1 3267 101 HEPATOCELLULAR CARCINOMA AND POSSIBLE CHEMICAL AND BIOLOGICAL CAUSES: A REVIEW. THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) IS A MULTISTEP PROCESS. IN HCC, PROGRESSIVE AND MORPHOLOGICALLY DISTINCT PRENEOPLASTIC LESIONS/ALTERATIONS ASSOCIATED WITH CHRONIC LIVER INJURY, INFLAMMATION, HEPATOCELLULAR DEGENERATION/REGENERATION, NECROSIS, AND SMALL-CELL DYSPLASIA CAN BE OBSERVED. THE INCIDENCE OF HCC EXHIBITS REGIONAL AND ETHNIC DIFFERENCES. SEVERAL CYTOTOXIC AND DNA-DAMAGING CHEMICALS ARE SUGGESTED TO BE THE UNDERLYING CAUSES OF HCC-FOR EXAMPLE, ACRYLAMIDE, PERFLUOROOCTANOIC ACID (PFOA), POLYCHLORINATED BIPHENYLS (PCBS), BENZO(A)PYRENE (BAP), PERFLUORINATED CHEMICALS (PFCS), VINYL CHLORIDE MONOMER (VCM), AND DIETARY CONTAMINANTS (AFLATOXINS, OCHRATOXINS). ALSO SUGGESTED ARE SUBSTANCES OF ABUSE (ALCOHOL) AND BIOLOGICAL AGENTS, SUCH AS HEPATITIS B AND C AND HUMAN IMMUNODEFICIENCY VIRUS 1 (HIV-1). THESE CAN ACT THROUGH GENETIC AND/OR EPIGENETIC MECHANISMS. THIS REVIEW WILL SHORTLY ADDRESS THE GENETIC AND EPIGENETIC MECHANISMS OF HCC AND FOCUS ON CYTOTOXIC AND DNA-DAMAGING CHEMICALS AND BIOLOGICAL AGENTS, EXPOSURE TO WHICH ARE SUGGESTED TO LEAD TO HCC INITIATION, PROMOTION, AND/OR PROGRESSION. 2017 2 452 29 APPLICATION OF THE KEY CHARACTERISTICS OF CARCINOGENS TO PER AND POLYFLUOROALKYL SUBSTANCES. PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) CONSTITUTE A LARGE CLASS OF ENVIRONMENTALLY PERSISTENT CHEMICALS USED IN INDUSTRIAL AND CONSUMER PRODUCTS. HUMAN EXPOSURE TO PFAS IS EXTENSIVE, AND PFAS CONTAMINATION HAS BEEN REPORTED IN DRINKING WATER AND FOOD SUPPLIES AS WELL AS IN THE SERUM OF NEARLY ALL PEOPLE. THE MOST WELL-STUDIED MEMBER OF THE PFAS CLASS, PERFLUOROOCTANOIC ACID (PFOA), INDUCES TUMORS IN ANIMAL BIOASSAYS AND HAS BEEN ASSOCIATED WITH ELEVATED RISK OF CANCER IN HUMAN POPULATIONS. GENX, ONE OF THE PFOA REPLACEMENT CHEMICALS, INDUCES TUMORS IN ANIMAL BIOASSAYS AS WELL. USING THE KEY CHARACTERISTICS OF CARCINOGENS FRAMEWORK FOR CANCER HAZARD IDENTIFICATION, WE CONSIDERED THE EXISTING EPIDEMIOLOGICAL, TOXICOLOGICAL AND MECHANISTIC DATA FOR 26 DIFFERENT PFAS. WE FOUND STRONG EVIDENCE THAT MULTIPLE PFAS INDUCE OXIDATIVE STRESS, ARE IMMUNOSUPPRESSIVE, AND MODULATE RECEPTOR-MEDIATED EFFECTS. WE ALSO FOUND SUGGESTIVE EVIDENCE INDICATING THAT SOME PFAS CAN INDUCE EPIGENETIC ALTERATIONS AND INFLUENCE CELL PROLIFERATION. EXPERIMENTAL DATA INDICATE THAT PFAS ARE NOT GENOTOXIC AND GENERALLY DO NOT UNDERGO METABOLIC ACTIVATION. DATA ARE CURRENTLY INSUFFICIENT TO ASSESS WHETHER ANY PFAS PROMOTE CHRONIC INFLAMMATION, CELLULAR IMMORTALIZATION OR ALTER DNA REPAIR. WHILE MORE RESEARCH IS NEEDED TO ADDRESS DATA GAPS, EVIDENCE EXISTS THAT SEVERAL PFAS EXHIBIT ONE OR MORE OF THE KEY CHARACTERISTICS OF CARCINOGENS. 2020 3 865 21 CHRONIC ACRYLAMIDE EXPOSURE IN MALE MICE RESULTS IN ELEVATED DNA DAMAGE IN THE GERMLINE AND HERITABLE INDUCTION OF CYP2E1 IN THE TESTES. ACUTE ACRYLAMIDE EXPOSURE IN MALE RODENTS RESULTS IN REDUCED REPRODUCTIVE PERFORMANCE AND DOMINANT LETHALITY. HOWEVER, THE REPRODUCTIVE EFFECTS OF LOW DOSE CHRONIC EXPOSURE, WHICH BETTER REFLECTS THE NATURE OF HUMAN EXPOSURE, REMAIN FAR LESS CERTAIN. HUMAN DIETARY CONSUMPTION OF ACRYLAMIDE HAS BEEN ESTIMATED AT AN AVERAGE OF 1-4 MICROG/KG BW/DAY. IN ORDER TO SIMULATE THIS EXPOSURE, MALE MICE WERE PROVIDED WITH ACRYLAMIDE (1 MICROG/ML) VIA THEIR DRINKING WATER CONTINUOUSLY FOR SIX MONTHS, WHICH WAS EQUIVALENT TO A HUMAN DOSE OF 10.5 MICROG/ KG BW/DAY. THIS EXPOSURE REGIME INCREASED DNA DAMAGE IN THE SPERMATOZOA, WITHOUT AFFECTING A CONCOMITANT REDUCTION IN OVERALL FERTILITY. THE OFFSPRING OF ACRYLAMIDE TREATED MICE DID NOT HAVE AN INCREASED INCIDENCE OF SKIN PAPILLOMA FORMATION FOLLOWING THE TWO-STAGE TUMOR INDUCTION PROTOCOL. HOWEVER, THE MALE OFFSPRING OF ACRYLAMIDE TREATED FATHERS HAD SIGNIFICANTLY INCREASED LEVELS OF DNA DAMAGE IN THEIR SPERMATOZOA, DESPITE HAVING HAD NO DIRECT TOXICANT EXPOSURE. IT WAS ALSO FOUND THAT THE F0, AND MOST CRUCIALLY, F1 MICE HAD INCREASED LEVELS OF CYP2E1 