalloproteins.
Chronic exposure to cadmium causes preferential accumulation of cadmium in the kidney, leading to nephrotoxicity. In the process of renal cadmium accumulation, the cadmium bound to a low-molecular-weight metal-binding protein, metallothionein, has been considered to play an important role in reabsorption by epithelial cells of proximal tubules in the kidney. However, the role and mechanism of the transport of Cd(2+) ions in proximal tubule cells remain unclear. Zinc transporters such as Zrt, Irt-related protein 8 (ZIP8) and ZIP14, and divalent metal transporter 1 (DMT1) have been reported to have affinities for Cd(2+) and Mn(2+). To examine the roles of these metal transporters in the absorption of luminal Cd(2+) and Mn(2+) into proximal tubule cells, we utilized a cell culture system, in which apical and basolateral transport of metals can be separately examined. The uptake of Cd(2+) and Mn(2+) from the apical side of proximal tubule cells was inhibited by simultaneous addition of Mn(2+) and Cd(2+), respectively. The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane. The excretion of Cd(2+) and Mn(2+) was detected predominantly in the apical side of the proximal tubule cells. In situ hybridization of these transporters revealed that ZIP8 and ZIP14 are highly expressed in the proximal tubules of the outer stripe of the outer medulla. These results suggest that ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney.
The ubiquitous food contaminant cadmium has features of an estrogen mimetic that may promote the development of estrogen-dependent malignancies, such as breast cancer. However, no prospective studies of cadmium exposure and breast cancer risk have been reported. We examined the association between dietary cadmium exposure (at baseline, 1987) and the risk of overall and estrogen receptor (ER)-defined (ER(+) or ER(-)) breast cancer within a population-based prospective cohort of 55,987 postmenopausal women. During an average of 12.2 years of follow-up, 2,112 incident cases of invasive breast cancer were ascertained (1,626 ER(+) and 290 ER(-)). After adjusting for confounders, including consumption of whole grains and vegetables (which account for 40% of the dietary exposure, but also contain putative anticarcinogenic phytochemicals), dietary cadmium intake was positively associated with overall breast cancer tumors, comparing the highest tertile with the lowest [rate ratio (RR), 1.21; 95% confidence interval (CI), 1.07-1.36; P(trend) = 0.02]. Among lean and normal weight women, statistically significant associations were observed for all tumors (RR, 1.27; 95% CI, 1.07-1.50) and for ER(+) tumors (RR, 1.25; 95% CI, 1.03-1.52) and similar, but not statistically significant associations were found for ER(-) tumors (RR, 1.22; 95% CI, 0.76-1.93). The risk of breast cancer increased with increasing cadmium exposure similarly within each tertile of whole grain/vegetable consumption and decreased with increasing consumption of whole grain/vegetables within each tertile of cadmium exposure (P(interaction) = 0.73). Overall, these results suggest a role for dietary cadmium in postmenopausal breast cancer development.
Cadmium, a ubiquitous environmental pollutant, is classified as a carcinogenic substance. Several laboratory and epidemiologic studies of workers and subjects in polluted areas have suggested a positive association between cadmium exposure and risk of several cancers. However, data from general populations are sparse. We prospectively examined the association between cadmium exposure and incidence of cancer in a Japanese population with a relatively high dietary intake of cadmium.
We conducted a population-based prospective study in 90,383 Japanese men and women 45-74 years of age. Participants responded to a validated questionnaire that included 138 food items. We estimated dietary cadmium intake from 6 food groups, based on the questionnaire data. During 9 years of follow-up, 5849 cancer cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer were calculated by Cox proportional hazards modeling.
There was no evidence of an association of cadmium consumption and total cancer, with HRs in the highest versus lowest cadmium intake group of 0.94 (95% CI = 0.82 to 1.08; test for trend, P = 0.46) for men and 0.96 (0.81 to 1.15; 0.60) for women. No site-specific cancers were associated with cadmium intake in men or women.
