1 865 146 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 2 3267 21 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 3 6484 27 TOXICOLOGIC PROFILE OF ACRYLONITRILE. ACRYLONITRILE IS A MONOMER USED EXTENSIVELY AS A RAW MATERIAL IN THE MANUFACTURING OF ACRYLIC FIBERS, PLASTICS, SYNTHETIC RUBBERS, AND ACRYLAMIDE. IT HAS BEEN CLASSIFIED AS A PROBABLE HUMAN CARCINOGEN ACCORDING TO THE RESULTS OF NUMEROUS CHRONIC RAT BIOASSAYS. THE PRESENT REPORT SUMMARIZES THE TOXICITY DATA ON ACRYLONITRILE AND REVIEWS AVAILABLE DATA CONCERNING THE MECHANISM (GENETIC VERSUS EPIGENETIC) BY WHICH ACRYLONITRILE IS CARCINOGENIC IN RATS. FROM THE EVALUATION OF THE RELEVANT TOXICITY DATA, IT CAN BE CONCLUDED THAT ACRYLONITRILE IS INDEED CARCINOGENIC TO RATS AFTER EITHER ORAL OR INHALATIONAL EXPOSURE. HOWEVER, INFORMATION ON OTHER MAMMALIAN SPECIES IS LACKING, AND, MOREOVER, THE EXACT MECHANISM OF THE CARCINOGENIC PROCESS IS UNCLEAR. THEREFORE, IT IS RECOMMENDED TO CONDUCT AN ADDITIONAL LONG-TERM INHALATION CARCINOGENICITY STUDY WITH ACRYLONITRILE IN MICE, AS WELL AS STUDIES INTO THE MECHANISM BY WHICH ACRYLONITRILE INDUCES (BRAIN) TUMORS IN RATS (GENETIC VERSUS EPIGENETIC). 1998 4 452 32 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 5 1819 30 EFFECTS OF CHRONIC OCHRATOXIN A EXPOSURE ON P53 HETEROZYGOUS AND P53 HOMOZYGOUS MICE. EXPOSURE TO THE MYCOTOXIN OCHRATOXIN A (OTA) CAUSES NEPHROPATHY IN DOMESTIC ANIMALS AND RODENTS AND RENAL TUMORS IN RODENTS AND POULTRY. HUMANS ARE EXPOSED TO OTA BY CONSUMING FOODS MADE WITH CONTAMINATED CEREAL GRAINS AND OTHER COMMODITIES. MANAGEMENT OF HUMAN HEALTH RISKS DUE TO OTA EXPOSURE DEPENDS, IN PART, ON ESTABLISHING A MODE OF ACTION (MOA) FOR OTA CARCINOGENESIS. TO FURTHER INVESTIGATE OTA'S MOA, P53 HETEROZYGOUS (P53+/-) AND P53 HOMOZYGOUS (P53+/+) MICE WERE EXPOSED TO OTA IN DIET FOR 26 WEEKS. THE FORMER ARE SUSCEPTIBLE TO TUMORIGENESIS UPON CHRONIC EXPOSURE TO GENOTOXIC CARCINOGENS. OTA-INDUCED RENAL DAMAGE BUT NO TUMORS WERE OBSERVED IN EITHER STRAIN, INDICATING THAT P53 HETEROZYGOSITY CONFERRED LITTLE ADDITIONAL SENSITIVITY TO OTA. RENAL CHANGES INCLUDED DOSE-DEPENDENT INCREASES IN CELLULAR PROLIFERATION, APOPTOSIS, KARYOMEGALY, AND TUBULAR DEGENERATION IN PROXIMAL TUBULES, WHICH WERE CONSISTENT WITH OCHRATOXICOSIS. THE LOWEST OBSERVED EFFECT LEVEL FOR RENAL CHANGES IN P53+/- AND P53+/+ MICE WAS 200 MUG OTA/KG BW/DAY. BASED ON THE LACK OF TUMORS AND THE SEVERITY OF RENAL AND BODY WEIGHT CHANGES AT A MAXIMUM TOLERATED DOSE, THE RESULTS WERE INTERPRETED AS SUGGESTIVE OF A PRIMARILY NONGENOTOXIC (EPIGENETIC) MOA FOR OTA CARCINOGENESIS IN THIS MOUSE MODEL. 