PROTEIN IN THEIR GERM CELLS. THIS IS SIGNIFICANT AS CYP2E1 IS THE SOLE ENZYME RESPONSIBLE FOR CONVERSION OF ACRYLAMIDE TO ITS HARMFUL METABOLITE GLYCIDAMIDE. THIS ALTERED EXPRESSION MAY BE DUE TO EPIGENETIC ALTERATIONS. ADDITIONALLY, THE F0 AND F1 MICE HAD INCREASED OXIDATIVE ADDUCTS IN THE DNA OF THEIR GERM CELLS, WHICH WAS HYPOTHESIZED TO ARISE AS A BYPRODUCT OF INCREASED CYP2E1 ACTIVITY. THEREFORE, CHRONIC PATERNAL ACRYLAMIDE EXPOSURE IN MICE HAS CONSEQUENCES FOR THEIR OFFSPRING, AND RAISES CONCERNS FOR THE EFFECTS OF ACRYLAMIDE EXPOSURE IN THE HUMAN POPULATION AND THE ACCUMULATED EFFECTS WITH MULTIPLE GENERATIONS OF EXPOSURE. 2016 4 6486 32 TP53 AND LIVER CARCINOGENESIS. PRIMARY HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON MALIGNANCIES AND HAS THE FOURTH HIGHEST MORTALITY RATE WORLDWIDE. THE MAJOR RISK FACTORS, INCLUDING CHRONIC INFECTIONS WITH THE HEPATITIS B OR C VIRUS, ARE EXPOSURE TO DIETARY AFLATOXIN B1(AFB1), VINYL CHLORIDE, OR ALCOHOL CONSUMPTION. SOUTHERN CHINA AND SUB-SAHARAN AFRICA HAVE THE HIGHEST DIETARY AFB1 EXPOSURE, MAKING IT AND HEPATITIS B VIRUS (HBV) THE MAJOR CAUSES OF CANCER MORTALITY IN THESE GEOGRAPHIC AREAS. RECENT STUDIES HAVE DISCOVERED GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE MOLECULAR PATHOGENESIS OF HCC, INCLUDING SOMATIC MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE (TP53). AFB1 INDUCES TYPICAL G:C TO T:A TRANSVERSIONS AT THE THIRD BASE IN CODON 249 OF P53. CHRONIC ACTIVE HEPATITIS B AND C (HCV) INFECTION, AND FURTHER INFLAMMATORY AND OXYRADICAL DISORDERS INCLUDING WILSON DISEASE (WD) OR HEMOCHROMATOSIS, GENERATE REACTIVE OXYGEN/NITROGEN SPECIES THAT CAN DAMAGE DNA AND MUTATE THE P53 GENE. THE X GENE OF HBV (HBX) IS THE MOST COMMON OPEN READING FRAME INTEGRATED INTO THE HOST GENOME IN HCC. THE INTEGRATED HBX IS FREQUENTLY MUTATED AND HAS A DIMINISHED ABILITY TO FUNCTION AS A TRANSCRIPTIONAL COTRANSACTIVATOR AND TO ACTIVATE THE NF-KAPPA B PATHWAY. HOWEVER, THE MUTANT HBX PROTEINS STILL RETAIN THEIR ABILITY TO BIND TO AND ABROGATE P53-MEDIATED APOPTOSIS. IN SUMMARY, BOTH VIRUSES AND CHEMICALS ARE IMPLICATED IN THE ETIOLOGY AND MOLECULAR PATHOGENESIS OF HCC. THE RESULTANT MOLECULAR CHANGES IN THE RAS AND WNT SIGNAL-TRANSDUCTION PATHWAYS, AND THE P53 AND RB TUMOR SUPPRESSOR PATHWAYS SIGNIFICANTLY CONTRIBUTE TO LIVER CARCINOGENESIS 2003 5 4602 18 NECESSITY OF EPIGENETIC EPIDEMIOLOGY STUDIES ON THE CARCINOGENESIS OF LUNG CANCER IN NEVER SMOKERS. BASED ON EPIDEMIOLOGICAL AND GENOMIC CHARACTERISTICS, LUNG CANCER IN NEVER SMOKERS (LCNS) IS A DIFFERENT DISEASE FROM LUNG CANCER IN SMOKERS. BASED ON CURRENT RESEARCH, THE MAIN RISK FACTOR FOR LCNS MAY BE AIR POLLUTION. A RECENT CASE-CONTROL STUDY IN KOREANS REPORTED THAT NITROGEN DIOXIDE (NO2) MAY BE A RISK FACTOR FOR LCNS. ADDITIONALLY, A COHORT STUDY SHOWED THAT EXPOSURE TO NO2 WAS ASSOCIATED WITH SIGNIFICANT HYPOMETHYLATION. THUS, EPIGENETIC EPIDEMIOLOGY STUDIES ARE NEEDED IN THE NEAR FUTURE TO EVALUATE THE CARCINOGENESIS OF LCNS ACCORDING TO CHRONIC EXPOSURE TO AIR POLLUTION AND/OR VIRAL INFECTIONS. 2018 6 1970 23 EPIGENETIC ALTERATIONS AND OCCUPATIONAL EXPOSURE TO BENZENE, FIBERS, AND HEAVY METALS ASSOCIATED WITH TUMOR DEVELOPMENT (REVIEW). THE CHRONIC OCCUPATIONAL EXPOSURE TO CONTAMINANTS AND CARCINOGENS LEADS TO THE DEVELOPMENT OF CANCER. OVER THE PAST DECADES, MANY CARCINOGENS HAVE BEEN FOUND IN THE OCCUPATIONAL ENVIRONMENT AND THEIR PRESENCE IS OFTEN ASSOCIATED WITH AN INCREASED INCIDENCE OF CANCER. ACCORDING TO THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC), THE MAJORITY OF CARCINOGENS ARE CLASSIFIED AS 'PROBABLE' AND 'POSSIBLE' HUMAN CARCINOGENS, WHILE, DIRECT EVIDENCE OF CARCINOGENICITY IS PROVIDED IN EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES. ADDITIONALLY, ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS MAY BE EARLY INDICATORS OF GENOTOXIC AND NON-GENOTOXIC CARCINOGEN EXPOSURE. IN THE PRESENT REVIEW, THE RELATIONSHIP BETWEEN EXPOSURES TO BENZENE, MINERAL FIBERS, METALS AND EPIGENETIC ALTERATIONS ARE DISCUSSED AS THE MOST IMPORTANT CANCER RISK FACTORS DURING WORK ACTIVITIES. 