In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B 1 (AFB 1 ) epoxide reacts ...In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B 1 (AFB 1 ) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB 1 exposure and mutations in the K -ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N -acetyltransferases and glutathione S -transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk.展开更多
In this paper our studies about the sequential testing program for predicting and identificating carcinogens, sequential discriminant method and cost- effectiveness analysis are summarized. The analysis of our databas...In this paper our studies about the sequential testing program for predicting and identificating carcinogens, sequential discriminant method and cost- effectiveness analysis are summarized. The analysis of our database of carcinogeniclty and genotoxicity of chemicals demonstrates the uncertainty . of short- term tests ( STTs ) to predict carcinogens and the results of most routine STTs are statistically dependent. We recommend the sequential testing program combining STTs and carclnogenicity assay, the optimal STT batteries, the rules of the sequential discrimination and the preferal choices of STTs tor specific chemical class. For illustrative pmposes the carclnogenicity prediction of several sample chamicals is presented. The results of cost-effectiveness analysis suggest that this program has vast social-economic effectiveness.展开更多
Although mutations clearly play a role in themulti-stage process of carcinogenesis,a challengewll be made to the paradigm that most chemical"carcinogens" act via mutagenic activity("carcinogens as mutag...Although mutations clearly play a role in themulti-stage process of carcinogenesis,a challengewll be made to the paradigm that most chemical"carcinogens" act via mutagenic activity("carcinogens as mutagens").Control ofproliferation and differentiation within andbetween tissues is mediated by展开更多
Environmental, occupational, or dietary exposure to certain chemicals has been shown to be associated with carcinogenesis in humans. In the 18th century, for example, Percival Pott (1775) noted a high incidence of scr...Environmental, occupational, or dietary exposure to certain chemicals has been shown to be associated with carcinogenesis in humans. In the 18th century, for example, Percival Pott (1775) noted a high incidence of scrotal cancer in chimney sweeps, which he attributed to their exposure to soot and a concomitant lack of bathing. Subsequent epidemiological studies have identified a number of additional carcinogenic agents, including aromatic amine-based dyes (Case et al., 1954), cigarette smoke (Wynder and Graham, 1950), asbestos (Doll, 1955), vinyl chloride (Creech and展开更多
The no-observed-effect level (NOEL) in a study of carcinogenicity for compounds that are both genotoxic and carcinogenic represents the limit of detection in that bioassay, rather than an estimate of a possible thresh...The no-observed-effect level (NOEL) in a study of carcinogenicity for compounds that are both genotoxic and carcinogenic represents the limit of detection in that bioassay, rather than an estimate of a possible threshold. Therefore, for those genotoxic and carcinogenic contaminants (e.g. acrylamides, PAHs, etc.) in foods it is not possible to develop health-based guidance values (e.g. ADI or PTWI) using the traditional NOEL and safety/uncertainty factors.展开更多
The decision to classify a chemical as a human carcinogen must depend upon agreed conclusions from epidemiology, bioassays, and some short-term corroborating tests; information from only one of these disciplines is in...The decision to classify a chemical as a human carcinogen must depend upon agreed conclusions from epidemiology, bioassays, and some short-term corroborating tests; information from only one of these disciplines is inadequate. Most pitfalls appear in interpreting the results from animal bioassays; this report will concentrate on them. Often the conclusion is accepted that a chemical is an animal carcinogen without a critical appraisal of the experimental design. By manipulating the experiment, 90 + % of all chemicals can induce some tumor in a rodent. Pitfalls encountered in bioassays result from not specifying the exact agent under test and how it relates to human exposure, using inappropriate routes of administration unrelated to humans, administering illogically high doses, or concluding that a cancer was induced without adequate histopathological description of the lesion. Importance of animal husbandry is often overlooked. Pitfalls are also related to short-term tests. Finally, a major pitfall in assessing carcinogenic risk from chemicals is drawing global conclusions about the carcinogenicity of an agent after the detection of only one or two tumors in the treated group.展开更多
Epidemiological studies support the idea that most human cancers are related to chemicals present in the human environment. In turn, chemicals are believed to cause cancer via either genotoxic or non-genotoxic mechani...Epidemiological studies support the idea that most human cancers are related to chemicals present in the human environment. In turn, chemicals are believed to cause cancer via either genotoxic or non-genotoxic mechanisms. There were described in literature several simple, rapid and inexpensive short term tests to reasonably predict the genotoxic nature of chemicals but in contrast, there is no reliable test or battery of tests available to predict the carcinogenicity of non-genotoxic compounds and this poses a major problem to their risk assessment. In addition, there are conflictive opinions about risk assessment needs for both classes of carcinogens. Some workers believe that for non-genotoxic carcinogens, thresholds for exposure can be drawn while others do not. In this review, the reasons behind both of these opinions and the present hypotheses about the mechanism of action of non-genotoxic carcinogens are described and analyzed in relation to future needs.展开更多