2015 6 2959 31 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 7 1816 24 EFFECTS OF CHRONIC EXPOSURE TO BENZOPHENONE AND DICLOFENAC ON DNA METHYLATION LEVELS AND REPRODUCTIVE SUCCESS IN A MARINE COPEPOD. THE UV-FILTER BENZOPHENONE AND THE ANTI-INFLAMMATORY DICLOFENAC ARE COMMONLY DETECTED IN THE ENVIRONMENT. THE AIM OF THIS STUDY WAS TO ASSESS THE MULTIGENERATIONAL EFFECTS OF CHRONIC EXPOSURE TO LOW CONCENTRATIONS OF THESE CHEMICALS ON TOXICITY AND DNA METHYLATION LEVELS IN THE COPEPOD GLADIOFERENS PECTINATUS. ACUTE TOXICITY TESTS WERE CONDUCTED TO DETERMINE THE SENSITIVITY OF G. PECTINATUS TO THE CHEMICALS. ALL CHEMICALS IMPACTED BREEDING, HATCHING AND EGG VIABILITY. DICLOFENAC (1 MG.L(-1)) REDUCED THE NUMBER OF EGGS PER GRAVID FEMALE. BENZOPHENONE (0.5 MG.L(-1)) DECREASED EGG HATCHING SUCCESS. EXPOSURE TO THE REFERENCE TOXICANT COPPER (0.02 MG.L(-1)) LED TO UNSUCCESSFUL HATCHING. EFFECTS ON DNA METHYLATION WAS ESTIMATED BY THE PERCENTAGE OF 5- METHYLCYTOSINE. THE TREATMENTS RESULTED IN STRONG DIFFERENCES IN DNA METHYLATION WITH INCREASED METHYLATION IN THE EXPOSED ANIMALS. THE TWO CHEMICALS IMPACTED BOTH EGG VIABILITY AND THE INDUCTION OF DIFFERENTIAL DNA METHYLATION, SUGGESTING POTENTIAL INTRA- AND TRANS-GENERATIONAL EVOLUTIONARY EFFECTS. 2018 8 5487 34 REVERSIBLE ALTERATION IN THE EXPRESSION OF THE GAP JUNCTIONAL PROTEIN CONNEXIN 32 DURING TUMOR PROMOTION IN RAT LIVER AND ITS ROLE DURING CELL PROLIFERATION. ALTHOUGH NUMEROUS BIOCHEMICAL MARKERS CAN IDENTIFY PUTATIVE PRENEOPLASTIC ALTERED HEPATIC FOCI (AHF) IN RAT LIVER, NO CONSISTENT PATTERN OF EXPRESSION DURING HEPATOCARCINOGENESIS HAS EMERGED. USING QUANTITATIVE STEREOLOGIC ANALYSES WE DEMONSTRATED THAT DECREASED EXPRESSION OF THE MAJOR HEPATOCYTE GAP JUNCTION PROTEIN, CONNEXIN 32 (CX32), IN RAT AHF IS A CONSISTENT OBSERVATION IN SEVERAL PROTOCOLS OF MULTISTAGE HEPATOCARCINOGENESIS. THIS CHANGE WAS OBSERVED AFTER INITIATION BY EITHER ETHYLNITROSOUREA (ENU) OR DIETHYLNITROSAMINE (DEN), FOLLOWED BY PROMOTION WITH PHENOBARBITAL (PB), DIOXIN, CHLORENDIC ACID, C.I. SOLVENT YELLOW, OR TAMOXIFEN. AHF GENERATED BY WY-14,643, CIPROFIBRATE, AND A CHOLINE/METHIONINE-DEFICIENT DIETARY REGIMEN ALSO SHOWED DECREASED CX32 EXPRESSION. THE DECREASE OF CX32 IN AHF WAS RAPIDLY REVERSIBLE AFTER WITHDRAWAL OF PB, AND THIS CHANGE PRECEDED A REDUCTION IN PLACENTAL ISOZYME OF GLUTATHIONE-S-TRANSFERASE (GST) EXPRESSION IN THE SAME AHF. WITHIN 20 DAYS OF WITHDRAWAL, FEWER THAN 4% OF GST-POSITIVE AHF WERE CX32 DEFICIENT, WHILE THE VOLUME OF TOTAL AHF DECREASED 30%. CHRONIC PB TREATMENT ALSO RESULTED IN A REVERSIBLE DECREASE IN CX32 SPECIFICALLY IN MID- AND CENTRO-LOBULAR HEPATOCYTES. CONTINUOUS