2017 7 6487 33 TP53 MUTATIONS AND HEPATOCELLULAR CARCINOMA: INSIGHTS INTO THE ETIOLOGY AND PATHOGENESIS OF LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON MALIGNANCIES WORLDWIDE AND THE MAJOR RISK FACTORS INCLUDE CHRONIC INFECTIONS WITH THE HEPATITIS B (HBV) OR C (HCV) VIRUS, AND EXPOSURE TO DIETARY AFLATOXIN B(1) (AFB(1)) OR ALCOHOL CONSUMPTION. MULTIPLE GENETIC AND EPIGENETIC CHANGES ARE INVOLVED IN THE MOLECULAR PATHOGENESIS OF HCC, FOR EXAMPLE, SOMATIC MUTATIONS IN THE P53 TUMOR SUPPRESSOR GENE (TP53) AND THE ACTIVATION OF THE WNT SIGNAL TRANSDUCTION PATHWAY. AFB(1) FREQUENTLY INDUCES G:C TO T:A TRANSVERSIONS AT THE THIRD BASE IN CODON 249 OF TP53 AND COOPERATES WITH HBV IN CAUSING P53 MUTATIONS IN HCC. THE DETECTION OF TP53 MUTANT DNA IN PLASMA IS A BIOMARKER OF BOTH AFB(1) EXPOSURE AND HCC RISK. CHRONIC INFECTION WITH HBV AND HCV VIRUSES, AND OXYRADICAL DISORDERS INCLUDING HEMOCHROMATOSIS, ALSO GENERATE REACTIVE OXYGEN/NITROGEN SPECIES THAT CAN BOTH DAMAGE DNA AND MUTATE CANCER-RELATED GENES SUCH AS TP53. CERTAIN MUTANT P53 PROTEINS MAY EXHIBIT A 'GAIN OF ONCOGENIC FUNCTION'. THE P53 BIOLOGICAL NETWORK IS A KEY RESPONDER TO THIS OXIDATIVE AND NITROSATIVE STRESS. DEPENDING ON THE EXTENT OF THE DNA DAMAGE, P53 REGULATES THE TRANSCRIPTION OF PROTECTIVE ANTIOXIDANT GENES AND WITH EXTENSIVE DNA DAMAGE, TRANSACTIVATES PRO-OXIDANT GENES THAT CONTRIBUTE TO APOPTOSIS. THE X GENE OF HBV (HBX) IS THE MOST COMMON OPEN READING FRAME INTEGRATED INTO THE HOST GENOME IN HCC AND THE INTEGRATED HBX IS FREQUENTLY MUTATED. MUTANT HBX PROTEINS STILL RETAIN THEIR ABILITY TO BIND TO P53, AND ATTENUATE DNA REPAIR AND P53-MEDIATED APOPTOSIS. IN SUMMARY, BOTH VIRUSES AND CHEMICALS ARE IMPLICATED IN THE ETIOLOGY OF TP53 MUTATIONS DURING THE MOLECULAR PATHOGENESIS OF HCC. 2007 8 4984 28 PATHWAYS OF GASTRIC CARCINOGENESIS, HELICOBACTER PYLORI VIRULENCE AND INTERACTIONS WITH ANTIOXIDANT SYSTEMS, VITAMIN C AND PHYTOCHEMICALS. HELICOBACTER PYLORI IS A CLASS ONE CARCINOGEN WHICH CAUSES CHRONIC ATROPHIC GASTRITIS, GASTRIC INTESTINAL METAPLASIA, DYSPLASIA AND ADENOCARCINOMA. THE MECHANISMS BY WHICH H. PYLORI INTERACTS WITH OTHER RISK AND PROTECTIVE FACTORS, PARTICULARLY VITAMIN C IN GASTRIC CARCINOGENESIS ARE COMPLEX. GASTRIC CARCINOGENESIS INCLUDES METABOLIC, ENVIRONMENTAL, EPIGENETIC, GENOMIC, INFECTIVE, INFLAMMATORY AND ONCOGENIC PATHWAYS. THE MOLECULAR CLASSIFICATION OF GASTRIC CANCER SUBTYPES HAS REVOLUTIONIZED THE UNDERSTANDING OF GASTRIC CARCINOGENESIS. THIS INCLUDES THE TUMOUR MICROENVIRONMENT, GERMLINE MUTATIONS, AND THE ROLE OF HELICOBACTER PYLORI BACTERIA, EPSTEIN BARR VIRUS AND EPIGENETICS IN SOMATIC MUTATIONS. THERE IS EVIDENCE THAT ASCORBIC ACID, PHYTOCHEMICALS AND ENDOGENOUS ANTIOXIDANT SYSTEMS CAN MODIFY THE RISK OF GASTRIC CANCER. GASTRIC JUICE ASCORBATE LEVELS DEPEND ON DIETARY INTAKE OF ASCORBIC ACID BUT CAN ALSO BE DECREASED BY H. PYLORI INFECTION, H. PYLORI CAGA SECRETION, TOBACCO SMOKING, ACHLORHYDRIA AND CHRONIC ATROPHIC GASTRITIS. ASCORBIC ACID MAY BE PROTECTIVE AGAINST GASTRIC CANCER BY ITS ANTIOXIDANT EFFECT IN GASTRIC CYTOPROTECTION, REGENERATING ACTIVE VITAMIN E AND GLUTATHIONE, INHIBITING ENDOGENOUS N-NITROSATION, REDUCING TOXIC EFFECTS OF INGESTED NITROSODIMETHYLAMINES AND HETEROCYCLIC AMINES, AND PREVENTING H. PYLORI INFECTION. THE EFFECTIVENESS OF SUCH CYTOPROTECTION IS RELATED TO H. PYLORI STRAIN VIRULENCE, PARTICULARLY CAGA EXPRESSION. THE ROLE OF VITAMIN C IN EPIGENETIC REPROGRAMMING IN GASTRIC CANCER IS STILL EVOLVING. OTHER FACTORS IN CONJUNCTION WITH VITAMIN C ALSO PLAY A ROLE IN GASTRIC CARCINOGENESIS. ERADICATION OF H. PYLORI MAY LEAD TO RECOVERY OF VITAMIN C SECRETION BY GASTRIC EPITHELIUM AND ENABLE REGRESSION OF PREMALIGNANT GASTRIC LESIONS, THEREBY INTERRUPTING THE CORREA CASCADE OF GASTRIC CARCINOGENESIS. 