Interactions of chemical carcinogens and genetic variation in hepatocellular carcinoma

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.

A SEQUENTIAL TESTING PROGRAM FOR PREDICTING AND IDENTIFICATING CARCINOGENS AND ITS APPLICATION

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.

CHEMICAL“CARCINOGENS”,AS MODULATORS OF INTER-CELLULAR COMMUNICATION,ARE MITOGENS,NOT MUTAGENS.

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

Biomarkers of Human Exposure to Carcinogens: An Overview

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

New development in risk assessment of genotoxic carcinogens in foods

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.

Pitfalls in Assessing Risks from Carcinogens

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.

Non-Genotoxic Carcinogens.Approaches to Their Risk Assessment

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.

Single-molecule force spectroscopy study of the effect of cigarette carcinogens on thrombomodulin–thrombin interaction

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.

Nitrosamines crisis in pharmaceuticals-Insights on toxicological implications,root causes and risk assessment:A systematic review

The presence of N-nitroso compounds,particularly N-nitrosamines,in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects.This systematic review investigates their toxicity in active pharmaceutical ingredients(APIs),drug products,and pharmaceutical excipients,along with novel analytical strategies for detection,root cause analysis,reformulation strategies,and regulatory guidelines for nitrosamines.This review emphasizes the molecular toxicity of N-nitroso compounds,focusing on genotoxic,mutagenic,carcinogenic,and other physiological effects.Additionally,it addresses the ongoing nitrosamine crisis,the development of nitrosamine-free products,and the importance of sensitive detection methods and precise risk evaluation.This comprehensive overview will aid molecular biologists,analytical scientists,formulation scientists in research and development sector,and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Contamination assessment,source apportionment and associated health risks of PTEs in agricultural soil under five land-use patterns in Sanya,China

To understand the levels of potentially toxic elements(PTEs)contamination in soils and their effects on human health from different agricultural land use in Sanya,China.128 soil samples(64 topsoil samples and corresponding subsoil samples)were collected from the five representative land-use patterns.Inductively coupled plasma mass spectrometry(ICP-MS),Atomic fluorescence spectrometry(AFS),and Inductively coupled plasma optical emission spectrometry(ICP-OES)were used to determine the content of PTEs(As,Cd,Hg,Cu,Cr,Ni,Pb,Zn,Co,Mo,Sb,and V).Correlation analysis and factor analysis were used to determine the source of PTEs.Geo-accumulation index(I_(geo)),hazard quotient(HQ),and total carcinogenic risk index(TR)were used to measure the PTEs contamination and its relative health impacts.Results showed that the average values of 12 PTEs in topsoil were higher than the Hainan soil geochemical baseline,showing different degrees of PTEs accumulation effect.The concentration of PTEs in the topsoil was lower than those in the subsoil except for Cd and Hg.The I_(geo)revealed that the major accumulated element in soils was As followed by Mo.Source apportionment suggested that parent materials and agricultural practices were the dominant factors for PTEs accumulation in the topsoil.Noncarcinogenic risks of soil samples from five land-use patterns presented a trend of paddy field>dry field>woodland>orchard>garden plot.However,the HQ values of 12 PTEs were less than the recommended limit of HQ=1,representing that there are no non-carcinogenic risks of PTEs for children and adults in the study area.The TR values are within 6.95×10^(-6)-1.38×10^(-5),which corresponds to the low level.Therefore the PTEs in the agricultural soil of the study area show little influence on the health status of the local population.

Health risk assessment of heavy metal pollution in groundwater of a karst basin,SW China

To investigate the presence of metal elements and assess their health risk for the populace in the Nandong Underground River Basin(NURB),we conducted an analysis of eleven common heavy metals in the water body.A Health risk assessment(HRA)model was employed to analyze 84 water samples from the NURB.The detection results revealed the following order of heavy metals concentrations:Fe>Al>Mn>Zn>As>Cd>Pb>Cr>Ni>Cu>Hg.Correlation analysis indicated a certain similarity in material source and migration transformation among these eleven metal elements.Our study identified that the health risks for local residents exposed to metal elements in the water of NURB primarily stem from carcinogenic risk(10^(−6)–10^(−4)a^(−1))through the drinking water pathway.Moreover,the health risk of heavy metal exposure for children through drinking water was notably higher than for adults.The maximum health risks of Cr in both underground and surface water exceeded the recommendation standard(5.0×10^(−5)a^(−1))from ICRP,surpassing the values recommended by the Swedish Environmental Protection Agency,the Dutch Ministry of Construction and Environment and the British Royal Society(5.0×10^(−6)a^(−1)).The results of the health risk assessment indicate that Cr in the water of NURB is the primary source of carcinogenic risk for local residents,followed by Cd and As.Consequently,it is imperative to control these three carcinogenic metals when the water was used as drinking water resource.

Carcinogens that induce the A：T 〉 T：A nucleotide substitutions in the genome

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.