We found no associations of cancer with cadmium, at least at the exposure levels observed in a general population in Japan.
Metallothionein affects the metabolism, transport and storage of micronutrients such as zinc, copper and iron, and the detoxification of heavy metals, especially cadmium. Cd is a common, highly toxic environmental pollutant that accumulates in human placenta, elevated concentrations of which are associated with impaired zinc transfer to the fetus. This prospective study investigated the effects of metallothionein 2A (MT2A) -5 A/G single nucleotide polymorphism on the accumulation of Cd in human placenta and micronutrient transfer to the fetus in 95 pregnant women and their newborns. Venous blood from the mother was collected to investigate Cd, Zn, Cu, Fe levels and MT2A polymorphism. Cord blood from the neonate and placenta was collected for metal levels. MT2A polymorphism was determined by the standard PCR-restriction fragment length polymorphism technique. Metal levels were analyzed by Atomic Absorption Spectrometry (AAS). Maternal blood Cd levels were statistically higher for mothers with a heterozygote genotype compared with a homozygote genotype (P<0.05). In contrast, placental Cd levels were significantly higher in mothers with a homozygote rather than a heterozygote genotype (P<0.05). No difference existed in cord blood Cd, Zn and Cu levels. However, cord blood Fe levels of newborns with heterozygote genotype mothers were higher than in others. Placental Cd levels of heterozygote genotype mothers were negatively associated with Zn in cord blood. Cd exposure at environmental levels may be associated with alteration of the umbilical cord micronutrient levels for newborns with mothers of a heterozygote genotype.
Breast cancer is a heterogeneous disease and existing clinicopathological classifications do not fully capture the diversity in clinical disease course. Since the oestrogen receptor (ER) plays a central role in the crosstalk between different signalling pathways in breast cancer, the expression of this receptor is important for the behaviour of breast cancer cells and is reflected in gene expression patterns of breast tumours. High throughput analysis of gene expression of breast cancer has increased the insights into ER signalling, including its relation with disease outcome and therapy response. Expression of ER and its numerous downstream targets are driving patterns of gene expression and dominate unsupervised analyses in the breast cancer specimens studied to date, regardless of microarray platform or statistical approach. This paper reviews gene expression studies either attempting to unravel the functional effect of ER or describing the gene expression profiles driven by ER in breast tumours. In addition, the development of molecular signatures predicting response to endocrine treatment will be discussed.
Cadmium is a toxic metal with no known biological function. It is increasingly important as an environmental hazard to both humans and wildlife, and it exemplifies the double edged nature of many toxic substances. Thus, on the one hand cadmium can act as a mitogen, stimulate cell proliferation, inhibit apoptosis, inhibit DNA repair, and promote cancer in a number of tissues. On the other hand, it causes tissue damage, notably in the kidney, by inducing cell death. At low and moderate concentrations in cell culture systems (e.g., 0.1-10μM) cadmium primarily causes apoptosis, and at higher concentrations (>50μM) necrosis becomes evident. This generalization appears to hold in vivo. There is also evidence of cadmium-induced autophagy, although whether this is a direct cause of cell death remains uncertain. After discussing these generalities, this review considers the details of apoptotic death, and its inhibition, in renal mesangial cells. We also present evidence for the effect of environmental exposure to cadmium in affecting renal function, and in particular review the evidence for the role of the mesangial cell in cadmium nephrotoxicity.
