1 1819 117 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 2 4822 33 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 3 4820 39 OCHRATOXIN A AS A POTENTIAL ETIOLOGIC FACTOR IN ENDEMIC NEPHROPATHY: LESSONS FROM TOXICITY STUDIES IN RATS. VARIOUS REPORTS SUGGEST THAT CHRONIC DIETARY EXPOSURE TO OCHRATOXIN A (OTA), A MYCOTOXIN FREQUENTLY DETECTED IN VARIOUS FOOD ITEMS MAY BE LINKED TO THE PATHOGENESIS OF ENDEMIC NEPHROPATHY, A CHRONIC TUBULOINTERSTITIAL KIDNEY DISEASE WHICH OCCURS IN GEOGRAPHICALLY LIMITED AREAS OF THE BALKAN REGION. OTA IS A POTENT NEPHROTOXIN AND RENAL CARCINOGEN. HOWEVER, THE PATHOLOGICAL LESIONS OBSERVED IN KIDNEYS OF RATS TREATED WITH OTA APPEAR BE RATHER DIFFERENT FROM THE CLINICAL AND PATHOLOGICAL CHARACTERISTICS OF ENDEMIC NEPHROPATHY. MOREOVER, INCREASING EVIDENCE SUGGESTS THAT OTA DOES NOT BIND TO DNA BUT INDUCES TUMORS BY AN EPIGENETIC, THRESHOLDED MECHANISM. THIS IMPLIES THAT THERE IS A DOSE BELOW WHICH NO ADVERSE HEALTH EFFECTS ARE EXPECTED TO OCCUR. BASED ON FOOD CONSUMPTION DATA AND OTA SERUM CONCENTRATIONS, IT APPEARS THAT HUMAN EXPOSURE - EVEN IN AREAS WITH RELATIVELY HIGH DIETARY EXPOSURE TO OTA SUCH AS ENDEMIC VILLAGES - IS SEVERAL ORDERS OF MAGNITUDE BELOW DOSES KNOWN TO CAUSE NEPHROTOXICITY AND TUMOR FORMATION IN LABORATORY ANIMALS. WHILE IT IS UNDOUBTEDLY IMPORTANT TO ENCOURAGE PREVENTION OF FOOD CONTAMINATION BY OTA AND OTHER MYCOTOXINS, THESE OBSERVATIONS SUGGEST THAT OTA IS NOT LIKELY TO BE AN ETIOLOGICAL FACTOR INVOLVED IN BEN AND INDICATE A NEED TO SEARCH FOR NEW CLUES FOR THE ETIOLOGY OF THIS ENDEMIC KIDNEY DISEASE. 2007 4 4821 41 OCHRATOXIN A: 13-WEEK ORAL TOXICITY AND CELL PROLIFERATION IN MALE F344/N RATS. OCHRATOXIN A (OTA) IS NEPHROTOXIC AND A POTENT RENAL CARCINOGEN. MALE RATS ARE MOST SUSCEPTIBLE TO OTA TOXICITY, AND CHRONIC ADMINISTRATION OF OTA (70 AND 210 MICROG/KG BW) FOR 2 YEARS HAS BEEN SHOWN TO INDUCE HIGH INCIDENCES OF ADENOMAS AND CARCINOMAS ARISING FROM THE STRAIGHT SEGMENT OF THE PROXIMAL TUBULE EPITHELIUM. IN CONTRAST, TREATMENT WITH A LOWER DOSE OF 21 MICROG/KG BW DID NOT RESULT IN INCREASED TUMOR RATES, SUGGESTING A NONLINEAR DOSE RESPONSE FOR RENAL TUMOR FORMATION BY OTA. SINCE THE MECHANISM OF OTA CARCINOGENICITY IS STILL LARGELY UNKNOWN, THIS STUDY WAS CONDUCTED TO INVESTIGATE EARLY FUNCTIONAL AND PATHOLOGICAL EFFECTS OF OTA AND TO DETERMINE IF SUSTAINED STIMULATION OF RENAL CELL PROLIFERATION PLAYS A ROLE. MALE F344/N RATS WERE TREATED WITH OTA FOR UP TO 13 WEEKS UNDER CONDITIONS OF THE NATIONAL TOXICOLOGY PROGRAM (NTP) BIOASSAY. CELL PROLIFERATION IN THE RENAL CORTEX AND OUTER STRIPE OF THE OUTER MEDULLA (OSOM) WAS DETERMINED USING BROMODEOXYURIDINE INCORPORATION AND IMMUNOHISTOCHEMISTRY. HISTOPATHOLOGICAL EXAMINATION SHOWED RENAL ALTERATIONS IN MID- AND HIGH-DOSE-TREATED ANIMALS INVOLVING SINGLE-CELL DEATH AND PROMINENT NUCLEAR ENLARGEMENT WITHIN THE STRAIGHT PROXIMAL TUBULES. TREATMENT WITH OTA AT DOSES OF 70 AND 210 MICROG/KG BW LED TO A MARKED DOSE- AND TIME-DEPENDENT INCREASE IN RENAL CELL PROLIFERATION, EXTENDING FROM THE MEDULLARY RAYS INTO THE OSOM. NO EFFECTS WERE EVIDENT IN KIDNEYS OF LOW-DOSE-TREATED ANIMALS OR IN THE LIVER, WHICH IS NOT A TARGET FOR OTA CARCINOGENICITY. A NO OBSERVED EFFECT LEVEL IN THIS STUDY WAS ESTABLISHED AT 21 MICROG/KG BW, CORRELATING WITH THE DOSE IN THE NTP 2-YEAR BIOASSAY THAT DID NOT PRODUCE RENAL TUMORS. THE APPARENT CORRELATION BETWEEN ENHANCED CELL TURNOVER AND TUMOR FORMATION INDUCED BY OTA INDICATES THAT STIMULATION OF CELL PROLIFERATION MAY PLAY AN IMPORTANT ROLE IN OTA CARCINOGENICITY AND PROVIDES FURTHER EVIDENCE FOR AN EPIGENETIC, THRESHOLDED MECHANISM. 