THYMIDINE LABELING DEMONSTRATED THAT CX32 COULD BE UNCOUPLED FROM THE CELL CYCLE, SUGGESTING THAT SOME LIVER PROMOTERS MAY ACT DIRECTLY TO ALTER THE EXPRESSION OF CX32. THESE OBSERVATIONS SUGGEST THAT A DECREASE IN CX32 CONTENT WAS A RELATIVELY COMMON EPIGENETIC CHANGE IN AHF INDUCED DURING HEPATOCARCINOGENESIS BY A NUMBER OF INITIATING AND PROMOTING AGENTS BUT THAT THIS CHANGE WAS NOT SUFFICIENT FOR CARCINOGENESIS. THIS CHANGE, HOWEVER, MAY BE NECESSARY FOR THE MECHANISM(S) OF TUMOR PROMOTION, SINCE CX32-POSITIVE AHF DID NOT PROLIFERATE AS READILY AS CX32-DEFICIENT AHF. 1990 9 1861 15 EMERGENCE OF CANCER STEM CELLS IN HEPATOCELLULAR CARCINOMA. LIVER CANCER REPRESENTS THE SECOND MOST DEADLY HUMAN MALIGNANCY. THE MAJOR HISTOLOGICAL SUBTYPE CALLED HEPATOCELLULAR CARCINOMA (HCC) ARISES BY CHRONIC INFLAMMATION-TRIGGERED REGENERATIVE RESPONSES OF NORMALLY QUIESCENT HEPATOCYTES AND PROGENITORS, RESPECTIVELY. SUCH REGENERATIVE STRESS ACCELERATES THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES (YAMASHITA & WANG, 2013), WHILE DETAILED MECHANISMS REMAIN UNCERTAIN. IN THIS ISSUE OF THE EMBO JOURNAL, NIKOLAOU ET AL PRESENT A NOVEL HCC MODEL THAT FACILITATES BOTH ISOLATION AND MOLECULAR CHARACTERIZATION OF SELF-RENEWING, HCC-PROPAGATING CANCER STEM CELLS THAT COULD INSTRUCT FUTURE INTERVENTIONS (NIKOLAOU ET AL, 2014). 2015 10 4155 32 MECHANISTIC UNDERSTANDING OF THE TOXIC EFFECTS OF ARSENIC AND WARFARE ARSENICALS ON HUMAN HEALTH AND ENVIRONMENT. WORLDWIDE, MORE THAN 200 MILLION PEOPLE ARE ESTIMATED TO BE EXPOSED TO UNSAFE LEVELS OF ARSENIC. CHRONIC EXPOSURE TO UNSAFE LEVELS OF GROUNDWATER ARSENIC IS RESPONSIBLE FOR MULTIPLE HUMAN DISORDERS, INCLUDING DERMAL, CARDIOVASCULAR, NEUROLOGICAL, PULMONARY, RENAL, AND METABOLIC CONDITIONS. CONSUMPTION OF RICE AND SEAFOOD (WHERE HIGH LEVELS OF ARSENIC ARE ACCUMULATED) IS ALSO RESPONSIBLE FOR HUMAN EXPOSURE TO ARSENIC. THE TOXICITY OF ARSENIC COMPOUNDS VARIES GREATLY AND MAY DEPEND ON THEIR CHEMICAL FORM, SOLUBILITY, AND CONCENTRATION. SURPRISINGLY, SYNTHETIC ORGANOARSENICALS ARE EXTREMELY TOXIC MOLECULES WHICH CREATED INTEREST IN THEIR DEVELOPMENT AS CHEMICAL WARFARE AGENTS (CWAS) DURING WORLD WAR I (WWI). AMONG THESE CWAS, ADAMSITE, CLARK I, CLARK II, AND LEWISITE ARE OF CRITICAL IMPORTANCE, AS STOCKPILES OF THESE AGENTS STILL EXIST WORLDWIDE. IN ADDITION, UNUSED WWII WEAPONIZED ARSENICALS DISCARDED IN WATER BODIES OR BURIED IN MANY PARTS OF THE WORLD CONTINUE TO POSE A SERIOUS THREAT TO THE ENVIRONMENT AND HUMAN HEALTH. METABOLIC INHIBITION, OXIDATIVE STRESS, GENOTOXICITY, AND EPIGENETIC ALTERATIONS INCLUDING MICRO-RNA-DEPENDENT REGULATION ARE SOME OF THE UNDERLYING MECHANISMS OF ARSENIC TOXICITY. MECHANISTIC UNDERSTANDING OF THE TOXICITY OF ORGANOARSENICALS IS ALSO CRITICAL FOR THE DEVELOPMENT OF EFFECTIVE THERAPEUTIC INTERVENTIONS. THIS REVIEW PROVIDES COMPREHENSIVE DETAILS AND A CRITICAL ASSESSMENT OF RECENTLY PUBLISHED DATA ON VARIOUS CHEMICAL FORMS OF ARSENIC, THEIR EXPOSURE, AND IMPLICATIONS ON HUMAN AND ENVIRONMENTAL HEALTH. 