Exposure to cigarette smoke is a major risk factor for cancer and cardiovascular disease. Thrombosis is regarded as the main reason for smoking-related car- diovascular disease. However, the detail mechanism of how sm...Exposure to cigarette smoke is a major risk factor for cancer and cardiovascular disease. Thrombosis is regarded as the main reason for smoking-related car- diovascular disease. However, the detail mechanism of how smoking promotes thrombosis is not fully under- stood. In this work, we investigated the impacts of one major cigarette carcinogens 4-（methylnitrosamino）-l-（3- pyridyl）-l-butanone （NNK） as well as its metabolite 4-（methylnitrosamino）- 1-（3-pyridyl）- 1-butanol （NNAL） on a key process in thrombosis regulation： thrombin- thrombomodulin （TM） binding. Atomic force microscopy based single-molecule force spectroscopy was applied to measure both in vitro and in vivo binding force of thrombin to TM in the absence and presence of NNK and NNAL respectively. The results revealed that NNK and NNAL can reduce the binding probability of TM and thrombin. The inhibition effect and underlying mechanism was further studied by molecular simulation. As indicated by our results, the cigarette carcinogens could cause a higher risk of thrombosis through the disruption of TM- thrombin interaction.展开更多
Recently, Ng et al. reported that the A：T 〉 T：A substitutions, proposed to be a signature of aristolochic acid （AA） exposure, were detected in 76/98 （78%） of patients with hepatocellular carcinoma （HCC） from ...Recently, Ng et al. reported that the A：T 〉 T：A substitutions, proposed to be a signature of aristolochic acid （AA） exposure, were detected in 76/98 （78%） of patients with hepatocellular carcinoma （HCC） from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients＇ exposure history is the key to determine the ＂culprit＂ of the A：T 〉 T：A mutations. Apparently, without estimation of the patients＇ exposure history, the conclusion of Ng et al, is unpersuasive and misleading.展开更多
Dear Editor,On March 8–15,2022,a board of international scientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimony trioxide,and weaponsgrade tungsten alloy harboring nickel ...Dear Editor,On March 8–15,2022,a board of international scientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimony trioxide,and weaponsgrade tungsten alloy harboring nickel and cobalt[1].The 131st International Agency for Research on Cancer(IARC)Monograph is the result of a 6–9-month work of perusing the literature,slide evaluation,data interpretation,and interim meetings.The assessment of cobalt,antimony,and nickelcontaining alloys will have tremendous consequences for the industry,health,and defense departments[1].展开更多
Fish constitutes the main protein source for the Amazonian population.However,the impact of different anthropogenic activities on trace element and metal accumulation in fish and their risks for human health at a regi...Fish constitutes the main protein source for the Amazonian population.However,the impact of different anthropogenic activities on trace element and metal accumulation in fish and their risks for human health at a regional scale remain largely unexplored.Here we assessed exposure levels of 10 trace elements andmetals(Cr,Mn,Fe,Ni,Cu,Zn,As,Cd,Pb,and Hg)in 56 samples belonging to 11 different species of fish from the Brazilian Amazon.We studied the relationship between exposure levels,fish origin,and fish feeding habits,and assessed toxicological and carcinogenic risks for the Amazonian population.No significant correlation was found between sampling site and exposure levels to the studied elements,but a significant difference was found between the accumulation of some metals and the position of the fish species in the food chain.The concentrations of Cr and Hg in fish flesh were found to exceed the Brazilian limits for human consumption.This study shows that current fish consumption patterns can lead to estimated daily intakes of Hg,As and Cr that exceed the oral reference dose,thus posing a toxicological concern.Furthermore,carcinogenic risks may be expected due to the continued exposure to Cr and As.The results of this study show that the consumption of wild caught fish in the Amazon region should be controlled.Moreover,continued monitoring of trace element and metal contamination in fish and on the health of the Amazonian population is recommended,particularly for riverine and indigenous communities.展开更多
Pollution of transboundary rivers can result from anthropogenic activities in their watersheds.In this study,sediment traps were deployed to determine the fluxes,concentrations,and health risks associated with arsenic...Pollution of transboundary rivers can result from anthropogenic activities in their watersheds.In this study,sediment traps were deployed to determine the fluxes,concentrations,and health risks associated with arsenic,cadmium,mercury,lead,and iron in the estuaries of three transboundary rivers(Comoé,Bia,and Tanoé)in West Africa.Thus,the analysis of metal-associated sedimentation particle samples collected in rainy,flood,and dry seasons was required.Sediment traps were used to calculate the metal fluxes associated with sedimentation particles towards the Atlantic Ocean.Finally,the carcinogenic and non-carcinogenic risks of ingestion and dermal contact associated with sedimentation particles were assessed.The results showed that the total concentrations of trace metals in particulate matter were higher than in the UCC(Upper Crust Continental),with the exception of lead.The highest fluxes of lead,mercury,iron and arsenic associated with sedimented particles were observed during flood periods in the estuary of the Comoé,Bia and Tanoérivers.Cadmium fluxes associated with sedimentation particles were highest in the rainy season in the Bia and Comoéestuaries and in the flood season in the Tanoéestuary.Pearson’s correlation analysis and the enrichment factor showed that the trace metals were derived from anthropogenic activities such as mining and farming.In addition,contamination indices showed that sediment particles in the estuaries of the three rivers were severely contaminated with mercury.However,the results of potential human health risks associated with trace metals show that there is no probability of exposure of the community to harmful and carcinogenic effects through ingestion and dermal absorption of sediment particles.It is essential to integrate the information from this study into policy-and decision-making processes for better management of transboundary river water resources in coastal countries,particularly the Côte d’Ivoire.展开更多