Plants absorb a number of elements from soil, some of which have no known biological function and some are known to be toxic at low concentrations. As plants constitute the foundation of the food chain, some concerns have been raised about the possibility of toxic concentrations of certain elements being transported from plants to higher strata of the food chain. Special attention has been given to the uptake and biotransformation mechanisms occurring in plants and its role in bioaccumulation and impact on consumers, especially human beings. While this review draws particular attention to metal accumulation in edible plants, researched studies of certain wild plants and their consumers are included. Furthermore, this review focuses on plant uptake of the toxic elements arsenic, cadmium, chromium, mercury, and lead and their possible transfer to the food chain. These elements were selected because they are well-established as being toxic for living systems and their effects in humans have been widely documented. Arsenic is known to promote cancer of the bladder, lung, and skin and can be acquired, for example, through the consumption of As-contaminated rice. Cadmium can attack kidney, liver, bone, and it also affects the female reproduction system. Cadmium also can be found in rice. Chromium can produce cancer, and humans can be exposed through smoking and eating Cr-laden vegetables. Lead and mercury are well known neurotoxins that can be consumed via seafood, vegetables and rice.
Cadmium is a toxic metal occurring in the environment naturally and as a pollutant emanating from industrial and agricultural sources. Food is the main source of cadmium intake in the non-smoking population. The bioavailability, retention and toxicity are affected by several factors including nutritional status such as low iron status. Cadmium is efficiently retained in the kidney (half-time 10-30 years) and the concentration is proportional to that in urine (U-Cd). Cadmium is nephrotoxic, initially causing kidney tubular damage. Cadmium can also cause bone damage, either via a direct effect on bone tissue or indirectly as a result of renal dysfunction. After prolonged and/or high exposure the tubular injury may progress to glomerular damage with decreased glomerular filtration rate, and eventually to renal failure. Furthermore, recent data also suggest increased cancer risks and increased mortality in environmentally exposed populations. Dose-response assessment using a variety of early markers of kidney damage has identified U-Cd points of departure for early kidney effects between 0.5 and 3 microg Cd/g creatinine, similar to the points of departure for effects on bone. It can be anticipated that a considerable proportion of the non-smoking adult population has urinary cadmium concentrations of 0.5 microg/g creatinine or higher in non-exposed areas. For smokers this proportion is considerably higher. This implies no margin of safety between the point of departure and the exposure levels in the general population. Therefore, measures should be put in place to reduce exposure to a minimum, and the tolerably daily intake should be set in accordance with recent findings.
Environmental pollutants mimicking the effects of estrogen are suggested to contribute to the high incidence of hormone-related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-alpha, has been shown in vivo. We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population-based prospective cohort of 30,210 postmenopausal women free of cancer diagnose at baseline (1987) and who completed a food frequency questionnaire at baseline and in 1997. We estimated the dietary cadmium intake based on the questionnaire data and the cadmium content in all foods. During 16.0 years (484,274 person-years) of follow-up between the baseline and mid-2006, we ascertained 378 incident cases of endometrioid adenocarcinoma. The average estimated dietary cadmium intake was 15 mug/day (80% from cereals and vegetables). Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women; the multivariate relative risk (RR) was 1.39 [95% confidence interval (CI), 1.04-1.86; P(trend) = 0.019], comparing highest tertile versus lowest. Among never-smoking women with body mass index (BMI) of <27 kg/m(2), the RR was 1.86 (95% CI, 1.13-3.08; P(trend) = 0.009). We observed a 2.9-fold increased risk (95% CI, 1.05-7.79) associated with long-term cadmium intake consistently above the median at both baseline 1987 and in 1997 in never-smoking women with low bioavailable estrogen (BMI of <27 kg/m(2) and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers.
The carcinogenic potential of cadmium might be affected by several factors such as smoking, hormones and presence of other metals, such as selenium and zinc. Cadmium was analyzed in breast-fat tissue of 43 breast cancer patients and 32 healthy control subjects. Patients were thoroughly characterized according to such variables as stage of cancer, smoking habits, and number of children. Correlation of cadmium levels with these variables, with hormone receptors, and with previously reported selenium and zinc were all analyzed. The mean cadmium concentration found in breast cancer patients (20.4 +/- 17.5 micrograms/g) did not differ significantly from that of the healthy controls (31.7 +/- 39.4 micrograms/g). However, unexpectedly high concentrations of cadmium (3.2-86.9 vs. 0.1-160.4 micrograms/g) were found in breast samples, which may indicate that cadmium binding proteins exist in human breast tissue. Correlation of cadmium with smoking rate of cancer patients was positive (Rs = 0.0505, p < 0.05). Correlation of cadmium with estrogen receptors in breast cancer was suggestive (Rs = 0.309, 28 cases, P = 0.06). No correlation was found with other trace elements such as selenium, zinc and copper. These results seem neither to prove nor to disprove the role of cadmium in breast cancer initiation, promotion or progression.