2007 5 4824 32 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 6 4823 30 OCHRATOXIN A: POTENTIAL EPIGENETIC MECHANISMS OF TOXICITY AND CARCINOGENICITY. ASSESSMENT OF THE SIGNIFICANCE TO HUMAN HEALTH OF OCHRATOXIN A (OTA) IN FOOD IS LIMITED BY A LACK OF HUMAN TOXICITY DATA. THEREFORE, OTA RISK EVALUATION RELIES MAINLY ON THE USE OF ANIMAL DATA, WITH RENAL CARCINOGENICITY IN RAT BEING CONSIDERED AS THE PIVOTAL EFFECT. THE ELUCIDATION OF THE MECHANISM OF ACTION WOULD IMPROVE THE USE OF THE CARCINOGENICITY DATA FOR RISK ASSESSMENT. DIRECT GENOTOXICITY VERSUS EPIGENETIC MECHANISMS APPEARS TO BE A KEY QUESTION. IN THIS PRESENTATION, NEW BIOCHEMICAL AND TOXICOGENOMIC RESULTS OBTAINED IN A RECENT EUROPEAN PROJECT (EU-GRANT # QLK1-CT-2001-011614) WILL BE SUMMARIZED IN THE CONTEXT OF PREVIOUSLY REPORTED MECHANISMS OF ACTION INCLUDING INHIBITION OF PROTEIN SYNTHESIS, PRODUCTION OF OXIDATIVE STRESS AND ALTERATION OF CELL SIGNALLING. AMONGST OTHERS, THE NEW DATA INDICATE THAT CHRONIC ADMINISTRATION OF A CARCINOGENIC DOSE OF OTA AFFECTED CELL-SIGNALLING PATHWAYS RESULTING IN A SIGNIFICANTLY REDUCED RENAL ANTIOXIDANT DEFENCE AND INCREASED OXIDATIVE DNA DAMAGE. THESE DATA CONFIRM PREVIOUS HYPOTHESES INVOLVING OXIDATIVE STRESS AS A POSSIBLE KEY EPIGENETIC MECHANISM OF OTA TOXICITY AND CARCINOGENICITY. 2005 7 126 43 A TOXICOGENOMICS APPROACH TO IDENTIFY NEW PLAUSIBLE EPIGENETIC MECHANISMS OF OCHRATOXIN A CARCINOGENICITY IN RAT. OCHRATOXIN A (OTA) IS A MYCOTOXIN OCCURRING NATURALLY IN A WIDE RANGE OF FOOD COMMODITIES. IN ANIMALS, IT HAS BEEN SHOWN TO CAUSE A VARIETY OF ADVERSE EFFECTS, NEPHROCARCINOGENICITY BEING THE MOST PROMINENT. BECAUSE OF ITS HIGH TOXIC POTENCY AND THE CONTINUOUS EXPOSURE OF THE HUMAN POPULATION, OTA HAS RAISED PUBLIC HEALTH CONCERNS. THERE IS SIGNIFICANT DEBATE ON HOW TO USE THE RAT CARCINOGENICITY DATA TO ASSESS THE POTENTIAL RISK TO HUMANS. IN THIS CONTEXT, THE QUESTION OF THE MECHANISM OF ACTION OF OTA APPEARS OF KEY IMPORTANCE AND WAS STUDIED THROUGH THE APPLICATION OF A TOXICOGENOMICS APPROACH. MALE FISCHER RATS WERE FED OTA FOR UP TO 2 YEARS. RENAL TUMORS WERE DISCOVERED DURING THE LAST 6 MONTHS OF THE STUDY. THE TOTAL TUMOR INCIDENCE REACHED 25% AT THE END OF THE STUDY. GENE EXPRESSION PROFILE WAS ANALYZED IN GROUPS OF ANIMALS TAKEN IN INTERVALS FROM 7 DAYS TO 12 MONTHS. TISSUE-SPECIFIC RESPONSES WERE OBSERVED IN KIDNEY VERSUS LIVER. FOR SELECTED GENES, MICROARRAY DATA WERE CONFIRMED AT BOTH MRNA AND PROTEIN LEVELS. IN KIDNEY, SEVERAL GENES KNOWN AS MARKERS OF KIDNEY INJURY AND CELL REGENERATION WERE SIGNIFICANTLY MODULATED BY OTA. THE EXPRESSION OF GENES KNOWN TO BE INVOLVED IN DNA SYNTHESIS AND REPAIR, OR GENES INDUCED AS A RESULT OF DNA DAMAGE, WAS ONLY MARGINALLY MODULATED. VERY LITTLE OR NO EFFECT WAS FOUND AMONGST GENES ASSOCIATED WITH APOPTOSIS. ALTERATIONS OF GENE EXPRESSION INDICATING EFFECTS ON CALCIUM HOMEOSTASIS AND A DISRUPTION OF PATHWAYS REGULATED BY THE TRANSCRIPTION FACTORS HEPATOCYTE NUCLEAR FACTOR 4 ALPHA (HNF4ALPHA) AND NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) WERE OBSERVED IN THE KIDNEY BUT NOT IN THE LIVER. PREVIOUS DATA HAVE SUGGESTED THAT A REDUCTION IN HNF4ALPHA MAY BE ASSOCIATED WITH NEPHROCARCINOGENICITY. MANY NRF2-REGULATED GENES ARE INVOLVED IN CHEMICAL DETOXICATION AND ANTIOXIDANT DEFENSE. THE DEPLETION OF THESE GENES IS LIKELY TO IMPAIR THE DEFENSE POTENTIAL OF THE CELLS, RESULTING IN CHRONIC ELEVATION OF OXIDATIVE STRESS IN THE KIDNEY. THE INHIBITION OF DEFENSE MECHANISM APPEARS AS A HIGHLY PLAUSIBLE NEW MECHANISM, WHICH COULD CONTRIBUTE TO OTA CARCINOGENICITY. 