Background:The precise insertion of large DNA fragments(>3–5 kb)remains one of the key obstacles in establishment of genetically modified murine models.Methods:A 21 kb large DNA fragment containing three tandemly ...Background:The precise insertion of large DNA fragments(>3–5 kb)remains one of the key obstacles in establishment of genetically modified murine models.Methods:A 21 kb large DNA fragment containing three tandemly linked copies of the human HRAS gene was inserted into the genome of C57BL/6J mouse,generating a mouse model designated as KI.C57-ras(or named NF-h HRAS).Whole-genome sequencing and Sanger sequencing were utilized to it confirm precise insertion and copy number.The stability of transgene expression among different generations was verified from multiple aspects using by digital PCR,western blot and DNA sequencing.To assess tumor susceptibility in the mouse model,N-Nitroso-N-methylurea(MNU)was administered at a dosage of 75 mg/kg.Histopathological examinations were conducted using hematoxylin and eosin(H&E)staining.Results:The HRAS DNA fragment was inserted into mouse chromosome 15E1 site,locating between 80623202 bp and 80625020 bp.NF-h HRAS mice exhibited stable inheritance and displayed consistent phenotypes across individuals.Moreover,this mouse model exhibited a high susceptibility to carcinogens.Upon administration of MNU the earliest mortality onset was earlier than that of wild-type littermates(day 65 vs.day 78 for male and day 56 vs.day 84 for female).Notably,100%of the NF-h HRAS transgenic mice developed tumors,with approximately 84%of male NF-h HRAS mice exhibiting specific tumor types,such as squamous cell carcinoma or squamous cell papilloma,which was consistent with the previously reported carcinogenic rasH2 mouse model.The types of tumors and the target organs exhibited diversity in NFh HRAS mice,while the spontaneous tumor incidence remained low(1/50).Conclusions:The NF-h HRAS mice demonstrated excellent genetic stability,a reproducible phenotype,and high susceptibility to carcinogens,indicating their potential utility in non-clinical safety evaluations of drugs as per the S1B guidelines issued by the ICH(The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use).展开更多
Long-term mining activities can result in the release of heavy metals into soil,ultimately posing a threat to human health.In arid and semi-arid regions,wind-driven transport of these toxic metals from mining areas re...Long-term mining activities can result in the release of heavy metals into soil,ultimately posing a threat to human health.In arid and semi-arid regions,wind-driven transport of these toxic metals from mining areas represents a primary mechanism for their spatial distribution.To evaluate pollution levels and associated health risks of eight metals,A total of 95 soil samples,corresponding 25 vegetable samples and 3 tailing samples were collected from various land types surrounding a typical Pb-Zn mine in northern China’s semi-arid region.The mean concentrations of As,Cd,Cr,Cu,Hg,Ni,Pb and Zn in soils were 62.8,0.27,29.6,11.5,0.02,14.4,49.9 and 109.5 mg/kg,respectively.Among these,As,Cd,Pb,and Zn emerged as the predominant pollutants,with some samples exceeding national risk screening values.The results of contamination factor(CF),pollution load index(PLI)and geo-accumulation index(I_(geo))indicated that heavy metals in most soils exhibited non-polluted level or slight pollution level,though localized severe contamination by As,Cd,Pb,and Zn was observed.Spatial distribution analysis demonstrated similar dispersion patterns for As,Cd,Pb,and Zn,with wind-mediated transport extending up to 2.0 km from contamination sources.Pearson’s correlation analysis and principal component analysis(PCA)suggested that As,Cd,Pb and Zn mainly originated from mining activities,and Cr,Ni,Cu and Hg derived from soil parent materials.All vegetable samples contained metal concentrations below food safety thresholds.Health risk assessment showed hazard quotient(HQ)values for individual metals below 1 across all exposure groups,indicating negligible non-carcinogenic risk.Similarly,carcinogenic risk(CR)values for As,Cd,Cr,and Pb fell within acceptable ranges.While mining activities have induced significant localized contamination,the overall affected area remains limited in arid and semi-arid regions.However,greater attention should be directed toward potential health implications from vegetable consumption in proximity to mining operations within arid and semi-arid regions.展开更多