The molecular mechanisms of carcinogenesis by cadmium were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with cadmium chloride were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in the present study. The proto-oncogenes c-fos and c-jun were overexpressed in 100% (10 out of 10) of the cell lines, while a statistically significant overexpression of c-myc was observed in 40% (4 out of 10) of the cell lines. Analysis of tumor cells stained with fluorescent dyes specific for reactive oxygen species revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by treating the cells with superoxide dismutase, catalase, and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra acetoxy methyl ester (BAPTA/AM), which are scavengers of superoxide anion, hydrogen peroxide, and calcium, respectively. This confirmed that the overexpression of the proto-oncogenes in the tumor cells required elevated intracellular levels of reactive oxygen species and calcium. In addition to the scavengers of reactive oxygen species and calcium, inhibitors specific for transcription (actinomycin D), protein kinase C (RO-31-8220), and MAP kinase (PD 98059) also blocked the cadmium-induced overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/c-3T3 cells to 20 microM cadmium chloride for 1 h caused elevated intracellular levels of superoxide anion, hydrogen peroxide, and calcium, with corresponding increases in the expression levels of c-fos, c-jun, and c-myc. As in the case of the tumor cells, treating the nontransformed cells with the various modulators prior to their exposure to cadmium chloride resulted in inhibition in the expression of the proto-oncogenes. Based on these data, we conclude that the cadmium-induced overexpression of cellular proto-oncogenes is mediated by the elevation of intracellular levels of superoxide anion, hydrogen peroxide, and calcium. Further, the cadmium-induced overexpression of the proto-oncogenes is dependent on transcriptional activation as well as on pathways involving protein kinase C and MAP kinase.
Cadmium (Cd) is an environmental pollutant of global concern with a 10-30-year biological half-life in humans. Accumulating evidence suggests that the lung is one of the major target organs of inhaled Cd compounds. Our previous report demonstrated that 100 microM Cd induces MRC-5 cells, normal human lung fibroblasts, to undergo caspase-independent apoptosis mediated by mitochondrial membrane depolarization and translocation of apoptosis-inducing factor (AIF) from mitochondria into the nucleus. Here, using benzyloxycarbonyl-Val-Ala-Asp-(ome) fluoromethyl ketone (Z-VAD.fmk) as a tool, we further demonstrated that Cd could induce caspase-independent apoptosis at concentrations varied from 25 to 150 microM, which was modulated by reactive oxygen species (ROS) scavengers, such as N-acetylcysteine (NAC), mannitol, and tiron, indicating that ROS play a crucial role in the apoptogenic activity of Cd. Consistent with this notion, the intracellular hydrogen peroxide (H2O2) was 2.9-fold elevated after 3 h of Cd treatment and diminished rapidly within 1 h as detected by flow cytometry with 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Using inhibitors of the mitochondrial electron transport chain (ETC) (oligomycin A and rotenone for complex I and V, respectively) and mitochondrial permeability transition pore (MPTP) (cyclosporin A and aristolochic acid), we coincidently found the ROS production, mitochondrial membrane depolarization, and apoptotic content were almost completely or partially abolished. As revealed by confocal microscopy staining with chloromethyl-X-rosamine (CMXRos) and an anti-AIF antibody, the collapse of mitochondrial membrane potential induced by Cd (3 h-treatment) was a prelude to the translocation of caspase-independent pro-apoptotic factor, AIF, into the nucleus (after 4 h of Cd treatment). In summary, this study demonstrated that, in MRC-5 fibroblasts, Cd induced caspase-independent apoptosis through a mitochondria-ROS pathway. More importantly, we provide several lines of evidence supporting a role of mitochondrial ETC and MPTP in the regulation of caspase-independent cell death triggered by Cd.