2006 8 1437 22 DIFFERENTIAL METHYLATION PATTERN OF XENOBIOTIC METABOLIZING GENES AND SUSCEPTIBILITY TO BALKAN ENDEMIC NEPHROPATHY, IN A COHORT OF ROMANIAN PATIENTS. A SEVERE, CHRONIC AND IRREVERSIBLE KIDNEY DISEASE AFFECTING DISCRETE RURAL POPULATIONS IN THE BALKAN PENINSULA COUNTRIES, BALKAN ENDEMIC NEPHROPATHY (BEN) HAS BEEN A SCIENTIFIC PUZZLE FOR MORE THAN HALF A CENTURY. MANY ENVIRONMENTAL AND OTHER FACTORS HAVE BEEN SUGGESTED AS THE PRIMARY CAUSE AND RECENT SIGNIFICANT FINDINGS HAVE LINKED BEN TO ARISTOLOCHIC ACIDS, PHYTOTOXINS DERIVED FROM THE PLANT ARISTOLOCHIA CLEMATITIS, FOUND IN HIGH DENSITY IN THE ENDEMIC AREAS. HOWEVER, GIVEN THAT THE INCIDENCE OF BEN IS LESS THAN 10% IN AFFECTED VILLAGES, AND IT TENDS TO HAVE A FAMILY AGGREGATION, AS YET UNIDENTIFIED GENETIC FACTORS MAY ALSO PLAY A ROLE. TO FURTHER EXPLORE THIS POSSIBILITY, A PILOT STUDY WAS INITIATED TO INVESTIGATE THE DNA METHYLATION OF CYP1A1, CYP1A2, NAT1, NQO1 AND GSTT1 IN BLOOD SAMPLES FROM A GROUP OF ROMANIAN BEN PATIENTS, COMPARED TO HEALTHY CONTROLS AND NON-BEN CHRONIC KIDNEY DISEASE (CKD) SUBJECTS. OUR STUDY REVEALED A MORE PRONOUNCED HYPOMETHYLATION PATTERN IN BEN AND NON-BEN CKD GROUPS, COMPARED TO THE HEALTHY CONTROL GROUP AT SPECIFIC CPGS ACROSS ALL FIVE GENES INTERROGATED. AVERAGE METHYLATION ACROSS THE FIVE REGIONS INVESTIGATED INDICATED SIGNIFICANT DIFFERENCES ONLY AT GSTT1, IN BOTH BEN PATIENTS (P = 0.028) AND NON-BEN DISEASE SUBJECTS (P = 0.015), RELATIVE TO HEALTHY INDIVIDUALS. SINCE GSTT1 ACTIVE GENOTYPE APPEARS TO BE A COMMON FEATURE OF SERBIAN AND ROMANIAN BEN PATIENTS, GSTT1 EPIGENETIC VARIATION AND INCREASED GENE ACTIVITY COULD ACT AS A PREDISPOSING (CO)FACTOR IN BEN POPULATIONS FROM THE AFFECTED COUNTRIES. BEN AND NON-BEN CKD GROUPS SHOW SIMILAR METHYLATION PATTERNS WITH EXCEPTION OF GSTT1 CPG8 (P = 0.046). 2020 9 3131 25 GLOBAL AND SPECIFIC HISTONE ACETYLATION PATTERN IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY, A WORLDWIDE DISEASE. ABSTRACT BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) IS A CHRONIC TUBULOINTERSTITIAL NEPHROPATHY PRESENT IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES. THERE APPEARS TO BE A POLYGENIC SUSCEPTIBILITY TO THE DISEASE IN INTERACTION WITH MULTIPLE ENVIRONMENTAL FACTORS (ARISTOLOCHIC ACID, OCHRATOXIN A). IN A PREVIOUS STUDY SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS OF BEN PATIENTS FROM SERBIA AND BULGARIA. EMERGING CONNECTIONS BETWEEN DNA METHYLATION AND HISTONE ACETYLATION PROMPTED THE PRESENT STUDY ON HISTONE ACETYLATION IN PATIENTS WITH BEN. METHODS: THE STUDY INVOLVED 39 PATIENTS WITH BEN, AND 39 CONTROLS COLLECTED FROM NON-ENDEMIC REGIONS IN SERBIA. THE EPISEEKER HISTONE H3 AND H4 TOTAL ACETYLATION DETECTION COLORIMETRIC KITS AND SPECIFIC ACETYLATED AT LYSINE 18 H3K18 AND H3K36 ACETYLATED AT LYSINE 36 DETECTION KITS WERE USED. RESULTS: IT WAS DOCUMENTED THAT TOTAL H4 HISTONE ACETYLATION LEVEL WAS INCREASED SIGNIFICANTLY, WHILE TOTAL H3 HISTONE ACETYLATION DID NOT DIFFER SIGNIFICANTLY. SPECIFIC HISTONE STRUCTURE AND FUNCTIONAL PROPERTIES MAY BE AFFECTED BY THE OBSERVED DERANGEMENT OF H3 HISTONE ACETYLATION PATTERN, SINCE H3K36 SITE WAS SIGNIFICANTLY MORE ACETYLATED, WHILE H3K18 TENDED TO BE LESS ACETYLATED THAN IN CONTROL SUBJECTS. MULTIPLE REGRESSION ANALYSIS REVEALED A STATISTICALLY SIGNIFICANT RELATIONSHIP BETWEEN H4, H3T AND H3K36 IN BEN PATIENTS. CONCLUSION: THIS PRELIMINARY STUDY SUGGESTS THAT THE ACETYLATION OF HISTONE LYSINE RESIDUES WAS DETECTABLE AND FOUND INCREASED AT SPECIFIC SITES OF H3 AND TOTAL H4 HISTONES ISOLATED FROM UROTHELIAL CELLS OF