Xining,a river valley city in China’s arid region,serves as an important industrial hub with a fragile ecological environment.While groundwater heavy metal pollution in this area has drawn increasing concern,the sour...Xining,a river valley city in China’s arid region,serves as an important industrial hub with a fragile ecological environment.While groundwater heavy metal pollution in this area has drawn increasing concern,the sources and associated human health risks remain inadequately understood.This study analyzed 144 shallow groundwater samples from urban Xining for 14 heavy metals(Fe,Al,B,Mn,Ba,Zn,Pb,Cr^(6+),Ni,Cu,Co,Sb,Cd,and As)using the Nemerow comprehensive pollution index,correlation analysis,and the USEPA health risk assessment model.Results identified Fe,Al,B,Mn,Ba,Pb,Cd,and As as the primary pollutants,especially concentrated in river valley plains.These contaminants primarily originate from natural sedimentary conditions and human activities such as industrial and agricultural development.The pollution indices for Al,Pb,Mn,and Fe exceeded clean water thresholds,indicating serious contamination and the need for enhanced regulation.Health risk assessments revealed that children face greater exposure risks than adults,with arsenic and nickel being the main contributors to carcinogenic risk.Sensitivity analysis further showed that As,Fe,and Cd posed the greatest non-carcinogenic and carcinogenic risks,particularly in human-impacted areas such as the Nanchuan and Beichuan valleys and Ganhegou.These findings provide essential insights for groundwater safety management in plateau river valley cities and similar vulnerable regions.展开更多
The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to ...The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.展开更多
AIM To explore the relationship betweenconsumption of fish sauce and the risk of gastriccancer in Fujian Province.METHODS An ecological study was carriedout.A total of 11000 subjects from 55 townshipswere randomly sel...AIM To explore the relationship betweenconsumption of fish sauce and the risk of gastriccancer in Fujian Province.METHODS An ecological study was carriedout.A total of 11000 subjects from 55 townshipswere randomly selected from 10 counties withinFujian Province.All subjects were localresidents who had been living in Fujian Provincefor more than 20 years,within the age group of45-74 years.Trained interviewers conductedface-to-face interviews with a standardizedquestionnaire,which covered the frequency andamount of food intake,dietary habit,tobaccoand alcohol consumption and history of chronicgastric diseases.Univariate and multivariateanalyses were performed using Epi-info and SASstatistical packages,respectively.RESULTS A significant correlation betweenmonthly consumption of fish sauce and mortalityof gastric cancer was found.Pearson’scoefficient of correlation was statisticallysignificant with r=0.7356 for males,r=0.5246for females(P【0.01).In the multivariateanalysis,consumption of fish sauce still showedan association with the risk of gastric cancer.No significant positive correlation betweenesophagus cancer,liver cancer,colon cancerand consumption of fish sauce were observed.CONCLUSION Long-term intake of fish saucemay be related to high mortality of gastriccancer.Consumption of fish sauce might be oneof important and unique etiologic factors ofgastric cancer in Fujian Province.Furtherstudies are needed to confirm this ecologicalstudy.展开更多
AIM: Hypermethylation of the promoter of the hMLH1gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was t...AIM: Hypermethylation of the promoter of the hMLH1gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer.METHODS: Data were obtained from a hospital-based,case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors.Hypermethylation of the hMLH1 gene promoter,polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1,ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated.RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1,ALDH2, and L-mycgenes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene.Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation,whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region.Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53gene.CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1,CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hypermethylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.展开更多
INTRODUCTIONChina is a country with a high incidence of liver cancer insome areas.Liver cancer has a wide distribution andthreatens human health seriously.A rough estimationshows that out of a population of 1.2×1...INTRODUCTIONChina is a country with a high incidence of liver cancer insome areas.Liver cancer has a wide distribution andthreatens human health seriously.A rough estimationshows that out of a population of 1.2×10~8 in liver展开更多
Trail, a tumor necrosis factor-related apoptosis-inducing ligand, is a novel potent endogenous activator of the cell death pathway through the activation of cell surface death receptors Trail-R1 and Trail-R2. Its role...Trail, a tumor necrosis factor-related apoptosis-inducing ligand, is a novel potent endogenous activator of the cell death pathway through the activation of cell surface death receptors Trail-R1 and Trail-R2. Its role, like FasL in activation-induced cell death (AICD), has been demonstrated in immune system. However the mechanism of Trail induced apoptosis remains unclear. In this report, the recombinant Trail protein was expressed and purified. The apoptosis-inducing activity and the regulation mechanism of recombinant Trail on Jurkat T cells were explored in vitro. Trypan blue exclusion assay demonstrated that the recombinant Trail protein actively killed Jurkat T cells in a dose-dependent manner. Trail-induced apoptosis in Jurkat T cells were remarkably reduced by Bcl-2 over expression in Bcl-2 gene transfected cells. Treatment with PMA (phorbol 12-myristate 13-acetate), a PKC activator, suppressed Trail-induced apoptosis in Jurkat T cells. The inhibition of apoptosis by PMA was abolished by pretreatment with Bis, a PKC inhibitor. Taken together, it was suggested that Bcl-2 over-expression and PMA activated PKC actively down-regulated the Trail-mediated apoptosis in Jurkat T cell.展开更多
文摘In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B 1 (AFB 1 ) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB 1 exposure and mutations in the K -ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N -acetyltransferases and glutathione S -transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk.