Our aim was to calculate the global burden of disease and risk factors for 2001, to examine regional trends from 1990 to 2001, and to provide a starting point for the analysis of the Disease Control Priorities Project (DCPP).
We calculated mortality, incidence, prevalence, and disability adjusted life years (DALYs) for 136 diseases and injuries, for seven income/geographic country groups. To assess trends, we re-estimated all-cause mortality for 1990 with the same methods as for 2001. We estimated mortality and disease burden attributable to 19 risk factors.
About 56 million people died in 2001. Of these, 10.6 million were children, 99% of whom lived in low-and-middle-income countries. More than half of child deaths in 2001 were attributable to acute respiratory infections, measles, diarrhoea, malaria, and HIV/AIDS. The ten leading diseases for global disease burden were perinatal conditions, lower respiratory infections, ischaemic heart disease, cerebrovascular disease, HIV/AIDS, diarrhoeal diseases, unipolar major depression, malaria, chronic obstructive pulmonary disease, and tuberculosis. There was a 20% reduction in global disease burden per head due to communicable, maternal, perinatal, and nutritional conditions between 1990 and 2001. Almost half the disease burden in low-and-middle-income countries is now from non-communicable diseases (disease burden per head in Sub-Saharan Africa and the low-and-middle-income countries of Europe and Central Asia increased between 1990 and 2001). Undernutrition remains the leading risk factor for health loss. An estimated 45% of global mortality and 36% of global disease burden are attributable to the joint hazardous effects of the 19 risk factors studied. Uncertainty in all-cause mortality estimates ranged from around 1% in high-income countries to 15-20% in Sub-Saharan Africa. Uncertainty was larger for mortality from specific diseases, and for incidence and prevalence of non-fatal outcomes.
Despite uncertainties about mortality and burden of disease estimates, our findings suggest that substantial gains in health have been achieved in most populations, countered by the HIV/AIDS epidemic in Sub-Saharan Africa and setbacks in adult mortality in countries of the former Soviet Union. Our results on major disease, injury, and risk factor causes of loss of health, together with information on the cost-effectiveness of interventions, can assist in accelerating progress towards better health and reducing the persistent differentials in health between poor and rich countries.
Cadmium, a highly persistent heavy metal, has been categorized as a probable human carcinogen by the U.S. Environmental Protection Agency. Primary exposure sources include food and tobacco smoke. We carried out a population-based case-control study of 246 women, aged 20-69 years, with breast cancer and 254 age-matched control subjects. We measured cadmium levels in urine samples by inductively coupled plasma mass spectrometry and conducted interviews by telephone to obtain information on known breast cancer risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer by creatinine-adjusted cadmium levels were calculated by multivariable analysis. Statistical tests were two-sided. Women in the highest quartile of creatinine-adjusted cadmium level (> or = 0.58 microg/g) had twice the breast cancer risk of those in the lowest quartile (<0.26 microg/g; OR = 2.29, 95% CI = 1.3 to 4.2) after adjustment for established risk factors, and there was a statistically significant increase in risk with increasing cadmium level (P(trend) = .01). Based on this study, the absolute risk difference is 45 (95% CI = 0 to 77) per 100,000 given an overall breast cancer rate of 124 per 100,000. Whether increased cadmium is a causal factor for breast cancer or reflects the effects of treatment or disease remains to be determined.