PATIENTS WITH BEN. HAVING IN MIND A POSSIBLE MECHANISM AND BIOLOGICAL ROLE OF EPIGENETIC CHROMATIN MODIFICATION IN UROTHELIAL TUMOR DEVELOPMENT THEY OBTAINED RESULTS MAY OPEN OPPORTUNITY FOR SELECTIVE THERAPEUTIC INTERVENTIONS IN PATIENTS WITH BEN. 2014 10 4121 32 MECHANISMS OF CHEMICALLY INDUCED RENAL CARCINOGENESIS IN THE LABORATORY RODENT. LABORATORY STUDIES WITH CLASSICAL RENAL CARCINOGENS IN THE RAT AND MOUSE, AS WELL AS RESEARCH INVESTIGATION WITH SOME OF THE CHEMICALS PROVING POSITIVE FOR THE KIDNEY IN NATIONAL TOXICOLOGY PROGRAM CARCINOGENICITY BIOASSAYS, HAVE DEMONSTRATED THE EXISTENCE OF A RANGE OF DIVERSE MECHANISMS UNDERLYING RODENT KIDNEY CARCINOGENESIS. THE CLASSICAL CARCINOGENS USED AS EXPERIMENTAL MODELS FOR STUDYING RENAL TUMOR PATHOGENESIS, SUCH AS THE NITROSAMINES, ARE GENOTOXIC AND INTERACT DIRECTLY WITH DNA, FORMING DNA ADDUCTS WITH MUTAGENIC POTENTIAL. IN CONTRAST, POTASSIUM BROMATE AND FERRIC NITRILOTRIACETATE (FE-NTA), ALSO EFFECTIVE RENAL CARCINOGENS, APPEAR TO CAUSE INDIRECT DAMAGE TO DNA MEDIATED BY OXIDATIVE STRESS. A NUMBER OF NONGENOTOXIC CHEMICALS ARE ASSOCIATED WITH EPIGENETIC RENAL TUMOR INDUCTION IN RODENTS, AND THE ACTIVITY OF THESE TENDS TO INVOLVE PROLONGED STIMULATION OF CELL PROLIFERATION THROUGHOUT THE DURATION OF EXPOSURE. THIS MODE OF ACTION REFLECTS A SUSTAINED REGENERATIVE RESPONSE, EITHER DUE TO DIRECT CHEMICAL TOXICITY TO THE TUBULE CELLS, AS WITH CHLOROFORM, OR TO INDIRECT CYTOTOXICITY ASSOCIATED WITH LYSOSOMAL OVERLOAD, AS IN ALPHA2U-GLOBULIN ACCUMULATION IN MALE RATS RESULTING FROM THE ADMINISTRATION OF SUCH CHEMICALS AS D-LIMONENE AND TETRACHLOROETHYLENE. THE HISTOPATHOLOGIC NATURE OF HYDROQUINONE RENAL CARCINOGENESIS SUGGESTS THAT AN ADDITIONAL EPIGENETIC PATHWAY TO RENAL TUBULE TUMOR FORMATION IN RATS MAY BE THROUGH CHEMICAL-MEDIATED EXACERBATION OF, AND INTERACTION WITH, THE AGE-RELATED SPONTANEOUS RENAL DISEASE, CHRONIC PROGRESSIVE NEPHROPATHY. THESE VARIOUS MECHANISTIC PATHWAYS HAVE IMPLICATIONS FOR THE NATURE OF THE INDUCED CANCER PROCESS WITH RESPECT TO TUMOR INCIDENCE, LATENCY, MALIGNANCY, AND SEX PREDISPOSITION. 1998 11 837 41 CHEMICALLY INDUCED RENAL TUBULE TUMORS IN THE LABORATORY RAT AND MOUSE: REVIEW OF THE NCI/NTP DATABASE AND CATEGORIZATION OF RENAL CARCINOGENS BASED ON MECHANISTIC INFORMATION. THE INCIDENCE OF RENAL TUBULE CARCINOGENESIS IN MALE AND FEMALE RATS OR MICE WITH 69 CHEMICALS FROM THE 513 BIOASSAYS CONDUCTED TO DATE BY THE NCI/NTP HAS BEEN COLLATED, THE CHEMICALS CATEGORIZED, AND THE RELATIONSHIP BETWEEN CARCINOGENESIS AND RENAL TUBULE HYPERPLASIA AND EXACERBATION OF THE SPONTANEOUS, AGE-RELATED RODENT DISEASE CHRONIC PROGRESSIVE NEPHROPATHY (CPN) EXAMINED. WHERE INFORMATION ON MECHANISM OR MODE OF ACTION EXISTS, THE CHEMICALS HAVE BEEN CATEGORIZED BASED ON THEIR ABILITY TO DIRECTLY OR INDIRECTLY INTERACT WITH RENAL DNA, OR ON THEIR ACTIVITY VIA EPIGENETIC PATHWAYS INVOLVING EITHER DIRECT OR INDIRECT CYTOTOXICITY WITH REGENERATIVE HYPERPLASIA, OR EXACERBATION OF CPN. NINE CHEMICALS WERE IDENTIFIED AS DIRECTLY INTERACTING WITH DNA, WITH SIX OF THESE PRODUCING RENAL TUBULE TUMORS AT HIGH INCIDENCE IN RATS OF BOTH SEXES, AND IN SOME CASES ALSO IN MICE. OCHRATOXIN A WAS THE MOST POTENT COMPOUND IN THIS GROUP, PRODUCING A HIGH TUMOR INCIDENCE AT VERY LOW DOSES, OFTEN WITH METASTASIS. THREE CHEMICALS WERE DISCUSSED IN THE CONTEXT OF INDIRECT DNA DAMAGE MEDIATED BY AN OXIDATIVE FREE RADICAL MECHANISM, ONE OF THESE BEING FROM THE NTP DATABASE. A THIRD CATEGORY INCLUDED FOUR CHEMICALS THAT HAD THE POTENTIAL TO CAUSE DNA DAMAGE FOLLOWING CONJUGATION WITH GLUTATHIONE AND SUBSEQUENT