The transcriptome analysis of cleft lip/palate-related PTCH1 variants in GMSM-K cells show carcinogenic potential

Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic disease and congenital disorder.To evaluate the relationship between PTCH1 and cancer,we applied the CRISPR/Cas9 system to knock out PTCH1 in oral nontumorous epithelial cells(GMSM-K).Then we screened six PTCH1 variants associated with cleft lip/palate(CL/P),one of the congenital disorders in NBCCs,and generated PTCH1 variant and wild-type recombinant PTCH1^(−/−)GMSM-K cell lines.Transcriptome sequencing was conducted in these cell lines.The results revealed that differentially expressed genes(DEGs)in PTCH1^(−/−)GMSM-K were enriched in extracellular compartments,contributing epithelial diseases by pathway enrichment analysis.RT-PCR confirmed that KRT34,KRT81,KRT86,PDGFB,and WNT10B genes,associated with extracellular compartments were highly expressed in PTCH1^(−/−).The Kyoto Encyclopedia of Genes and Genomes analysis also suggested that DEGs are closely related to focal adhesion,transcriptional misregulation,and proteoglycans in breast and gastric cancers.Comparative analysis of samples revealed that the CL/P-associated PTCH1 variants A443G and V908G are potentially carcinogenic.These findings provide new insights into the carcinogenic potential of PTCH1 dysfunction.

Impact of mycotoxins and their metabolites associated with food grains

Mycotoxins are secondary toxic metabolites synthesized by numerous filamentous fungi including members of the genus Fusarium,Penicillium,Drechslera,Aspergillus,Claviceps,Monascum,Alternaria,Cephalosporium,Nigrospora,and Trichoderma.Among them,Aspergillus and Fusarium species are major plant pathogens recognized to induce infection and produce mycotoxins in food crops.More than 400 mycotoxins have been documented and among them,aflatoxin,fumonisins,trichothecenes,zearalenone,ochratoxin A,citrinin,ergot alkaloids,and patulin are the most prominent compounds linked to a variety of human and animal health disorders.Genus Fusarium and Aspergillus belong to a saprophytic group,which can infect and contaminate many crops at pre and post-harvest stages.Mycotoxins can have a variety of negative effects on health in both humans and animals.Mycotoxins and their metabolites can cause severe acute poisoning,which can result in death,as well as long-term negative health effects,such as cancer and immune-suppressive disorders in living beings(animals and humans).Mycotoxin contamination of agricultural goods has gained global significance,due to its toxic effects on living beings,as well as its importance to international trade.Our objective is to provide a consolidated information on the potential mycotixs in food grains and their significant impact on the health of the human beings.

Human Health Risks from Exposure to Heavy Metals of Suspended Particulate Matter around the Tongon Gold Mine, Côte d’Ivoire

The Tongon mine, the largest gold mine in C?te d’Ivoire, has been in operation since April 2010. However, to our knowledge to date, no study has been conducted on metallic contamination in suspended particulate matter (PM10 and PM2.5) where there is a lack of information on the carcinogenic and non-carcinogenic risk to human health associated with the exposure of populations in the Tongon area to these pollutants. The general objective of this study is to evaluate the level of contamination of PM10;PM2.5 by heavy metals and their impact on the health of populations exposed to these pollutants in the Tongon gold mine area. The sampling and measurement of suspended particulate matter (PM10 and PM2.5) were done using a MiniVol TAS passive air sampler. Heavy metal concentrations were determined by inductively coupled plasma mass spectroscopy (Nex ION 2000 ICP-MS, USA). The results indicate that the average concentrations of suspended particles (PM2.5 and PM10) obtained are all above the recommended exposure limits. In addition, among the heavy metals contained in the suspended particles, the concentrations of arsenic and nickel are high and all above the standard limit values. The assessment of the health risks related to the inhalation of PM10 particles reveals that their inhalation over a long period could cause a carcinogenic risk.

Health Impacts and Mechanisms of Per- and Polyfluoroalkyl Substances (PFAS) from Epidemiological to Toxicological

This research provides a comprehensive analysis of the health impacts of Per- and Polyfluoroalkyl Substances (PFAS) through an integration of epidemiological and toxicological studies. The study identifies significant correlations between PFAS exposure and adverse health outcomes, including thyroid dysfunction, elevated cholesterol levels, and increased risk of specific cancers. Utilizing a mixed-methods approach, the research combines a systematic review and meta-analysis of recent literature with in vitro and in vivo toxicological experiments. The epidemiological analysis reveals increased risks of thyroid dysfunction, cholesterol elevation, and certain cancers among PFAS-exposed individuals. Toxicological findings further corroborate these results, showing dose-dependent cytotoxic effects in human cell lines and endocrine disruption in rodent models. The study emphasizes the importance of regulatory measures to mitigate PFAS exposure and the urgent need for more comprehensive research into their long-term effects. The integration of epidemiological and toxicological data underscores the significant health risks posed by PFAS, highlighting the necessity of immediate action to limit exposure and develop safer alternatives.

The prognostic molecular markers in hepatocellular carcinoma

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.

Fish sauce and gastric cancer:an ecological study in Fujian Province,China

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.

Effects of dietary intake and genetic factors on hypermethyiation of the hMLH1 gene promoter in gastric cancer

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.