文摘In this paper our studies about the sequential testing program for predicting and identificating carcinogens, sequential discriminant method and cost- effectiveness analysis are summarized. The analysis of our database of carcinogeniclty and genotoxicity of chemicals demonstrates the uncertainty . of short- term tests ( STTs ) to predict carcinogens and the results of most routine STTs are statistically dependent. We recommend the sequential testing program combining STTs and carclnogenicity assay, the optimal STT batteries, the rules of the sequential discrimination and the preferal choices of STTs tor specific chemical class. For illustrative pmposes the carclnogenicity prediction of several sample chamicals is presented. The results of cost-effectiveness analysis suggest that this program has vast social-economic effectiveness.
文摘Although mutations clearly play a role in themulti-stage process of carcinogenesis,a challengewll be made to the paradigm that most chemical"carcinogens" act via mutagenic activity("carcinogens as mutagens").Control ofproliferation and differentiation within andbetween tissues is mediated by
文摘Environmental, occupational, or dietary exposure to certain chemicals has been shown to be associated with carcinogenesis in humans. In the 18th century, for example, Percival Pott (1775) noted a high incidence of scrotal cancer in chimney sweeps, which he attributed to their exposure to soot and a concomitant lack of bathing. Subsequent epidemiological studies have identified a number of additional carcinogenic agents, including aromatic amine-based dyes (Case et al., 1954), cigarette smoke (Wynder and Graham, 1950), asbestos (Doll, 1955), vinyl chloride (Creech and
文摘The no-observed-effect level (NOEL) in a study of carcinogenicity for compounds that are both genotoxic and carcinogenic represents the limit of detection in that bioassay, rather than an estimate of a possible threshold. Therefore, for those genotoxic and carcinogenic contaminants (e.g. acrylamides, PAHs, etc.) in foods it is not possible to develop health-based guidance values (e.g. ADI or PTWI) using the traditional NOEL and safety/uncertainty factors.
文摘The decision to classify a chemical as a human carcinogen must depend upon agreed conclusions from epidemiology, bioassays, and some short-term corroborating tests; information from only one of these disciplines is inadequate. Most pitfalls appear in interpreting the results from animal bioassays; this report will concentrate on them. Often the conclusion is accepted that a chemical is an animal carcinogen without a critical appraisal of the experimental design. By manipulating the experiment, 90 + % of all chemicals can induce some tumor in a rodent. Pitfalls encountered in bioassays result from not specifying the exact agent under test and how it relates to human exposure, using inappropriate routes of administration unrelated to humans, administering illogically high doses, or concluding that a cancer was induced without adequate histopathological description of the lesion. Importance of animal husbandry is often overlooked. Pitfalls are also related to short-term tests. Finally, a major pitfall in assessing carcinogenic risk from chemicals is drawing global conclusions about the carcinogenicity of an agent after the detection of only one or two tumors in the treated group.
文摘Epidemiological studies support the idea that most human cancers are related to chemicals present in the human environment. In turn, chemicals are believed to cause cancer via either genotoxic or non-genotoxic mechanisms. There were described in literature several simple, rapid and inexpensive short term tests to reasonably predict the genotoxic nature of chemicals but in contrast, there is no reliable test or battery of tests available to predict the carcinogenicity of non-genotoxic compounds and this poses a major problem to their risk assessment. In addition, there are conflictive opinions about risk assessment needs for both classes of carcinogens. Some workers believe that for non-genotoxic carcinogens, thresholds for exposure can be drawn while others do not. In this review, the reasons behind both of these opinions and the present hypotheses about the mechanism of action of non-genotoxic carcinogens are described and analyzed in relation to future needs.
基金supported by the National Basic Research Program of China (2013CB933701, 2013CB933704)the National Natural Science Foundation of China (21127901)
文摘Exposure to cigarette smoke is a major risk factor for cancer and cardiovascular disease. Thrombosis is regarded as the main reason for smoking-related car- diovascular disease. However, the detail mechanism of how smoking promotes thrombosis is not fully under- stood. In this work, we investigated the impacts of one major cigarette carcinogens 4-（methylnitrosamino）-l-（3- pyridyl）-l-butanone （NNK） as well as its metabolite 4-（methylnitrosamino）- 1-（3-pyridyl）- 1-butanol （NNAL） on a key process in thrombosis regulation： thrombin- thrombomodulin （TM） binding. Atomic force microscopy based single-molecule force spectroscopy was applied to measure both in vitro and in vivo binding force of thrombin to TM in the absence and presence of NNK and NNAL respectively. The results revealed that NNK and NNAL can reduce the binding probability of TM and thrombin. The inhibition effect and underlying mechanism was further studied by molecular simulation. As indicated by our results, the cigarette carcinogens could cause a higher risk of thrombosis through the disruption of TM- thrombin interaction.