ENZYMATIC ACTIVATION TO A REACTIVE SPECIES, USUALLY A THIOL-CONTAINING ENTITY. TWO CHEMICALS WERE ALLOCATED INTO THE CATEGORY INVOLVING A DIRECT CYTOTOXIC ACTION ON THE RENAL TUBULE FOLLOWED BY SUSTAINED COMPENSATORY CELL PROLIFERATION, WHILE NINE WERE INCLUDED IN A GROUP WHERE THE CELL LOSS AND SUSTAINED INCREASE IN RENAL TUBULE CELL TURNOVER WERE DEPENDENT ON LYSOSOMAL ACCUMULATION OF THE MALE RAT-SPECIFIC PROTEIN, ALPHA2MU-GLOBULIN. IN A SIXTH CATEGORY, MORPHOLOGIC EVIDENCE ON TWO CHEMICALS INDICATED THAT THE RENAL TUMORS WERE A CONSEQUENCE OF EXACERBATED CPN. FOR THE REMAINING CHEMICALS, THERE WERE NO PERTINENT DATA ENABLING ASSIGNMENT TO A MECHANISTIC CATEGORY. ACCORDINGLY, THESE CHEMICALS, ACTING THROUGH AN AS YET UNKNOWN MECHANISM, WERE GROUPED AS EITHER BEING ASSOCIATED WITH AN ENHANCEMENT OF CPN (CATEGORY 7, 16 CHEMICALS), OR NOT ASSOCIATED WITH ENHANCED CPN (CATEGORY 8, 4 CHEMICALS). A NINTH CATEGORY DEALT WITH 11 CHEMICALS THAT WERE REGARDED AS PRODUCING INCREASES IN RENAL TUBULE TUMORS THAT DID NOT REACH STATISTICAL SIGNIFICANCE. A 10TH CATEGORY DISCUSSED 6 CHEMICALS THAT INDUCED RENAL TUMORS IN MICE BUT NOT IN RATS, PLUS 8 CHEMICALS THAT PRODUCED A LOW INCIDENCE OF RENAL TUBULE TUMORS IN MICE THAT DID NOT REACH STATISTICAL SIGNIFICANCE. AS MORE MECHANISTIC DATA ARE GENERATED, SOME CHEMICALS WILL INEVITABLY BE PLACED IN DIFFERENT GROUPS, PARTICULARLY THOSE FROM CATEGORIES 7 AND 8. A LARGE NUMBER OF CHEMICALS IN THE SERIES EXACERBATED CPN, BUT THOSE IN CATEGORY 7 ESPECIALLY MAY BE CANDIDATES FOR INCLUSION IN CATEGORY 6 WHEN FURTHER INFORMATION IS GLEANED FROM THE RELEVANT NTP STUDIES. ALSO, NEW DATA ON SPECIFIC CHEMICALS WILL PROBABLY EXPAND CATEGORY 5 AS CYTOTOXICITY AND CELL REGENERATION ARE IDENTIFIED AS OBLIGATORY STEPS IN RENAL CARCINOGENESIS IN MORE CASES. ADDITIONAL CONFIRMATORY OUTCOMES ARISING FROM THIS REVIEW ARE THAT METASTASES FROM RENAL TUBULE TUMORS, WHILE ENCOUNTERED WITH CHEMICALS CAUSING DNA DAMAGE, ARE RARE WITH THOSE ACTING THROUGH AN EPIGENETIC PATHWAY, WITH THE EXCEPTION BEING FUMONISIN B1; THAT MALE RATS AND MICE ARE GENERALLY MORE SUSCEPTIBLE THAN FEMALE RATS AND MICE TO CHEMICAL INDUCTION OF RENAL TUBULE TUMORS; AND THAT A BACKGROUND OF ATYPICAL TUBULE HYPERPLASIA IS A USEFUL INDICATOR REFLECTING A CHEMICALLY ASSOCIATED RENAL TUBULE TUMOR RESPONSE. WITH RESPECT TO RENAL TUBULE TUMORS AND HUMAN RISK ASSESSMENT, CHEMICALS IN CATEGORIES 1 AND 2, AND POSSIBLY 3, WOULD CURRENTLY BE JUDGED BY LINEAR DEFAULT METHODS; CHEMICALS IN CATEGORY 4 (AND PROBABLY SOME IN CATEGORY 3) AS EXHIBITING A THRESHOLD OF ACTIVITY WARRANTING THE BENCHMARK APPROACH; AND THOSE IN CATEGORIES 5 AND 6 AS REPRESENTING MECHANISMS THAT HAVE NO RELEVANCE FOR EXTRAPOLATION TO HUMANS. 2004 12 865 30 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 13 4819 28 OCCURRENCE OF TOXICITY AND CELL PROLIFERATION AFTER A SINGLE GAVAGE ADMINISTRATION OF CHLOROFORM TO MALE F344 RATS. CHLOROFORM, AN INDUSTRIAL SOLVENT AND ONE OF THE MOST COMMON ENVIRONMENTAL CONTAMINANTS WHICH PRODUCES CARCINOGENIC EFFECTS IN THE LIVER AND KIDNEY OF RODENTS, IS NOT GENOTOXIC IN MOST TRADITIONAL BACTERIAL AND MAMMALIAN TEST SYSTEMS. ITS CARCINOGENIC POTENTIAL APPEARS ATTRIBUTABLE TO THE SUSTAINED CELL TURNOVER (REGENERATIVE HYPERPLASIA) WHICH RESULTS FROM CHRONIC CHLOROFORM TOXICITY. IN THIS PRESENT STUDY, CELL PROLIFERATION (REPLICATIVE DNA SYNTHESIS, RDS) AND HISTOPATHOLOGICAL CHANGES IN HEPATOCYTES AND RENAL TUBULAR EPITHELIAL CELLS WERE ASSESSED IN MALE F344 RATS FOLLOWING A SINGLE GAVAGE CHLOROFORM EXPOSURE (50, 150 OR 500 MG/KG). IN ADDITION, BIOCHEMICAL PARAMETERS (BUN, GOT, LDH AND NAG) WERE EXAMINED USING PLASMA AND URINE SAMPLES. CELL PROLIFERATION AND HISTOPATHOLOGICAL CHANGES (E.G. HYPERTROPHY, NECROSIS, VACUOLATION) WERE ONLY SEEN AT THE DOSE OF 500 MG/KG IN THE LIVER AND KIDNEY. AT THE SAME DOSE, ALL BIOCHEMICAL MARKERS WERE INCREASED AT THE 24 TO 48 HR TIME POINTS. THESE RESULTS OBTAINED ARE THUS IN LINE WITH EARLIER FINDINGS POINTING TO EPIGENETIC CARCINOGENICITY. 