The increased awareness of traffic as a major diffuse metal emission source emphasizes the need for more detailed information on the various traffic-related sources and how and where the metals are dispersed. In this study, metal emission patterns in the road traffic environment were examined from the perspective of different surrounding factors, e.g. the importance of intersections, deceleration, vehicle speed and traffic density. A total of 148 topsoil samples from 18 south Swedish roads were analysed (using GFAAS) for traffic-emitted metals, i.e. Cd, Cr, Cu, Ni, Pb, Sb and Zn. The roadside topsoil metal concentrations were used to examine correlations between metals and surrounding factors. The studied metals were divided into three groups corresponding to different emission sources: metals from decelerating activities (Cu, Sb and Zn), metals as historical residues from the combustion of petrol (Pb and Cd), and non-source-specific metals (Cr and Ni). It was found that Cu and Sb, despite their rather short history as traffic-emitted metals, have increased more than eightfold in roadside soils compared to background levels. The major source of road traffic related Cu and Sb is brake linings. The significant increase of Cu and Sb in roadside topsoil stresses the need for metal transport studies as well as effect studies of these metals. Metals emitted due to decelerating activities were not correlated to elevated concentrations near road junctions. Emission patterns of traffic-related metals alongside roads are crucial in order to be able to evaluate the optimal localization of storm water treatment ponds.
The objective of this study was to determine which elements in serum best differentiated breast cancer in a case-control study. Concentrations of 13 elements in serum of 68 breast tumor patients (25 malignant and 43 benign) and 26 healthy controls were measured. Logistic regression with different variable-selection procedures was used to determine a possible configuration of elements. Sensitivity and specificity of the model were calculated to obtain the optimal cutoff point for discriminating malignant breast cancers vs other individuals (including benign breast disease and normal ones). Acombination of Cd, Mn, and Fe was found to have a specificity and sensitivity of 100% using forward-type logistic regression, when the cutoff value of the combination score was 52.71. Using stepwise-type logistic regression, a combination of Cr and Mn had a sensitivity of 100% and a specificity of 97.1% when the combination score of 17.4 was chosen as the cutoff. Similar analysis could be implemented to compare the malignant and control groups. Specificity and sensitivity were 100% for Mn (forward and stepwise type) with a cutoff point of 6.40. For the backward regression, specificity was 84.6% and sensitivity was 100% for Zn, with a cutoff point of 869.1. In conclusion, there was a significant difference in concentrations of all 13 elements in serum between breast cancer patients and controls. A combination among Cd, Mn, Fe, Cr, and Zn might be important to determine a differentiating reference for breast cancers if a long-term followed-up study is to be conducted.
The objectives of the present study were to assess the relative impact of different pathways of environmental cadmium (Cd) exposure and to evaluate the contribution from locally produced vegetables and root crops to the total dietary intake of Cd.
Cadmium in urine was determined for 492 individuals living near a closed down battery factory in Sweden. For each individual we created an environmental exposure-index based on Cd emissions to ambient air and number of years living at various distances from the plant. This information as well as dietary data were collected via questionnaires. Samples of soil, carrots and/or potatoes were collected from 37 gardens and analysed for Cd concentration.
Eating home grown vegetables/potatoes, environmental Cd-exposure-index, female gender, age above 30 years and smoking more than one pack of cigarettes daily for at least 10 years were found to be significantly associated with increased urine concentrations of Cd (UCd>1.0 nmol/mmol creatinine). We found a statistically significant relation between Cd in urine and environmental Cd-exposure-index in persons eating home grown vegetables/potatoes regularly. Cd concentrations in home grown carrots, potatoes and in garden soil were highest in the area closest to the factory. Daily consumption of potatoes and vegetables cultivated in the vicinity of the closed battery factory was estimated to increase Cd intake by 18-38%.
The present study shows that consumption of locally grown vegetables and root crops was an important exposure pathway, in subjects living near a nickel-cadmium battery plant, whereas direct exposure via ambient air was less important.