2020 9 4822 24 OCHRATOXIN A: 50 YEARS OF RESEARCH. SINCE OCHRATOXIN A (OTA) WAS DISCOVERED, IT HAS BEEN UBIQUITOUS AS A NATURAL CONTAMINANT OF MOLDY FOOD AND FEED. THE MULTIPLE TOXIC EFFECTS OF OTA ARE A REAL THREAT FOR HUMAN BEINGS AND ANIMAL HEALTH. FOR EXAMPLE, OTA CAN CAUSE PORCINE NEPHROPATHY BUT CAN ALSO DAMAGE POULTRIES. HUMANS EXPOSED TO OTA CAN DEVELOP (NOTABLY BY INHALATION IN THE DEVELOPMENT OF ACUTE RENAL FAILURE WITHIN 24 H) A RANGE OF CHRONIC DISORDERS SUCH AS UPPER UROTHELIAL CARCINOMA. OTA PLAYS THE MAIN ROLE IN THE PATHOGENESIS OF SOME RENAL DISEASES INCLUDING BALKAN ENDEMIC NEPHROPATHY, KIDNEY TUMORS OCCURRING IN CERTAIN ENDEMIC REGIONS OF THE BALKAN PENINSULA, AND CHRONIC INTERSTITIAL NEPHROPATHY OCCURRING IN NORTHERN AFRICAN COUNTRIES AND LIKELY IN OTHER PARTS OF THE WORLD. OTA LEADS TO DNA ADDUCT FORMATION, WHICH IS KNOWN FOR ITS GENOTOXICITY AND CARCINOGENICITY. THE PRESENT ARTICLE DISCUSSES HOW RENAL CARCINOGENICITY AND NEPHROTOXICITY CAUSE BOTH OXIDATIVE STRESS AND DIRECT GENOTOXICITY. CAREFUL ANALYSES OF THE DATA SHOW THAT OTA CARCINOGENIC EFFECTS ARE DUE TO COMBINED DIRECT AND INDIRECT MECHANISMS (E.G., GENOTOXICITY, OXIDATIVE STRESS, EPIGENETIC FACTORS). ALTOGETHER THIS PROVIDES STRONG EVIDENCE THAT OTA CARCINOGENICITY CAN ALSO OCCUR IN HUMANS. 2016 10 2959 24 GENETIC AND EPIGENETIC INSTABILITY INDUCED BY BETEL QUID ASSOCIATED CHEMICALS. OVER THE YEARS, BETEL QUID CHEWING AND TOBACCO USE HAVE ATTRACTED CONSIDERABLE INTEREST AS THEY ARE IMPLICATED AS THE MOST LIKELY CAUSATIVE RISK FACTORS OF ORAL AND ESOPHAGEAL CANCERS. ALTHOUGH ARECA NUT USE AND BETEL QUID CHEWING MAY LEAD TO APOPTOSIS, CHRONIC EXPOSURE TO ARECA NUT AND SLAKED LIME MAY PROMOTE PRE-MALIGNANT AND MALIGNANT TRANSFORMATION OF ORAL CELLS. THE PUTATIVE MUTAGENIC AND CARCINOGENIC MECHANISMS MAY INVOLVE ENDOGENOUS NITROSATION OF ARECA AND TOBACCO ALKALOIDS AS WELL AS THE PRESENCE OF DIRECT ALKYLATING AGENTS IN BETEL QUID AND SMOKELESS TOBACCO. METABOLIC ACTIVATION OF CARCINOGENIC N-NITROSAMINES BY PHASE-I ENZYMES IS REQUIRED NOT ONLY TO ELICIT THE GENOTOXICITY VIA THE REACTIVE INTERMEDIATES BUT ALSO TO POTENTIATE THE MUTAGENICITY WITH THE SPORADIC ALKYLATIONS OF NUCLEOTIDE BASES, RESULTING IN THE FORMATION OF DIVERSE DNA ADDUCTS. PERSISTENT DNA ADDUCTS PROVIDES THE IMPETUS FOR GENETIC AND EPIGENETIC LESIONS. THE GENETIC AND EPIGENETIC FACTORS CUMULATIVELY INFLUENCE THE DEVELOPMENT AND PROGRESSION OF DISORDERS SUCH AS CANCER. ACCUMULATION OF NUMEROUS GENETIC AND EPIGENETIC ABERRATIONS DUE TO LONG-TERM BETEL QUID (WITH OR WITHOUT TOBACCO) CHEWING AND TOBACCO USE CULMINATES INTO THE DEVELOPMENT OF HEAD AND NECK CANCERS. WE REVIEW RECENT EVIDENCE THAT SUPPORTS PUTATIVE MECHANISMS FOR MUTAGENICITY AND CARCINOGENICITY OF BETEL QUID CHEWING ALONG WITH TOBACCO (SMOKING AND SMOKELESS) USE. THE DETAILED MOLECULAR MECHANISMS OF THE EXTENT OF ACCUMULATION AND PATTERNS OF GENETIC ALTERATIONS, INDICATIVE OF THE PRIOR EXPOSURE TO CARCINOGENS AND ALKYLATING AGENTS BECAUSE OF BQ CHEWING AND TOBACCO USE, HAVE NOT YET BEEN ELUCIDATED. 2023 11 6798 29 [EPIDEMIOLOGY, RISK FACTORS AND MOLECULAR PATHOGENESIS OF PRIMARY LIVER CANCER]. PRIMARY LIVER CANCER IS THE FIFTH MOST COMMON CANCER WORLDWIDE. HEPATOCELLULAR CARCINOMA ACCOUNTS FOR 85-90% OF PRIMARY LIVER CANCERS. DISTRIBUTION OF HEPATOCELLULAR CARCINOMA SHOWS VARIATIONS AMONG GEOGRAPHIC REGIONS AND ETHNIC GROUPS. MALES HAVE HIGHER LIVER CANCER RATES THAN FEMALES. HEPATOCELLULAR CARCINOMA OCCURS WITHIN AN ESTABLISHED BACKGROUND OF CHRONIC LIVER DISEASE AND CIRRHOSIS (70-90%). MAJOR CAUSES (80%) OF HEPATOCELLULAR CARCINOMA ARE HEPATITIS B, C VIRUS INFECTION, AND AFLATOXIN EXPOSITION. ITS DEVELOPMENT IS A MULTISTEP PROCESS. WE HAVE A GROWING UNDERSTANDING ON THE MOLECULAR PATHOGENESIS. GENETIC AND EPIGENETIC CHANGES ACTIVATE ONCOGENES, INHIBIT TUMORSUPPRESSOR GENES, WHICH RESULT IN AUTONOMOUS CELL PROLIFERATION. THE CHROMOSOMAL INSTABILITY CAUSED BY TELOMERE DYSFUNCTION, THE GROWTH-RETRAINED ENVIRONMENT AND THE ALTERATIONS OF THE MICRO- AND MACROENVIRONMENT HELP THE EXPANSION OF THE MALIGNANT CELLS. UNDERSTANDING THE MOLECULAR MECHANISMS COULD IMPROVE THE SCREENING OF PATIENTS WITH CHRONIC LIVER DISEASE, OR CIRRHOSIS, AND THE PREVENTION AS WELL AS TREATMENT OF HEPATOCELLULAR CARCINOMA. 