文摘Recently, Ng et al. reported that the A：T 〉 T：A substitutions, proposed to be a signature of aristolochic acid （AA） exposure, were detected in 76/98 （78%） of patients with hepatocellular carcinoma （HCC） from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients＇ exposure history is the key to determine the ＂culprit＂ of the A：T 〉 T：A mutations. Apparently, without estimation of the patients＇ exposure history, the conclusion of Ng et al, is unpersuasive and misleading.
文摘Dear Editor,On March 8–15,2022,a board of international scientists assembled in Lyon to evaluate the carcinogenicity of cobalt metal,cobalt(Ⅱ)salts,antimony trioxide,and weaponsgrade tungsten alloy harboring nickel and cobalt[1].The 131st International Agency for Research on Cancer(IARC)Monograph is the result of a 6–9-month work of perusing the literature,slide evaluation,data interpretation,and interim meetings.The assessment of cobalt,antimony,and nickelcontaining alloys will have tremendous consequences for the industry,health,and defense departments[1].
基金supported by the National Geographic Society through an early career grant to A.Rico (EC-59809C-19)Support Programme-PlanGenT (CIDEGENT/2020/043)of the Generalitat ValencianaR.Oliveira acknowledges"Fundacao de Amparo a Pesquisa do Estado de Sao Paulo"-FAPESP (Project 2018/03108-0).
文摘Fish constitutes the main protein source for the Amazonian population.However,the impact of different anthropogenic activities on trace element and metal accumulation in fish and their risks for human health at a regional scale remain largely unexplored.Here we assessed exposure levels of 10 trace elements andmetals(Cr,Mn,Fe,Ni,Cu,Zn,As,Cd,Pb,and Hg)in 56 samples belonging to 11 different species of fish from the Brazilian Amazon.We studied the relationship between exposure levels,fish origin,and fish feeding habits,and assessed toxicological and carcinogenic risks for the Amazonian population.No significant correlation was found between sampling site and exposure levels to the studied elements,but a significant difference was found between the accumulation of some metals and the position of the fish species in the food chain.The concentrations of Cr and Hg in fish flesh were found to exceed the Brazilian limits for human consumption.This study shows that current fish consumption patterns can lead to estimated daily intakes of Hg,As and Cr that exceed the oral reference dose,thus posing a toxicological concern.Furthermore,carcinogenic risks may be expected due to the continued exposure to Cr and As.The results of this study show that the consumption of wild caught fish in the Amazon region should be controlled.Moreover,continued monitoring of trace element and metal contamination in fish and on the health of the Amazonian population is recommended,particularly for riverine and indigenous communities.
文摘Pollution of transboundary rivers can result from anthropogenic activities in their watersheds.In this study,sediment traps were deployed to determine the fluxes,concentrations,and health risks associated with arsenic,cadmium,mercury,lead,and iron in the estuaries of three transboundary rivers(Comoé,Bia,and Tanoé)in West Africa.Thus,the analysis of metal-associated sedimentation particle samples collected in rainy,flood,and dry seasons was required.Sediment traps were used to calculate the metal fluxes associated with sedimentation particles towards the Atlantic Ocean.Finally,the carcinogenic and non-carcinogenic risks of ingestion and dermal contact associated with sedimentation particles were assessed.The results showed that the total concentrations of trace metals in particulate matter were higher than in the UCC(Upper Crust Continental),with the exception of lead.The highest fluxes of lead,mercury,iron and arsenic associated with sedimented particles were observed during flood periods in the estuary of the Comoé,Bia and Tanoérivers.Cadmium fluxes associated with sedimentation particles were highest in the rainy season in the Bia and Comoéestuaries and in the flood season in the Tanoéestuary.Pearson’s correlation analysis and the enrichment factor showed that the trace metals were derived from anthropogenic activities such as mining and farming.In addition,contamination indices showed that sediment particles in the estuaries of the three rivers were severely contaminated with mercury.However,the results of potential human health risks associated with trace metals show that there is no probability of exposure of the community to harmful and carcinogenic effects through ingestion and dermal absorption of sediment particles.It is essential to integrate the information from this study into policy-and decision-making processes for better management of transboundary river water resources in coastal countries,particularly the Côte d’Ivoire.