1998 14 3623 38 IN VIVO COMET ASSAY ON ISOLATED KIDNEY CELLS TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS OR CYTOTOXIC COMPOUNDS. THE OBJECTIVE OF THIS STUDY WAS TO DETERMINE THE ABILITY OF THE ALKALINE IN VIVO COMET ASSAY (PH>13) TO DISTINGUISH GENOTOXIC CARCINOGENS FROM EPIGENETIC CARCINOGENS WHEN PERFORMED ON FRESHLY ISOLATED KIDNEY CELLS AND TO DETERMINE THE POSSIBLE INTERFERENCE OF CYTOTOXICITY BY ASSESSING DNA DAMAGE INDUCED BY RENAL GENOTOXIC, EPIGENETIC OR TOXIC COMPOUNDS AFTER ENZYMATIC ISOLATION OF KIDNEY CELLS FROM OFA SPRAGUE-DAWLEY MALE RATS. THE ABILITY OF THE COMET ASSAY TO DISTINGUISH (1) GENOTOXICITY VERSUS CYTOTOXICITY AND (2) GENOTOXIC VERSUS NON-GENOTOXIC (EPIGENETIC) CARCINOGENS, WAS THUS INVESTIGATED BY STUDYING FIVE KNOWN GENOTOXIC RENAL CARCINOGENS ACTING THROUGH DIVERSE MECHANISMS OF ACTION, I.E. STREPTOZOTOCIN, ARISTOLOCHIC ACIDS, 2-NITROANISOLE, POTASSIUM BROMATE AND CISPLATIN, TWO RODENT RENAL EPIGENETIC CARCINOGENS: D-LIMONENE AND CICLOSPORINE AND TWO NEPHROTOXIC COMPOUNDS: STREPTOMYCIN AND INDOMETHACIN. ANIMALS WERE TREATED ONCE WITH THE TEST COMPOUND BY THE APPROPRIATE ROUTE OF ADMINISTRATION AND GENOTOXIC EFFECTS WERE MEASURED AT THE TWO SAMPLING TIMES OF 3-6 AND 22-26H AFTER TREATMENT. REGARDING THE TISSUE PROCESSING, THE LIMITED BACKGROUND LEVEL OF DNA MIGRATION OBSERVED IN THE NEGATIVE CONTROL GROUPS THROUGHOUT ALL EXPERIMENTS DEMONSTRATED THAT THE ENZYMATIC ISOLATION METHOD IMPLEMENTED IN THE CURRENT STUDY IS APPROPRIATE. ON THE OTHER HAND, STREPTOZOTOCIN, 20MG/KG, USED AS POSITIVE REFERENCE CONTROL CONCURRENTLY TO EACH ASSAY, CAUSED A CLEAR INCREASE IN THE MEAN OLIVE TAIL MOMENT MEDIAN VALUE, WHICH ALLOWS VALIDATING THE CURRENT METHODOLOGY. UNDER THESE EXPERIMENTAL CONDITIONS, THE IN VIVO RODENT COMET ASSAY DEMONSTRATED GOOD SENSITIVITY AND GOOD SPECIFICITY: ALL THE FIVE RENAL GENOTOXIC CARCINOGENS WERE CLEARLY DETECTED IN AT LEAST ONE EXPRESSION PERIOD EITHER DIRECTLY OR INDIRECTLY, AS IN THE CASE OF CISPLATIN: FOR THIS CROSS-LINKING AGENT, THE SIGNIFICANT DECREASE IN DNA MIGRATION OBSERVED UNDER STANDARD ELECTROPHORESIS CONDITIONS WAS CLEARLY AMPLIFIED WHEN THE DURATION OF ELECTROPHORESIS WAS INCREASED UP TO 40MIN. IN CONTRAST, EPIGENETIC AND NEPHROTOXIC COMPOUNDS FAILED TO INDUCE ANY SIGNIFCANT INCREASE IN DNA MIGRATION. IN CONCLUSION, THE IN VIVO RODENT COMET ASSAY PERFORMED ON ISOLATED KIDNEY CELLS COULD BE USED AS A TOOL TO INVESTIGATE THE GENOTOXIC POTENTIAL OF A TEST COMPOUND IF NEOPLASIC/PRENEOPLASIC CHANGES OCCUR AFTER SUBCHRONIC OR CHRONIC TREATMENTS, IN ORDER TO DETERMINE THE ROLE OF GENOTOXICITY IN TUMOR INDUCTION. MOREOVER, THE EPIGENETIC CARCINOGENS AND CYTOTOXIC COMPOUNDS DISPLAYED CLEARLY NEGATIVE RESPONSES IN THIS STUDY. THESE RESULTS ALLOW EXCLUDING A DNA DIRECT-ACTING MECHANISM OF ACTION AND CAN THUS SUGGEST THAT A THRESHOLD EXISTS. THEREFORE, THE CURRENT IN VIVO RODENT COMET ASSAY COULD CONTRIBUTE TO ELUCIDATE AN EPIGENETIC MECHANISM AND THUS, TO UNDERTAKE A RISK ASSESSMENT ASSOCIATED WITH HUMAN USE, DEPENDING ON THE EXPOSURE LEVEL. 