2008 12 5100 22 POLYCHLORINATED BIPHENYLS (PCBS) ALTER DNA METHYLATION AND GENOMIC INTEGRITY OF SHEEP FETAL CELLS IN A SIMPLIFIED IN VITRO MODEL OF PREGNANCY EXPOSURE. POLYCHLORINATED BIPHENYLS (PCBS) ARE PERSISTENT ORGANIC POLLUTANTS UBIQUITOUSLY DETECTABLE IN THE ENVIRONMENT AND IN THE FOOD CHAIN. PRENATAL EXPOSURE TO PCBS NEGATIVELY AFFECTS FETAL DEVELOPMENT AND PRODUCES LONG-TERM DETRIMENTAL EFFECTS ON CHILD HEALTH. THE PRESENT STUDY SOUGHT TO EVALUATE THE CYTOTOXIC AND GENOTOXIC EFFECTS OF CHRONIC PCB EXPOSURE ON FETAL CELLS DURING PREGNANCY. TO THIS AIM, SHEEP EMBRYONIC FIBROBLASTS (SEF) AND AMNIOCYTES (SA) WERE CULTURED IN VITRO IN THE PRESENCE OF LOW DOSES OF PCBS FOR A PERIOD OF 120DAYS, COMPARABLE TO THE FULL TERM OF OVINE PREGNANCY. CELLULAR PROLIFERATION RATES, GLOBAL DNA METHYLATION, CHROMOSOME INTEGRITY, AND MARKERS OF DNA DAMAGE WERE EVALUATED AT DIFFERENT TIME POINTS. MOREOVER, SEF TREATED WITH PCBS FOR 60DAYS WERE LEFT UNTREATED FOR ONE FURTHER MONTH AND THEN EXAMINED IN ORDER TO EVALUATE THE REVERSIBILITY OF PCB-INDUCED EPIGENETIC DEFECTS. PCB-TREATED SEF WERE MORE SENSITIVE THAN SA TREATED WITH PCBS, IN TERMS OF LOW CELL PROLIFERATION, AND INCREASED DNA DAMAGE AND GLOBAL DNA METHYLATION, WHICH WERE STILL DETECTABLE AFTER INTERRUPTION OF PCB TREATMENT. THESE DATA INDICATE THAT CHRONIC EXPOSURE OF FETAL CELLS TO PCBS CAUSES PERMANENT GENOMIC AND EPIGENETIC INSTABILITY, WHICH MAY INFLUENCE BOTH PRENATAL AND POST-NATAL GROWTH UP TO ADULTHOOD. OUR IN VITRO MODEL OFFER A SIMPLE AND CONTROLLED MEANS OF STUDYING THE EFFECTS OF DIFFERENT CONTAMINANTS ON FETAL CELLS - ONE THAT COULD SET THE STAGE FOR TARGETED IN VIVO STUDIES. 2018 13 4929 26 PAST, PRESENT, AND FUTURE OF CHEMICALLY INDUCED HEPATOCARCINOGENESIS RODENT MODELS: PERSPECTIVES CONCERNING CLASSIC AND NEW CANCER HALLMARKS. HEPATOCELLULAR CARCINOMA (HCC), THE MAIN PRIMARY LIVER CANCER, ACCOUNTS FOR 5 % OF ALL INCIDENT CASES AND 8.4 % OF ALL CANCER-RELATED DEATHS WORLDWIDE. HCC DISPLAYS A SPECTRUM OF ENVIRONMENTAL RISK FACTORS (VIRAL CHRONIC INFECTIONS, AFLATOXIN EXPOSURE, ALCOHOLIC- AND NONALCOHOLIC FATTY LIVER DISEASES) THAT RESULT IN MOLECULAR COMPLEXITY AND HETEROGENEITY, CONTRIBUTING TO A RISING EPIDEMIOLOGICAL BURDEN, POOR PROGNOSIS, AND NON-SATISFACTORY TREATMENT OPTIONS. THE EMERGENCE OF HCC (I.E., HEPATOCARCINOGENESIS) IS A MULTISTEP AND COMPLEX PROCESS THAT ADDRESSES MANY (EPI)GENETIC ALTERATIONS AND PHENOTYPIC TRAITS, THE SO-CALLED CANCER HALLMARKS. "POLYMORPHIC MICROBIOMES", "EPIGENETIC REPROGRAMMING", "SENESCENT CELLS" AND "UNLOCKING PHENOTYPIC PLASTICITY" ARE TRENDING HALLMARKS/ENABLING FEATURES IN CANCER BIOLOGY. AS THE MAIN MOLECULAR DRIVERS OF HCC ARE STILL UNDRUGGABLE, CHEMICALLY INDUCED IN VIVO MODELS OF HEPATOCARCINOGENESIS ARE USEFUL TOOLS IN PRECLINICAL RESEARCH. THUS, THIS NARRATIVE REVIEW AIMED AT RECAPITULATING THE BASIC FEATURES OF CHEMICALLY INDUCED RODENT MODELS OF HEPATOCARCINOGENESIS, ELICITING THEIR PERMANENT TRANSLATIONAL VALUE REGARDING THE "CLASSIC" AND THE "NEW" CANCER HALLMARKS/ENABLING FEATURES. WE GATHERED STATE-OF-ART PRECLINICAL EVIDENCE ON NON-CIRRHOTIC, INFLAMMATION-, ALCOHOLIC LIVER DISEASE- AND NONALCOHOLIC FATTY LIVER-ASSOCIATED HCC MODELS, DEMONSTRATING THAT THESE BIOASSAYS INDEED EXPRESS THE RECENTLY ADDED HALLMARKS, AS WELL AS REFLECT THE INTERPLAY BETWEEN CLASSICAL AND NEW CANCER TRAITS. OUR REVIEW DEMONSTRATED THAT THESE PROTOCOLS REMAIN VALUABLE FOR TRANSLATIONAL PRECLINICAL APPLICATION, AS THEY RECAPITULATE TRENDING FEATURES OF CANCER SCIENCE. FURTHER "OMICS-BASED" APPROACHES ARE WARRANTED WHILE MULTIMODEL INVESTIGATIONS ARE ENCOURAGED IN ORDER TO AVOID "MODEL-BIASED" RESPONSES. 