2023 11 3620 20 IN VIVO AND IN VITRO GENOTOXIC AND EPIGENETIC EFFECTS OF TWO TYPES OF COLA BEVERAGES AND CAFFEINE: A MULTIASSAY APPROACH. THE AIM OF THIS WORK WAS TO ASSESS THE BIOLOGICAL AND FOOD SAFETY OF TWO DIFFERENT BEVERAGES: CLASSIC COCA COLA (CCC) AND CAFFEINE-FREE COCA COLA (CFCC). TO THIS END, WE DETERMINED THE GENOTOXICOLOGICAL AND BIOLOGICAL EFFECTS OF DIFFERENT DOSES OF LYOPHILISED CCC AND CFCC AND CAFFEINE (CAF), THE MAIN DISTINCTIVE CONSTITUENT. THEIR TOXIC/ANTITOXIC, GENOTOXIC/ANTIGENOTOXIC, AND CHRONIC TOXICITY (LIFESPAN ASSAY) EFFECTS WERE DETERMINED IN VIVO USING THE DROSOPHILA MODEL. THEIR CYTOTOXIC ACTIVITIES WERE DETERMINED USING THE HL-60 IN VITRO CANCER MODEL. IN ADDITION, CLASTOGENIC DNA TOXICITY WAS MEASURED USING INTERNUCLEOSOMAL FRAGMENTATION AND SCGE ASSAYS. THEIR EPIGENETIC EFFECTS WERE ASSESSED ON THE HL-60 METHYLATION STATUS USING SOME REPETITIVE ELEMENTS. THE EXPERIMENTAL RESULTS SHOWED A SLIGHT CHEMOPREVENTIVE EFFECT OF THE TWO COLA BEVERAGES AGAINST HL-60 LEUKAEMIA CELLS, PROBABLY MEDIATED BY NONAPOPTOTIC MECHANISMS. FINALLY, CCC AND CAF INDUCED A GLOBAL GENOME HYPOMETHYLATION EVALUATED IN LINE-1 AND ALU M1 REPETITIVE ELEMENTS. OVERALL, WE DEMONSTRATED FOR THE FIRST TIME THE SAFETY OF THIS FAMOUS BEVERAGE IN IN VIVO AND IN VITRO MODELS. 2016 12 5100 25 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 3883 27 KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. BACKGROUND: A RECENT REVIEW BY THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) UPDATED THE ASSESSMENTS OF THE > 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912. 2016 14 4527 33 MULTIGENERATIONAL EFFECTS OF 4-METHYLBENZYLIDENE CAMPHOR (4-MBC) ON THE SURVIVAL, DEVELOPMENT AND REPRODUCTION OF THE MARINE COPEPOD TIGRIOPUS JAPONICUS. ONE OF THE MOST WIDELY USED ORGANIC UV FILTERS, 4-METHYLBENZYLIDENE CAMPHOR (4-MBC), IS PRESENT AT HIGH CONCENTRATIONS IN OFFSHORE WATERS. THE MARINE COPEPOD TIGRIOPUS JAPONICUS WAS EXPOSED TO DIFFERENT CONCENTRATIONS OF 4-MBC (I.E., 0, 0.5, 1, 5 AND 10MUGL(-1)) FOR 4 CONSECUTIVE GENERATIONS (F0-F3) TO EVALUATE THE IMPACT OF 4-MBC ON MARINE ECOSYSTEMS. THE RESULTS SHOWED THAT IN THE F0 GENERATION, 4-MBC CAUSED SIGNIFICANT LETHAL TOXICITY IN T. JAPONICAS AT CONCENTRATIONS OF 5 AND 10MUGL(-1) AND THE