2007 15 3006 18 GENETIC, GENOMIC AND EPIGENOMIC STUDIES OF BALKAN ENDEMIC NEPHROPATHY (BEN). BEN IS A PRIMARY, CHRONIC TUBULOINTERSTITIAL NEPHRITIS CHARACTERIZED WITH CHRONIC ANEMIA, ABSENCE OF EDEMA, XANTODERMA, NORMAL BLOOD PRESSURE AND NORMAL FINDINGS ON THE FUNDUS OCULI. THE DISEASE IS DISTRIBUTED IN RESTRICTED AREAS IN BULGARIA, ROMANIA, CROATIA, BOSNIA, FORMER YUGOSLAVIA. DESPITE NUMEROUS STUDIES ON GENETIC AND ENVIRONMENTAL FACTORS AND THEIR POSSIBLE INVOLVEMENT IN BEN, ITS ETIOPATHOGENESIS STILL REMAINS ELUSIVE. OUR RECENT STUDY AIM TO ELUCIDATE THE POSSIBLE EPIGENETIC COMPONENT IN BEN DEVELOPMENT. WHOLE GENOME DNA ARRAY METHYLATION ANALYSIS WAS APPLIED TO COMPARE THE METHYLATION PROFILES OF MALE AND FEMALE BEN PATIENTS FROM ENDEMIC REGIONS IN BULGARIA AND SERBIA AND HEALTHY CONTROLS. ALL THREE MOST PROMINENT CANDIDATE GENES WITH ABERRATIONS IN THE EPIGENETIC PROFILE DISCOVERED WITH THIS STUDY ARE INVOLVED IN THE INFLAMMATORY/IMMUNE PROCESSES AND ONCOGENESIS. THESE DATA ARE IN CONCORDANCE WITH THE REPORTED PATHOLOGICAL ALTERATIONS IN BEN. THIS RESEARCH SUPPORTS THE ROLE OF EPIGENETIC CHANGES IN BEN PATHOLOGY. EXOME SEQUENCING OF 22.000 GENES WITH ILLUMINA NEXTERA EXOME ENRICHMENT KIT REVEALED THREE MUTANT GENES (CELA1, HSPG2, AND KCNK5) IN BEN PATIENTS WHICH ENCODE PROTEINS INVOLVED IN BASEMENT MEMBRANE/EXTRACELLULAR MATRIX AND VASCULAR TONE, TIGHTLY CONNECTED TO PROCESS OF ANGIOGENESIS. WE SUGGEST THAT AN ABNORMAL PROCESS OF ANGIOGENESIS PLAYS A KEY ROLE IN THE MOLECULAR PATHOGENESIS OF BEN. 2015 16 818 25 CHARACTERISTICS OF THE SPECTRUM OF PROLIFERATIVE LESIONS OBSERVED IN THE KIDNEY AND URINARY BLADDER OF FISCHER 344 RATS AND B6C3F1 MICE. MANY RODENT RENAL AND BLADDER CARCINOGENS RELY UPON EPIGENETIC MECHANISMS OF CARCINOGENESIS; SUCH MECHANISMS ARE LIKELY TO INFLUENCE THE SPECTRUM OF URINARY TRACT TUMORS OBSERVED IN CONTROL AND TREATED ANIMALS. THIS IS REFLECTED IN SEVERAL FEATURES OF CHEMICALLY INDUCED RODENT URINARY TRACT NEOPLASMS, INCLUDING A LOW OVERALL TUMOR INCIDENCE, AN INCREASED PREVALENCE OF URINARY TRACT TUMORS IN RATS COMPARED TO MICE AND MALES COMPARED TO FEMALES, THE TENDENCY FOR EPITHELIAL TUMORS TO PREDOMINATE OVER NONEPITHELIAL TYPES, AND DEMONSTRATED LINKS TO CHRONIC PROGRESSIVE NEPHROPATHY AND UROLITHIASIS. SUCH TENDENCIES ARE ALSO CHARACTERISTIC OF SPONTANEOUS URINARY TRACT TUMORS IN RODENTS. DATA TO SUPPORT THESE OBSERVATIONS CAN BE DERIVED FROM LARGE HISTORICAL DATABASES SUCH AS THE TOXICOLOGY DATA MANAGEMENT SYSTEM, MAINTAINED BY NATIONAL TOXICOLOGY PROGRAM. 2002 17 6748 18 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS. 2013 18 5295 25 PROTECTIVE POTENTIAL OF THYMOQUINONE AGAINST CADMIUM, ARSENIC, AND LEAD TOXICITY: A SHORT REVIEW WITH EMPHASIS ON OXIDATIVE PATHWAYS. HEAVY METALS ARE AMONG THE MOST IMPORTANT ENVIRONMENTAL POLLUTIONS USED IN VARIOUS INDUSTRIES. THEIR EXTENSIVE USE HAS INCREASED HUMAN SUSCEPTIBILITY TO DIFFERENT CHRONIC DISEASES. TOXIC METAL EXPOSURE, ESPECIALLY CADMIUM, ARSENIC, AND LEAD, CAUSES OXIDATIVE DAMAGES, MITOCHONDRIAL DYSFUNCTION, AND GENETIC AND EPIGENETIC MODIFICATIONS. MEANWHILE, THYMOQUINONE (TQ) IS AN EFFECTIVE COMPONENT OF NIGELLA SATIVA OIL THAT PLAYS AN IMPORTANT ROLE IN PREVENTING THE DESTRUCTIVE EFFECTS OF HEAVY METALS. THE PRESENT REVIEW DISCUSSES HOW TQ CAN PROTECT VARIOUS TISSUES AGAINST OXIDATIVE DAMAGE OF HEAVY METALS. THIS REVIEW IS BASED ON THE RESEARCH REPORTED ABOUT THE PROTECTIVE EFFECTS OF TQ IN THE TOXICITY OF HEAVY METALS, APPROXIMATELY THE LAST 10 YEARS (2010-2021). SCIENTIFIC DATABASES, INCLUDING SCOPUS, WEB OF SCIENCE, AND PUBMED, WERE SEARCHED USING THE FOLLOWING KEYWORDS EITHER ALONE OR IN COMBINATION: CADMIUM, ARSENIC, LEAD, TQ, AND OXIDATIVE STRESS. TQ, AS A POTENT ANTIOXIDANT, CAN DISTRIBUTE TO CELLULAR COMPARTMENTS AND PREVENT OXIDATIVE DAMAGE OF TOXIC METALS. HOWEVER, DEPENDING ON THE TYPE OF TOXIC METAL AND THE CARRIER SYSTEM USED TO RELEASE TQ IN BIOLOGICAL SYSTEMS, ITS THERAPEUTIC DOSAGE RANGE MAY BE VARIED. 