2023 14 6381 29 THE ROLE OF ONCOGENIC DNA VIRUSES IN PENILE CANCER DEVELOPMENT. PENILE CANCER IS A RELATIVELY RARE NEOPLASIA IN DEVELOPED COUNTRIES, WITH SIGNIFICANT MORBIDITY AND MORTALITY IN DEVELOPING COUNTRIES. PENILE CANCER CAN BE SUBDIVIDED INTO HUMAN PAPILLOMAVIRUS (HPV)-POSITIVE AND HPV-NEGATIVE CASES. WORLDWIDE, THE HPV PREVALENCE IN PENILE CANCER SAMPLES IS AROUND 50%, AND HPV16 IS THE MOST PREVALENT GENOTYPE. ALTHOUGH HPV IS AN IMPORTANT FACTOR FOR CANCER DEVELOPMENT, OTHER ONCOGENIC FACTORS MAY BE ASSOCIATED WITH CARCINOGENESIS. SOME OF THESE FACTORS CAN BE INFECTIOUS, SUCH AS THE EPSTEIN-BARR VIRUS (EBV), AS WELL AS THE MERKEL CELL POLYOMAVIRUS (MCPYV). THE PREVALENCE RATES OF NEARLY 50% FOR BOTH HPV AND EBV INFECTIONS INDICATE AN IMPORTANT ROLE OF THESE VIRUSES IN PENILE TISSUE MALIGNANCY, REINFORCING THE IDEA OF A MULTIFACTORIAL ETIOLOGY OF THE DISEASE. ALTHOUGH THE HPV ROLE IS BETTER UNDERSTOOD, EBV IS THOUGHT TO FACILITATE PERSISTENCE, INTEGRATION, AND MUTATIONS. RECENT STUDIES ON THE MERKEL CELL POLYOMAVIRUS HAVE NOT SHOWN A RELEVANT PREVALENCE IN PENILE CANCER SAMPLES, BUT ITS PRESENCE INDICATES THE OPPORTUNISTIC INFECTIOUS POTENTIAL OF THIS VIRUS. REGARDING HPV-NEGATIVE CASES, THE LITERATURE SUGGESTS A LINK WITH YOUNGER AGE AND EPIGENETIC ALTERATIONS, MAINLY THROUGH THE P16INK4A PATHWAY. RECENTLY, SEVERAL BIOMARKERS THAT MIGHT ACT AS PROGNOSTIC TOOLS (E.G., KI-67, SQUAMOUS CELL CARCINOMA ANTIGEN, AMONG OTHERS) HAVE BEEN PROPOSED, BUT THE RESULTS REMAIN CONTROVERSIAL. IN ADDITION, OTHER RISK FACTORS HAVE ALSO BEEN ASSOCIATED WITH PENILE CARCINOGENESIS, SUCH AS THE PRESENCE OF PHIMOSIS, NONCIRCUMCISION, CHRONIC INFLAMMATION, AND NUMBER OF SEXUAL PARTNERS. FURTHER STUDIES ARE NEEDED TO DEVELOP TOOLS FOR EARLY DETECTION AND EPIDEMIOLOGICAL SURVEILLANCE OF PENILE CANCER. 2019 15 4824 28 OCHRATOXIN A: THE CONTINUING ENIGMA. THE MYCOTOXIN OCHRATOXIN A (OTA) HAS BEEN LINKED TO THE GENESIS OF SEVERAL DISEASE STATES IN BOTH ANIMALS AND HUMANS. IT HAS BEEN DESCRIBED AS NEPHROTOXIC, CARCINOGENIC, TERATOGENIC, IMMUNOTOXIC, AND HEPATOTOXIC IN LABORATORY AND DOMESTIC ANIMALS, AS WELL AS BEING THOUGHT TO BE THE PROBABLE CAUSAL AGENT IN THE DEVELOPMENT OF NEPHROPATHIES (BALKAN ENDEMIC NEPHROPATHY, BEN AND CHRONIC INTERSTITIAL NEPHROPATHY, CIN) AND UROTHELIAL TUMORS IN HUMANS. AS A RESULT, SEVERAL INTERNATIONAL AGENCIES ARE CURRENTLY ATTEMPTING TO DEFINE SAFE LEGAL LIMITS FOR OTA CONCENTRATION IN FOODSTUFFS (E.G., GRAIN, MEAT, WINE, AND COFFEE), IN PROCESSED FOODS, AND IN ANIMAL FODDER. IN ORDER TO ACHIEVE THIS GOAL, AN ACCURATE RISK ASSESSMENT OF OTA TOXICITY INCLUDING MECHANISTIC AND EPIDEMIOLOGICAL STUDIES MUST BE CARRIED OUT. OCHRATOXIN HAS BEEN SUGGESTED BY VARIOUS RESEARCHERS TO MEDIATE ITS TOXIC EFFECTS VIA INDUCTION OF APOPTOSIS, DISRUPTION OF MITOCHONDRIAL RESPIRATION AND/OR THE CYTOSKELETON, OR, INDEED, VIA THE GENERATION OF DNA ADDUCTS. THUS, IT IS STILL UNCLEAR IF THE PREDOMINANT MECHANISM IS OF A GENOTOXIC OR AN EPIGENETIC NATURE. ONE ASPECT THAT IS CLEAR, HOWEVER, IS THAT THE TOXICITY OF OTA IS SUBJECT TO AND CHARACTERIZED BY LARGE SPECIES- AND SEX-SPECIFIC DIFFERENCES, AS WELL AS AN APPARENTLY STRICT STRUCTURE-ACTIVITY RELATIONSHIP. THESE CONSIDERATIONS COULD BE CRUCIAL IN THE INVESTIGATION OF OTA-MEDIATED TOXICITY. FURTHERMORE, THE USE OF APPROPRIATE IN VIVO AND IN VITRO MODEL SYSTEMS APPEARS TO BE VITAL IN THE GENERATION OF RELEVANT EXPERIMENTAL DATA. THE INTENTION OF THIS REVIEW IS TO COLLATE AND DISCUSS THE CURRENTLY AVAILABLE DATA ON OTA-MEDIATED TOXICITY WITH PARTICULAR FOCUS ON THEIR RELEVANCE FOR THE IN VIVO SITUATION, AND ALSO TO SUGGEST POSSIBLE FUTURE STRATEGIES FOR UNLOCKING THE SECRETS OF OCHRATOXIN A. 2005 16 6848 32 [MOLECULAR GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR TYPE OF PRIMARY LIVER CANCER AND ONE OF THE MOST FREQUENT HUMAN MALIGNANT NEOPLASMS. COMMON RISK FACTORS OF HUMAN HCC INCLUDE CHRONIC HEPATITIS VIRUS (HBV AND HCV) INFECTION, DIETARY AFLATOXIN B1 (AFB1) INGESTION, CHRONIC ALCOHOL ABUSE, AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES. HEPATOCARCINOGENESIS IS THE RESULT OF INTERACTION BETWEEN HEREDITARY AND ENVIRONMENTAL FACTORS. INHERITANCE DETERMINES INDIVIDUAL SUSCEPTIBILITY TO CANCER; ENVIRONMENT DETERMINES WHICH SUSCEPTIBLE INDIVIDUALS EXPRESS CANCER. STUDIES OF GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS SHOWED THAT HCC DEVELOPMENT IS A COMPLEX POLYGENE AND MULTIPATHWAY PROCESS; THE ACTIVATION OF PROTO-ONCOGENES AND THE INACTIVATION OF TUMOR SUPPRESSOR GENES INDUCED BY GENETIC AND EPIGENETIC ALTERATIONS ARE CORE BIOLOGICAL PROCESSES OF HEPATOCARCINOGENESIS; RB1, P53, AND WNT PATHWAYS ARE COMMONLY AFFECTED IN HCCS OF DIFFERENT ETIOLOGIES, WHICH MAY REFLECT COMMON PATHOLOGIC SEQUENCE OF HCC: CHRONIC LIVER INJURY, CIRRHOSIS, ATYPICAL HYPERPLASTIC NODULES, AND HCC OF EARLY STAGES. HEPATITIS VIRUS INFECTION-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN RB1 PATHWAY, INCLUDING METHYLATION OF P16INK4A AND RB1 GENES AND AMPLIFICATION OF CYCLIN D1. AFB1 EXPOSURE-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN P53 PATHWAY; THE G-->T MUTATION OF P53 GENE AT CODON 249 HAS BEEN IDENTIFIED AS A GENETIC HALLMARK OF HCC CAUSED BY AFB1. ALCOHOLISM-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN BOTH RB1 AND P53 PATHWAYS. THE ROLES OF SOME IMPORTANT GENES RELATED TO CELL APOPTOSIS, DNA REPAIR, DRUG METABOLISM, AND TUMOR METASTASIS IN HEPATOCARCINOGENESIS HAD BEEN DISCUSSED. 2005 17 3272 44 HEPATOCELLULAR CARCINOMA: AN UPDATE. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF MALES IN THE WORLD, WITH AN INCIDENCE OF 1,000,000 NEW CASES A YEAR. IT IS ENDEMIC IN SOUTHEAST ASIA AND SUB-SAHARAN AFRICA. RISK FACTORS INCLUDE CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), AFLATOXIN B1 UPTAKE, HEMOCHROMATOSIS, AND ALPHA1 -ANTITRIPSIN DEFICIENCY. EPIDEMIOLOGICAL STUDIES PROVIDE EVIDENCE FOR THE ASSOCIATION OF HCC WITH HBV INFECTION. THE INCIDENCE OF HCC IS HIGH IN REGIONS HYPERENDEMIC FOR HBV. CHRONIC CARRIER STATE AND MATERNAL-INFANT TRANSMISSION ARE IMPORTANT FACTORS IN THE DEVELOPMENT OF HCC. EVIDENCE OF DIRECT ONCOGENIC EFFECT OF H BV IS WELL ESTABLISHED, HCCS CONTAIN VIRAL DNA SEQUENCES INTEGRATED INTO HEPATOCYTE DNA THAT ACT AS RANDOM INSERTIONAL MUTAGENS, AND THESE SITES ARE NEAR GENES INVOLVED IN THE CONTROL OF PROLIFERATION AND DIFFERENTIATION. THE MECHANISM OF HEPATITIS C VIRUS IN HEPATOCARCINOGENESIS IS STILL IMPRECISE BUT A HIGH PERCENTAGE OF CASES ARE RELATED TO THIS VIRUS. CHRONIC ALCOHOL CONSUMPTION AND CIRRHOSIS ARE COFACTORS THAT INCREASE THE DEVELOPMENT OF HCC IN PATIENTS WITH CHRONIC VIRAL INFECTION. IN EXPERIMENTAL CARCINOGENESIS A MULTIPOTENTIAL ELEMENT CALLED OVAL CELL PROLIFERATES IN THE EARLY STAGES. THE CELLULAR EVENTS ARE ACCOMPANIED BY INCREASED EXPRESSION OF SEVERAL GROWTH FACTORS THAT ENHANCE THE SURVIVAL OF CARCINOGEN-ACTIVATED CELLS BY SUPPRESSING APOPTOSIS AND INCREASING ELEMENTS ENTERING THE CELL CYCLE. HEPATIC CARCINOGENESIS IS A COMPLEX PROCESS ASSOCIATED WITH ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES THAT RUN THROUGH STEPS OF INITIATION, PROMOTION AND PROGRESSION. ACTIVATION OF ONCOGENES OF THE "RAS" FAMILY AND OTHERS HAS BEEN DETECTED DURING CHEMICALLY-INDUCED HCC IN RODENTS, BUT THERE IS LITTLE EVIDENCE OF SUCH ACTIVATION IN HUMAN TUMORS. THE ROLE OF TUMOR SUPRESSOR GENES SUCH AS RETINOBLASTOMA (RB) AND P53 GENES HAS BEEN DOCUMENTED. AFLATOXIN B1 THAT CONTAMINATES FOODS IN ENDEMIC AREAS HAS A CLEAR ROLE IN HEPATOCARCINOGENESIS. METABOLITES OF THIS TOXIN PROMOTE APURINIC SITES AND G TO T MUTATIONS IN CHROMOSOMAL DNA, THE THIRD BASE OF CODON 249 OF THE P53 GENE IS PREFERENTIALLY TARGETED TO FORM ADUCTS WITH AFLATOXIN B1, AND THIS MUTATION HAS BEEN SPECIFICALLY IDENTIFIED IN HBV INFECTION. HISTOLOGICAL AND CYTOLOGICAL CRITERIA FOR THE DIAGNOSIS OF HCC ARE WELL ESTABLISHED AND ARE BASED IN ARCHITECTURAL AND CYTOLOGICAL CHANGES. AN IMPORTANT ISSUE IS THE DIAGNOSIS OF LIVER "NODULES" DETECTED BY IMAGE, FROM WHICH SMALL BIOPSIES OR ASPIRATION MATERIAL IS OBTAINED. SPECIAL STUDIES SUCH AS RETICULIN, CD34, CYTOKERATIN PROFILE, AND MOC-31 CAN BE VERY USEFUL FOR THE DIFFERENTIAL DIAGNOSIS OF PRIMARY AND METASTATIC TUMORS. TELOMERASE ACTIVITY HAS BEEN FOUND IN HCC AND NEGATIVE IN PERICANCEROUS TISSUE. IT IS MORE PRONOUNCED IN POORLY DIFFERENTIATED TUMORS AND CORRELATES