NAUPLII WERE MORE SENSITIVE TO 4-MBC TOXICITY THAN THE ADULTS. HOWEVER IN THE F1-F3 GENERATIONS, 4-MBC EXPOSURE DID NOT AFFECT THE SURVIVAL RATE. THE HATCHING RATE AND THE DEVELOPMENTAL DURATION FROM THE NAUPLII TO THE COPEPODITE (N-C) AND FROM THE NAUPLII TO ADULT (N-A) DECREASED SIGNIFICANTLY IN THE F1-F2 GENERATIONS AND IN THE F2-F3 GENERATIONS, RESPECTIVELY, EVEN AT THE LOWEST EXPOSURE CONCENTRATION (0.5MUGL(-1)). IN THE SUBSEQUENT TWO GENERATIONS (I.E., THE F4-F5 GENERATIONS) OF RECOVERY EXPOSURE IN CLEAN SEAWATER, THE GROWTH RATES OF THE ORIGINAL 4-MBC EXPOSURE GROUPS WERE STILL FASTER THAN THE CONTROL IN BOTH THE N-C AND N-A STAGES, SUGGESTING POSSIBLE TRANSGENERATIONAL GENETIC AND/OR EPIGENETIC CHANGES UPON CHRONIC 4-MBC EXPOSURE. THE EXPRESSION OF THE ECDYSONE RECEPTOR GENE WAS UP-REGULATED BY 4-MBC, WHICH WAS CONSISTENT WITH THE DECREASE OF THE N-C/N-A DURATION. IN ADDITION, 4-MBC MAY INDUCE OXIDATIVE STRESS AND TRIGGER APOPTOSIS IN T. JAPONICAS, RESULTING IN DEVELOPMENTAL, REPRODUCTIVE AND EVEN LETHAL TOXICITY. A PRELIMINARY RISK ASSESSMENT SUGGESTED THAT UNDER ENVIRONMENTALLY REALISTIC CONCENTRATIONS, 4-MBC HAD SIGNIFICANT POTENTIAL TO POSE A THREAT TO MARINE CRUSTACEANS AND MARINE ECOSYSTEMS. 2018 15 876 19 CHRONIC ARSENIC INTOXICATION DIAGNOSTIC SCORE (CASIDS). ARSENIC AND ITS COMPOUNDS ARE WELL-ESTABLISHED, POTENT, ENVIRONMENTALLY WIDESPREAD AND PERSISTENT TOXICANTS WITH METABOLIC, GENOTOXIC, MUTAGENIC, TERATOGENIC, EPIGENETIC AND CARCINOGENIC EFFECTS. ARSENIC OCCURS NATURALLY IN THE EARTH'S CRUST, BUT ANTHROPOGENIC ARSENIC EMISSIONS HAVE SURMOUNTED THE EMISSIONS FROM IMPORTANT NATURAL SOURCES SUCH AS VOLCANISM. INORGANIC ARSENICALS EXHIBIT ACUTE AND CHRONIC TOXICITIES IN VIRTUALLY ALL CELL TYPES AND TISSUES, AND HENCE ARSENIC INTOXICATION AFFECTS MULTIPLE SYSTEMS. WHEREAS ACUTE ARSENIC INTOXICATION IS RARE AND RELATIVELY EASY TO DIAGNOSE, CHRONIC ARSENIC INTOXICATION (CASI) IS COMMON BUT GOES OFTEN MISDIAGNOSED. BASED ON A REVIEW OF THE LITERATURE AS WELL AS OUR OWN CLINICAL EXPERIENCE, WE PROPOSE A CHRONIC ARSENIC INTOXICATION DIAGNOSTIC SCORE (CASIDS). A DISTINCTIVE FEATURE OF CASIDS IS THE USE OF BONE ARSENIC LOAD AS AN ESSENTIAL CRITERION FOR THE INDIVIDUAL RISK ASSESSMENT OF CHRONIC ARSENIC INTOXICATION, COMBINED WITH A SYSTEMIC CLINICAL ASSESSMENT. WE PRESENT CLINICAL EXAMPLES WHERE CASIDS IS APPLIED FOR THE DIAGNOSIS OF CASI, REVIEW THE MAIN TOPICS OF THE TOXICITY OF ARSENIC IN DIFFERENT CELL AND ORGAN SYSTEMS AND DISCUSS THE THERAPY AND PREVENTION OF DISEASE CAUSED OR AGGRAVATED BY CHRONIC ARSENIC INTOXICATION. CASIDS CAN HELP PHYSICIANS ESTABLISH THE DIAGNOSIS OF CASI AND ASSOCIATED CONDITIONS. 