基金National Key R&D Program of China,Grant/Award Number:2023YFC3402000National Institutes for Food and Drug Control,State Key Laboratory of Drug Regulatory Science,Grant/Award Number:2023SKLDRS0124。
文摘Background:The precise insertion of large DNA fragments(>3–5 kb)remains one of the key obstacles in establishment of genetically modified murine models.Methods:A 21 kb large DNA fragment containing three tandemly linked copies of the human HRAS gene was inserted into the genome of C57BL/6J mouse,generating a mouse model designated as KI.C57-ras(or named NF-h HRAS).Whole-genome sequencing and Sanger sequencing were utilized to it confirm precise insertion and copy number.The stability of transgene expression among different generations was verified from multiple aspects using by digital PCR,western blot and DNA sequencing.To assess tumor susceptibility in the mouse model,N-Nitroso-N-methylurea(MNU)was administered at a dosage of 75 mg/kg.Histopathological examinations were conducted using hematoxylin and eosin(H&E)staining.Results:The HRAS DNA fragment was inserted into mouse chromosome 15E1 site,locating between 80623202 bp and 80625020 bp.NF-h HRAS mice exhibited stable inheritance and displayed consistent phenotypes across individuals.Moreover,this mouse model exhibited a high susceptibility to carcinogens.Upon administration of MNU the earliest mortality onset was earlier than that of wild-type littermates(day 65 vs.day 78 for male and day 56 vs.day 84 for female).Notably,100%of the NF-h HRAS transgenic mice developed tumors,with approximately 84%of male NF-h HRAS mice exhibiting specific tumor types,such as squamous cell carcinoma or squamous cell papilloma,which was consistent with the previously reported carcinogenic rasH2 mouse model.The types of tumors and the target organs exhibited diversity in NFh HRAS mice,while the spontaneous tumor incidence remained low(1/50).Conclusions:The NF-h HRAS mice demonstrated excellent genetic stability,a reproducible phenotype,and high susceptibility to carcinogens,indicating their potential utility in non-clinical safety evaluations of drugs as per the S1B guidelines issued by the ICH(The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use).
基金financially supported by the Institute of Mineral Resources,CAGS Research Fund(KK2416)National Natural Science Foundation of China(41807134),China Geological Survey(DD20190182).
文摘Long-term mining activities can result in the release of heavy metals into soil,ultimately posing a threat to human health.In arid and semi-arid regions,wind-driven transport of these toxic metals from mining areas represents a primary mechanism for their spatial distribution.To evaluate pollution levels and associated health risks of eight metals,A total of 95 soil samples,corresponding 25 vegetable samples and 3 tailing samples were collected from various land types surrounding a typical Pb-Zn mine in northern China’s semi-arid region.The mean concentrations of As,Cd,Cr,Cu,Hg,Ni,Pb and Zn in soils were 62.8,0.27,29.6,11.5,0.02,14.4,49.9 and 109.5 mg/kg,respectively.Among these,As,Cd,Pb,and Zn emerged as the predominant pollutants,with some samples exceeding national risk screening values.The results of contamination factor(CF),pollution load index(PLI)and geo-accumulation index(I_(geo))indicated that heavy metals in most soils exhibited non-polluted level or slight pollution level,though localized severe contamination by As,Cd,Pb,and Zn was observed.Spatial distribution analysis demonstrated similar dispersion patterns for As,Cd,Pb,and Zn,with wind-mediated transport extending up to 2.0 km from contamination sources.Pearson’s correlation analysis and principal component analysis(PCA)suggested that As,Cd,Pb and Zn mainly originated from mining activities,and Cr,Ni,Cu and Hg derived from soil parent materials.All vegetable samples contained metal concentrations below food safety thresholds.Health risk assessment showed hazard quotient(HQ)values for individual metals below 1 across all exposure groups,indicating negligible non-carcinogenic risk.Similarly,carcinogenic risk(CR)values for As,Cd,Cr,and Pb fell within acceptable ranges.While mining activities have induced significant localized contamination,the overall affected area remains limited in arid and semi-arid regions.However,greater attention should be directed toward potential health implications from vegetable consumption in proximity to mining operations within arid and semi-arid regions.
基金supported by the projects of the Geological Survey(DD20240501104,DD20230422).
文摘Xining,a river valley city in China’s arid region,serves as an important industrial hub with a fragile ecological environment.While groundwater heavy metal pollution in this area has drawn increasing concern,the sources and associated human health risks remain inadequately understood.This study analyzed 144 shallow groundwater samples from urban Xining for 14 heavy metals(Fe,Al,B,Mn,Ba,Zn,Pb,Cr^(6+),Ni,Cu,Co,Sb,Cd,and As)using the Nemerow comprehensive pollution index,correlation analysis,and the USEPA health risk assessment model.Results identified Fe,Al,B,Mn,Ba,Pb,Cd,and As as the primary pollutants,especially concentrated in river valley plains.These contaminants primarily originate from natural sedimentary conditions and human activities such as industrial and agricultural development.The pollution indices for Al,Pb,Mn,and Fe exceeded clean water thresholds,indicating serious contamination and the need for enhanced regulation.Health risk assessments revealed that children face greater exposure risks than adults,with arsenic and nickel being the main contributors to carcinogenic risk.Sensitivity analysis further showed that As,Fe,and Cd posed the greatest non-carcinogenic and carcinogenic risks,particularly in human-impacted areas such as the Nanchuan and Beichuan valleys and Ganhegou.These findings provide essential insights for groundwater safety management in plateau river valley cities and similar vulnerable regions.