WITH FACTORS OF CLINICAL IMPORTANCE, SUCH AS PROGNOSIS AND RECURRENCES. CELLS OF WELL-DIFFERENTIATED HCC HAVE AN ULTRASTRUCTURAL APPEARANCE SIMILAR TO NORMAL HEPATOCYTES. DURING THE PROCESS OF DEDIFFERENTIATION, THERE IS PROGRESSIVE LOSS OF ORGANIZATION OF INTRACELLULAR ORGANELLES. THE CELL COHESION IS LOST, INTERCELLULAR GAPS WITH MICROVILLI APPEAR, THE SINUSOIDS BECOME CAPILLARIZED, AND REPARATIVE CHANGES ARE SEEN IN THE SPACES OF DISSE. A VARIETY OF INCLUSIONS, SUCH AS MALLORY BODIES, GRANULAR MATERIAL, SECONDARY LYSOSOMES, AND DUBIN-JOHNSON PIGMENT, HAVE BEEN DESCRIBED. FIBROLAMELLAR CARCINOMA HAS A CHARACTERISTIC HISTOLOGICAL PICTURE AND ULTRASTRUCTURALLY ONCOCYTIC FEATURES. NEUROENDOCRINE GRANULES AND COMBINATION OF HCC WITH BILE DUCT CARCINOMA ARE SEEN BY ELECTRON MICROSCOPY. 2001 18 1644 30 DOES THE ENVIRONMENT AFFECT MENOPAUSE? A REVIEW OF THE EFFECTS OF ENDOCRINE DISRUPTING CHEMICALS ON MENOPAUSE. ENDOCRINE DISRUPTING CHEMICALS ARE WIDELY DISTRIBUTED IN OUR ENVIRONMENT. HUMANS ARE EXPOSED TO THESE COMPOUNDS NOT ONLY THROUGH THEIR OCCUPATIONS, BUT ALSO THROUGH DIETARY CONSUMPTION AND EXPOSURE TO CONTAMINATED WATER, PERSONAL CARE PRODUCTS AND TEXTILES. CHEMICALS THAT ARE PERSISTENT IN THE BODY AND IN OUR ENVIRONMENT INCLUDE DIOXINS AND POLYCHLORINATED BIPHENYLS. NON-PERSISTENT CHEMICALS INCLUDING BISPHENOL A, PHTHALATES AND PARABENS ARE EQUALLY AS IMPORTANT BECAUSE THEY ARE UBIQUITOUS IN OUR ENVIRONMENT. HEAVY METALS, INCLUDING LEAD AND CADMIUM, CAN ALSO HAVE ENDOCRINE DISRUPTING PROPERTIES. ALTHOUGH DIFFICULT TO STUDY DUE TO THEIR VARIETY OF SOURCES OF EXPOSURES AND MECHANISMS OF ACTION, THESE CHEMICALS HAVE BEEN ASSOCIATED WITH EARLY MENOPAUSE, INCREASED FREQUENCY OF VASOMOTOR SYMPTOMS, ALTERED STEROID HORMONE LEVELS AND MARKERS OF DIMINISHED OVARIAN RESERVE. UNDERSTANDING THE IMPACTS OF THESE EXPOSURES IS IMPORTANT GIVEN THE POTENTIAL FOR EPIGENETIC MODIFICATION, WHICH CAN ALTER GENE FUNCTION AND RESULT IN MULTI-GENERATIONAL EFFECTS. THIS REVIEW SUMMARIZES FINDINGS IN HUMANS AND ANIMALS OR CELL-BASED MODELS FROM THE PAST DECADE OF RESEARCH. CONTINUED RESEARCH IS NEEDED TO ASSESS THE EFFECTS OF MIXTURES OF CHEMICALS, CHRONIC EXPOSURES AND NEW COMPOUNDS THAT ARE CONTINUOUSLY BEING DEVELOPED AS REPLACEMENTS FOR TOXIC CHEMICALS THAT ARE BEING PHASED OUT. 2023 19 6868 26 [PATHOGENESIS OF HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCER WORLDWIDE. MOST OF THE HCC OCCUR IN DEVELOPING COUNTRIES. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HCC DEVELOPMENT. HBV INDUCES IMMUNE-MEDIATED CHRONIC HEPATITIS, LIVER INJURY, REGENERATION AND SCAR FORMING RESPONSES, LEADING TO AN INFLAMMATORY, FIBROTIC AND IMMUNE DEFICIENT MICROENVIRONMENT. HBV MAY INTEGRATE INTO HOST GENOME, INDUCING GENETIC ABNORMALITY AND ALTERING THE EXPRESSION OF HCC-RELATED GENES. HBV ALSO EXPRESSES ACTIVE PROTEINS SUCH AS X (HBX) AND S PROTEINS, WHICH MAY TRANS-ACTIVATE HCC-RELATED PROTEINS EXPRESSION, INTERACT WITH INTRACELLULAR SPECIFIC PROTEINS, ACTIVATE A VARIETY OF SIGNALING PATHWAYS, AND INDUCE ABERRANT EPIGENETIC MODIFICATIONS. HBV MUTATION ALSO HAS IMPACT ON HBV RELATED HCC DEVELOPMENT. 2016 20 4133 29 MECHANISMS OF HEPATITIS B VIRUS-INDUCED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). THERE ARE APPROXIMATELY 250 MILLION PEOPLE IN THE WORLD THAT ARE CHRONICALLY INFECTED BY THIS VIRUS, RESULTING IN NEARLY 1 MILLION DEATHS EVERY YEAR. MANY OF THESE PATIENTS DIE FROM SEVERE LIVER DISEASES, INCLUDING HCC. HBV MAY INDUCE HCC THROUGH THE INDUCTION OF CHRONIC LIVER INFLAMMATION, WHICH CAN CAUSE OXIDATIVE STRESS AND DNA DAMAGE. HOWEVER, MANY STUDIES ALSO INDICATED THAT HBV COULD INDUCE HCC VIA THE ALTERATION OF HEPATOCELLULAR PHYSIOLOGY THAT MAY INVOLVE GENETIC AND EPIGENETIC CHANGES OF THE HOST DNA, THE ALTERATION OF CELLULAR SIGNALING PATHWAYS, AND THE INHIBITION OF DNA REPAIR MECHANISMS. THIS ALTERATION OF CELLULAR PHYSIOLOGY CAN LEAD TO THE ACCUMULATION OF DNA DAMAGES AND THE PROMOTION OF CELL CYCLES AND PREDISPOSE HEPATOCYTES TO ONCOGENIC TRANSFORMATION. 2021