2018 16 4757 27 NOVEL TREATMENT OPPORTUNITIES FOR SULFUR MUSTARD-RELATED CANCERS: GENETIC AND EPIGENETIC PERSPECTIVES. SULFUR MUSTARD (SM), ALSO KNOWN AS MUSTARD GAS, IS A CHEMICAL WEAPON WHICH BY NOW HAS BEEN USED IN MANY WARS. THE MOST CONCERNING SM TOXIC EFFECT IS PROBABLE CARCINOGENICITY. IN THIS STUDY, THE GENETIC AND EPIGENETIC MECHANISMS OF SM CARCINOGENICITY, BY FOCUSING ON TREATMENT OF SM-ASSOCIATED MALIGNANCIES, PARTICULARLY GENE THERAPEUTICS, CANCER VACCINES, AND EPIGENETIC MEDICATIONS, HAVE BEEN CRITICIZED. THE REQUIRED DATA WERE COLLECTED THROUGH AN ORGANIZED SEARCH ON VALID SCIENTIFIC DATABASES. FOR SM CARCINOGENICITY DUE TO ACUTE OR CHRONIC EXPOSURE, THE ENTIRE ORIGINAL AND REVIEW ARTICLES WERE EVALUATED. IN ADDITION, STUDIES ON THE THERAPEUTIC EFFECTS OF AVAILABLE GENETIC AND EPIGENETIC MEDICATIONS WERE INCLUDED. CURRENTLY, FOUR GENE THERAPEUTICS, TWO CANCER VACCINES WITH GENETIC BASES, AND SEVEN EPIGENETIC MEDICATIONS ARE AVAILABLE FOR CANCER TREATMENT. GENETIC AND EPIGENETIC CANCER TREATMENTS INCLUDING GENDICINE, IMLYGIC, PROVENGE, CIMAVAX-EGF, AZACITIDINE, VORINOSTAT, ROMIDEPSIN, AND BELINOSTAT WILL YIELD OUTSTANDING BENEFITS FOR SM-EXPOSED PATIENTS WHO SUFFER FROM CANCER. 2017 17 6849 23 [MOLECULAR MECHANISM OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IN JAPAN IS CLOSELY ASSOCIATED WITH THE CHRONIC LIVER DISEASES OF INFECTION WITH THE HEPATITIS B OR C VIRUSES. ANALYSIS OF HCC TISSUES FREQUENTLY DETECTS LOSS OF HETEROZYGOSITY AT CHROMOSOMES 1P, 4, 6Q, 8P, 10Q, 13Q, 16Q, 17P, AND MANY GENOMIC AND EPIGENOMIC ABNORMALITIES HAVE BEEN FOUND IN P53, BETA-CATENIN, P16CDKI, DNA MISMATCH REPAIR GENES, AND OTHERS. HOWEVER, NO SPECIFIC ABNORMAL GENETIC OR EPIGENETIC CHANGES FOR HCC HAVE BEEN FOUND SO FAR. THE DEVELOPMENT OF HCC HAS BEEN REPORTED IN MICE TRANSGENIC FOR THE HEPATITIS B VIRUS X GENE OR THE HEPATITIS C VIRUS CORE GENE, AND THESE VIRAL PROTEINS MIGHT PLAY ESSENTIAL ROLES IN HEPATOCARCINOGENESIS. CHRONIC HEPATITIS AND FIBROSIS DUE TO PERSISTENT VIRAL INFECTION MIGHT ALSO INFLUENCE THE GENOMIC INSTABILITY OF HEPATOCYTES, LEADING TO ACCUMULATION OF GENOMIC CHANGES. 1999 18 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 19 6526 33 TRANSCRIPTIONAL CHANGES IN THE OVARIES OF PERCH FROM CHERNOBYL. FISH HAVE BEEN HIGHLY EXPOSED TO RADIATION IN FRESHWATER SYSTEMS AFTER THE CHERNOBYL NUCLEAR POWER PLANT (NPP) ACCIDENT IN 1986 AND IN FRESHWATER AND MARINE SYSTEMS AFTER THE MORE RECENT FUKUSHIMA NPP ACCIDENT IN 2011. IN THE YEARS AFTER THE ACCIDENT, THE RADIOACTIVITY LEVELS RAPIDLY DECLINED DUE TO RADIOACTIVE DECAY AND ENVIRONMENTAL PROCESSES, BUT CHRONIC LOWER DOSE EXPOSURES