文摘The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
基金Natural Science Foundation of Fujian Province,China,No.K98036
文摘AIM To explore the relationship betweenconsumption of fish sauce and the risk of gastriccancer in Fujian Province.METHODS An ecological study was carriedout.A total of 11000 subjects from 55 townshipswere randomly selected from 10 counties withinFujian Province.All subjects were localresidents who had been living in Fujian Provincefor more than 20 years,within the age group of45-74 years.Trained interviewers conductedface-to-face interviews with a standardizedquestionnaire,which covered the frequency andamount of food intake,dietary habit,tobaccoand alcohol consumption and history of chronicgastric diseases.Univariate and multivariateanalyses were performed using Epi-info and SASstatistical packages,respectively.RESULTS A significant correlation betweenmonthly consumption of fish sauce and mortalityof gastric cancer was found.Pearson’scoefficient of correlation was statisticallysignificant with r=0.7356 for males,r=0.5246for females(P【0.01).In the multivariateanalysis,consumption of fish sauce still showedan association with the risk of gastric cancer.No significant positive correlation betweenesophagus cancer,liver cancer,colon cancerand consumption of fish sauce were observed.CONCLUSION Long-term intake of fish saucemay be related to high mortality of gastriccancer.Consumption of fish sauce might be oneof important and unique etiologic factors ofgastric cancer in Fujian Province.Furtherstudies are needed to confirm this ecologicalstudy.
基金Supported by the Korea Health 21 R and D Project, Ministry of Health and Welfare, Republic of Korea. No. 00-PJ1-PG3-21900-0008
文摘AIM: Hypermethylation of the promoter of the hMLH1gene, which plays an important role in mismatch repair during DNA replication, occurs in more than 30% of human gastric cancer tissues. The purpose of this study was to investigate the effects of environmental factors, genetic polymorphisms of major metabolic enzymes, and microsatellite instability on hypermethylation of the promoter of the hMLH1 gene in gastric cancer.METHODS: Data were obtained from a hospital-based,case-control study of gastric cancer. One hundred and ten gastric cancer patients and 220 age- and sex-matched control patients completed a structured questionnaire regarding their exposure to environmental risk factors.Hypermethylation of the hMLH1 gene promoter,polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1,ALDH2 and L-myc genes, microsatellite instability and mutations of p53 and Ki-ras genes were investigated.RESULTS: Both smoking and alcohol consumption were associated with a higher risk of gastric cancer with hypermethylation of the hMLH1 gene promoter. High intake of vegetables and low intake of potato were associated with increased likelihood of gastric cancer with hypermethylation of the hMLH1 gene promoter. Genetic polymorphisms of the GSTM1, GSTT1, CYP1A1, CYP2E1,ALDH2, and L-mycgenes were not significantly associated with the risk of gastric cancer either with or without hypermethylation in the promoter of the hMLH1 gene.Hypermethylation of the hMLH1 promoter was significantly associated with microsatellite instability (MSI): 10 of the 14 (71.4%) MSI-positive tumors showed hypermethylation,whereas 28 of 94 (29.8%) the MSI-negative tumors were hypermethylated at the hMLH1 promoter region.Hypermethylation of the hMLH1 gene promoter was significantly inversely correlated with mutation of the p53gene.CONCLUSION: These results suggest that cigarette smoking and alcohol consumption may influence the development of hMLH1-positive gastric cancer. Most dietary factors and polymorphisms of GSTM1, GSTT1,CYP1A1, CYP2E1, ALDH2, and L-myc genes are not independent risk factors for gastric cancer with hypermethylation of the hMLH1 promoter. These data also suggest that there could be two or more different molecular pathways in the development of gastric cancer, perhaps involving tumor suppression mechanisms or DNA mismatch repair.
基金National Natural Science Foundation of China,№48970193
文摘INTRODUCTIONChina is a country with a high incidence of liver cancer insome areas.Liver cancer has a wide distribution andthreatens human health seriously.A rough estimationshows that out of a population of 1.2×10~8 in liver
基金Major State BasicResearch (973) Program of China, (G1999053905).
文摘Trail, a tumor necrosis factor-related apoptosis-inducing ligand, is a novel potent endogenous activator of the cell death pathway through the activation of cell surface death receptors Trail-R1 and Trail-R2. Its role, like FasL in activation-induced cell death (AICD), has been demonstrated in immune system. However the mechanism of Trail induced apoptosis remains unclear. In this report, the recombinant Trail protein was expressed and purified. The apoptosis-inducing activity and the regulation mechanism of recombinant Trail on Jurkat T cells were explored in vitro. Trypan blue exclusion assay demonstrated that the recombinant Trail protein actively killed Jurkat T cells in a dose-dependent manner. Trail-induced apoptosis in Jurkat T cells were remarkably reduced by Bcl-2 over expression in Bcl-2 gene transfected cells. Treatment with PMA (phorbol 12-myristate 13-acetate), a PKC activator, suppressed Trail-induced apoptosis in Jurkat T cells. The inhibition of apoptosis by PMA was abolished by pretreatment with Bis, a PKC inhibitor. Taken together, it was suggested that Bcl-2 over-expression and PMA activated PKC actively down-regulated the Trail-mediated apoptosis in Jurkat T cell.