Studies on quantitative soil contamination due to heavy metals were carried out in Katedan Industrial Development Area (KIDA), south of Hyderabad, Andhra Pradesh, India under the Indo-Norwegian Institutional Cooperation Programme. The study area falls under a semi-arid type of climate and consists of granites and pegmatite of igneous origin belonging to the Archaean age. There are about 300 industries dealing with dyeing, edible oil production, battery manufacturing, metal plating, chemicals, etc. Most of the industries discharge their untreated effluents either on open land or into ditches. Solid waste from industries is randomly dumped along roads and open grounds. Soil samples were collected throughout the industrial area and from downstream residential areas and were analysed by X-ray Fluorescence Spectrometer for fourteen trace metals and ten major oxides. The analytical data shows very high concentrations of lead, chromium, nickel, zinc, arsenic and cadmium through out the industrial area. The random dumping of hazardous waste in the industrial area could be the main cause of the soil contamination spreading by rainwater and wind. In the residential areas the local dumping is expected to be the main source as it is difficult to foresee that rain and wind can transport the contaminants from the industrial area. If emission to air by the smokestacks is significant, this may contribute to considerable spreading of contaminants like As, Cd and Pb throughout the area. A comparison of the results with the Canadian Soil Quality Guidelines (SQGL) show that most of the industrial area is heavily contaminated by As, Pb and Zn and local areas by Cr, Cu and Ni. The residential area is also contaminated by As and some small areas by Cr, Cu, Pb and Zn. The Cd contamination is detected over large area but it is not exceeding the SQGL value. Natural background values of As and Cr exceed the SQGL values and contribute significantly to the contamination in the residential area. However, the availability is considerably less than anthropogenic contaminants and must therefore be assessed differently. The pre- and post-monsoon sampling over two hydrological cycles in 2002 and 2003 indicate that the As, Cd and Pb contaminants are more mobile and may expect to reach the groundwater. The other contaminants seem to be much more stable. The contamination is especially serious in the industrial area as it is housing a large permanent residing population. The study not only aims at determining the natural background levels of trace elements as a guide for future pollution monitoring but also focuses on the pollution vulnerability of the watershed. A plan of action for remediation is recommended.
Selected trace metals were analyzed in human malignant and nonmalignant (benign) breast tissue samples by the flame atomic absorption spectrophotometric method. In malignant tissues, dominant mean concentrations were revealed by Na, K, Ca, Mg, Fe, Zn, and Al at 927, 552, 231, 61.7, 36.5, 18.3, and 8.94 microg/g, respectively, while the mean metal levels in benign tissues were 903, 435, 183, 63.3, 24.7, 14.5, and 10.1 microg/g, respectively. Average concentrations of Cd, Co, Cr, Cu, Fe, Mn, K, Ca, and Zn were noted to be significantly higher in the malignant tissues compared with the benign tissues. Significantly strong correlations (r > 0.50) in malignant tissues were observed between Mn and Co, Mn and Cd, Cd and Cr, Fe and Mn, Cd and Co, Fe and Co, Mg and Pb, Cd and Fe, Mg and Ni, Pb and Ni, Ni and Sr, and Fe and Pb, whereas, Cd and Co, Cd and Mn, Co and Mg, Co and Mn, Cu and Mn, Co and Ni, Mg and Ni, Cd and Cu, Cd and Ni, Ca and Mg, Mn and Pb, Cu and Ni, Fe and Ni, Cd and Mg, Co and Cu, Cr and Na, and Cd and Cr revealed strong and significant relationships in benign tissues at p < 0.001. Principal component analysis of the metals data yielded six principal components for malignant tissues and five principal components for benign tissues, with considerably different loadings, duly supported by cluster analysis. The study revealed a considerably different pattern of distribution and mutual correlations of trace metals in the breast tissues of benign and cancerous patients.
Current status of cadmium as an environmental health problem
- L Jarup
- A Akesson
Jarup L, Akesson A (2009). Current status of cadmium as an
environmental health problem. Toxicol Appl Pharmacol,
238, 201-8.
Differentiation of serum levels of trace elements in normal and malignant breast patients
- Hd Wu
- Sy Chou
- Dr Chen
- Hw Kuo