PERSISTED. TO GAIN INSIGHTS INTO THE LONG-TERM EFFECTS OF ENVIRONMENTAL LOW DOSE RADIATION ON FISH OVARIES DEVELOPMENT, A HIGH-THROUGHPUT TRANSCRIPTOMIC APPROACH INCLUDING A DE NOVO ASSEMBLY WAS APPLIED TO DIFFERENT GONAD PHENOTYPES OF FEMALE PERCH: DEVELOPED GONADS FROM REFERENCE LAKES, DEVELOPED/IRRADIATED FROM MEDIUM CONTAMINATED LAKE, AND BOTH DEVELOPED/IRRADIATED AND UNDEVELOPED FROM MORE HIGHLY CONTAMINATED LAKES. THIS IS THE MOST COMPREHENSIVE ANALYSIS TO DATE OF THE GENE RESPONSES IN WILDLIFE REPRODUCTIVE SYSTEM TO RADIATION. SOME GENE RESPONSES THAT WERE MODULATED IN IRRADIATED GONADS WERE FOUND TO BE INVOLVED IN BIOLOGICAL PROCESSES INCLUDING CELL DIFFERENTIATION AND PROLIFERATION (GGNB2, MOD5, RERGL), CYTOSKELETON ORGANIZATION (K1C18, MTPN), GONAD DEVELOPMENT (NELL2, TCP4), LIPID METABOLISM (LDAH, AT11B, NLTP), REPRODUCTION (CYB5, CYP17A, OVOS), DNA DAMAGE REPAIR (WDHD1, RAD51, HUS1), AND EPIGENETIC MECHANISMS (DMAP1). IDENTIFICATION OF THESE GENES PROVIDES A BETTER UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS UNDERPINNING THE DEVELOPMENT OF THE GONAD PHENOTYPES OF WILD PERCH AND HOW FISH MAY RESPOND TO CHRONIC EXPOSURE TO RADIATION IN THEIR NATURAL ENVIRONMENT, THOUGH CAUSAL ATTRIBUTION OF GENE RESPONSES REMAINS UNCLEAR IN THE UNDEVELOPED GONADS. 2020 20 6829 25 [HEPATITIS C VIRUS INFECTION AND HEPATOCARCINOGENESIS]. HEPATITIS C VIRUS INFECTION CAUSES APPROXIMATELY 4 MILLION NEW INFECTIONS WORLDWIDE, AND 399 000 DEATHS DUE TO ITS COMPLICATIONS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). MICROENVIRONMENTAL CHANGES, CHRONIC INFLAMMATION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS CAUSED BY HCV INFECTION, VIA GENETIC AND EPIGENETIC CHANGES CAN RESULT IN PRIMARY LIVER CANCER DURING DECADES. THE DIRECT ONCOGENIC PROPERTY OF HCV IS WELLKNOWN. THE TRANSFORMING EFFECT OF FOUR HCV PROTEINS (CORE, NS3, NS4B, NS5A) HAS BEEN PROVEN. EFFECTIVE ANTIVIRAL THERAPY, SUSTAINED VIRAL RESPONSE DECREASES THE HCV-RELATED GENERAL AND LIVER-RELATED MORTALITY. INTERFERON-BASED THERAPY REDUCES THE RISK OF HCC DEVELOPMENT. SHORTER THERAPY WITH DIRECT ACTING ANTIVIRAL AGENTS (DAA) HAS HIGHER EFFICACY, FEWER SIDE-EFFECTS. PUBLICATIONS HAVE REPORTED THE UNEXPECTED EFFECTS OF DAA. THE AUTHORS REVIEW THE ARTICLES FOCUSING ON THE OCCURRENCE OF HCC IN CONNECTION WITH DAA THERAPIES. THERE IS A NEED FOR PROSPECTIVE, MULTICENTRIC STUDIES WITH LONGER FOLLOW-UP TO EXAMINE THE RISK OF HCC FORMATION. AFTER ANTIVIRAL THERAPY, HCC SURVEILLANCE IS OF HIGH IMPORTANCE WHICH MEANS ABDOMINAL ULTRASOUND EVERY 3-6-12 MONTHS IN SUSTAINED VIRAL RESPONSE PATIENTS AS WELL. ORV HETIL. 2019; 160(22): 846-853. 2019