2023 19 2838 24 FORMALDEHYDE CARCINOGENICITY RESEARCH: 30 YEARS AND COUNTING FOR MODE OF ACTION, EPIDEMIOLOGY, AND CANCER RISK ASSESSMENT. FORMALDEHYDE IS A WIDELY USED HIGH PRODUCTION CHEMICAL THAT IS ALSO RELEASED AS A BYPRODUCT OF COMBUSTION, OFF-GASSING OF VARIOUS BUILDING PRODUCTS, AND AS A FIXATIVE FOR PATHOLOGISTS AND EMBALMERS. WHAT IS NOT OFTEN REALIZED IS THAT FORMALDEHYDE IS ALSO PRODUCED AS A NORMAL PHYSIOLOGIC CHEMICAL IN ALL LIVING CELLS. IN 1980, CHRONIC INHALATION OF HIGH CONCENTRATIONS OF FORMALDEHYDE WAS SHOWN TO BE CARCINOGENIC, INDUCING A HIGH INCIDENCE OF NASAL SQUAMOUS CELL CARCINOMAS IN RATS. SOME EPIDEMIOLOGIC STUDIES HAVE ALSO FOUND INCREASED NUMBERS OF NASOPHARYNGEAL CARCINOMA AND LEUKEMIA IN HUMANS EXPOSED TO FORMALDEHYDE THAT RESULTED IN FORMALDEHYDE BEING CONSIDERED A KNOWN HUMAN CARCINOGEN. THIS ARTICLE REVIEWS THE DATA FOR RODENT AND HUMAN CARCINOGENICITY, EARLY MODE OF ACTION STUDIES, MORE RECENT MOLECULAR STUDIES OF BOTH ENDOGENOUS AND EXOGENOUS DNA ADDUCTS, AND EPIGENETIC STUDIES. IT GOES ON TO DEMONSTRATE THE POWER OF THESE RESEARCH STUDIES TO PROVIDE CRITICAL DATA TO IMPROVE OUR ABILITY TO DEVELOP SCIENCE-BASED CANCER RISK ASSESSMENTS, INSTEAD OF DEFAULT APPROACHES. THE COMPLEXITY OF CONSTANT PHYSIOLOGIC EXPOSURE TO A KNOWN CARCINOGEN REQUIRES THAT NEW WAYS OF THINKING BE INCORPORATED INTO DETERMINATIONS OF CANCER RISK ASSESSMENT FOR FORMALDEHYDE, OTHER ENDOGENOUS CARCINOGENS, AND THE ROLE OF BACKGROUND ENDOGENOUS DNA DAMAGE AND MUTAGENESIS. 2013 20 2961 27 GENETIC AND EPIGENETIC MECHANISMS IN METAL CARCINOGENESIS AND COCARCINOGENESIS: NICKEL, ARSENIC, AND CHROMIUM. CHRONIC EXPOSURE TO NICKEL(II), CHROMIUM(VI), OR INORGANIC ARSENIC (IAS) HAS LONG BEEN KNOWN TO INCREASE CANCER INCIDENCE AMONG AFFECTED INDIVIDUALS. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND THAT CARCINOGENIC RISKS ASSOCIATED WITH CHROMATE AND IAS EXPOSURES WERE SUBSTANTIALLY HIGHER THAN PREVIOUSLY THOUGHT, WHICH LED TO MAJOR REVISIONS OF THE FEDERAL STANDARDS REGULATING AMBIENT AND DRINKING WATER LEVELS. GENOTOXIC EFFECTS OF CR(VI) AND IAS ARE STRONGLY INFLUENCED BY THEIR INTRACELLULAR METABOLISM, WHICH CREATES SEVERAL REACTIVE INTERMEDIATES AND BYPRODUCTS. TOXIC METALS ARE CAPABLE OF POTENT AND SURPRISINGLY SELECTIVE ACTIVATION OF STRESS-SIGNALING PATHWAYS, WHICH ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF HUMAN CANCERS. DEPENDING ON THE METAL, ASCORBATE (VITAMIN C) HAS BEEN FOUND TO ACT EITHER AS A STRONG ENHANCER OR SUPPRESSOR OF TOXIC RESPONSES IN HUMAN CELLS. IN ADDITION TO GENETIC DAMAGE VIA BOTH OXIDATIVE AND NONOXIDATIVE (DNA ADDUCTS) MECHANISMS, METALS CAN ALSO CAUSE SIGNIFICANT CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS, LEADING TO EPIGENETIC SILENCING OR REACTIVATION OF GENE EXPRESSION. IN VITRO GENOTOXICITY EXPERIMENTS AND RECENT ANIMAL CARCINOGENICITY STUDIES PROVIDED STRONG SUPPORT FOR THE IDEA THAT METALS CAN ACT AS COCARCINOGENS IN COMBINATION WITH NONMETAL CARCINOGENS. COCARCINOGENIC AND COMUTAGENIC EFFECTS OF METALS ARE LIKELY TO STEM FROM THEIR ABILITY TO INTERFERE WITH DNA REPAIR PROCESSES. OVERALL, METAL CARCINOGENESIS APPEARS TO REQUIRE THE FORMATION OF SPECIFIC METAL COMPLEXES, CHROMOSOMAL DAMAGE, AND ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS PROMOTING SURVIVAL AND EXPANSION OF GENETICALLY/EPIGENETICALLY ALTERED CELLS. 2008