1 6296 191 THE PROSPECTS FOR A SIMPLIFIED AND INTERNATIONALLY HARMONIZED APPROACH TO THE DETECTION OF POSSIBLE HUMAN CARCINOGENS AND MUTAGENS. IT IS PROPOSED THAT THE MANY SETS OF REGULATORY GUIDELINES FOR THE ASSESSMENT OF CHEMICAL CARCINOGENICITY AND MUTAGENICITY SHOULD BE SIMPLIFIED AND HARMONIZED IN LIGHT OF CURRENT EXPERIMENTAL DATA. DATA ARE DISCUSSED WHICH ILLUSTRATE THAT AN ABSOLUTE DISTINCTION WOULD BE DRAWN BETWEEN ASSAYS CONDUCTED IN VITRO FROM THOSE IN VIVO, AND THAT THE GENOTOXICITY OF A CHEMICAL CAN BE ADEQUATELY DEFINED USING A COMBINATION OF THE SALMONELLA MUTATION ASSAY AND ONE FOR THE ASSESSMENT OF CHROMOSOME ABERRATIONS IN VITRO. IT IS SPECIFICALLY RECOMMENDED THAT ONCE A CHEMICAL HAS SHOWN A CLEAR POSITIVE RESPONSE IN VITRO, FURTHER SHORT-TERM ASSAYS SHOULD BE CONDUCTED IN VIVO; THIS AVOIDS CONSIDERING THE 'WEIGHT OF EVIDENCE' OF IN VITRO DATA, THE DANGERS OF WHICH ARE ILLUSTRATED. IT HAS NOW BEEN UNEQUIVOCALLY ESTABLISHED THAT NOT ALL IN VITRO GENOTOXINS PROVE CARCINOGENIC TO MAMMALS. IT IS THEREFORE RECOMMENDED THAT ALL NEW IN VITRO GENOTOXINS SHOULD BE ASSESSED IN VIVO USING THE MOUSE BONE MARROW MICRONUCLEUS ASSAY, AND IF A NEGATIVE RESPONSE IS OBSERVED, A LIVER GENOTOXICITY TEST. AT PRESENT AN ASSAY FOR THE INDUCTION OF UNSCHEDULED DNA SYNTHESIS (UDS) IN THE LIVER IS THE MOST WELL DEVELOPED FOR THIS PURPOSE. CURRENT DATA INDICATE THAT AN IN VITRO GENOTOXIN FOUND TO BE INACTIVE IN THESE TWO IN VIVO ASSAYS WILL BE NEITHER CARCINOGENIC NOR MUTAGENIC TO THE GERM CELLS OF MAMMALS. EQUALLY, GENOTOXICITY PRODUCED IN MAMMALS INDICATES A CARCINOGENIC AND MUTAGENIC POTENTIAL WHICH CAN USUALLY ONLY BE COUNTERED BY APPROPRIATE CHRONIC BIOASSAYS. THE USE OF SHORT-TERM IN VIVO ASSAYS IN THIS CRITICAL ROLE REQUIRES ATTENTION TO THE SELECTION OF APPROPRIATE DOSE-LEVELS AND ROUTES OF EXPOSURE - THESE ISSUES ARE DISCUSSED. THE ABOVE TESTING STRATEGY WILL NOT DETECT CERTAIN ANIMAL CARCINOGENS, SOME OF WHICH ARE SPECIFICALLY DISCUSSED. THESE CARCINOGENS HAVE BEEN VARIOUSLY REFERRED TO IN THE LITERATURE AS EPIGENETIC/NON-GENOTOXIC/HORMONAL/TOXIC/AMBIGUOUS OR AMBIVALENT CARCINOGENS. IT IS SUGGESTED THAT THEY PRESENT A MINOR POTENTIAL HAZARD TO MAN WHEN COMPARED WITH THAT OF GENOTOXIC CARCINOGENS AND THAT THEIR SHORT-TERM DETECTION CAN ONLY BE ACHIEVED BY THE DEVELOPMENT OF NEW WHOLE MAMMAL ASSAYS EMPLOYING NON-GENETIC ENDPOINTS. THIS IS IN CONTRAST TO THE PRESENT TENDENCY TO EMPLOY ADDITIONAL GENOTOXICITY ASSAYS FOR THEIR DETECTION IN THE UNJUSTIFIED BELIEF THAT THEY POSSESS AN EXQUISITE SPECIFICITY OF GENOTOXIC ACTION. THIS ARTICLE REPRESENTS A PERSONAL VIEW, BUT THE TESTING STRATEGY PROPOSED IS BASED TO A LARGE EXTENT ON THE ORIGINAL THREE-TIER APPROACH OF BRIDGES.(ABSTRACT TRUNCATED AT 400 WORDS) 1986 2 1707 34 DYSBIOTIC 1-CARBON METABOLISM IN CARDIAC MUSCLE REMODELING. UNLESS THERE IS A GENETIC DEFECT/MUTATION/DELETION IN A GENE, THE CAUSATION OF A GIVEN DISEASE IS CHRONIC DYSREGULATION OF GUT METABOLISM. MOST OF THE TIME, IF NOT ALWAYS, STARTS WITHIN THE GUT; THAT IS WHAT WE EAT. RECENT RESEARCH SHOWS THAT THE IMBALANCE BETWEEN GOOD VERSUS BAD MICROBIAL POPULATION, ESPECIALLY IN THE GUT, CAUSES SYSTEMIC DISEASES. THUS, AN APPROPRIATE BALANCE OF THE GUT MICROBIOTA (EUBIOSIS OVER DYSBIOSIS) NEEDS TO BE MAINTAINED FOR NORMAL HEALTH (VEERANKI AND TYAGI, 2017, JOURNAL OF CELLULAR PHYSIOLOGY, 232, 2929-2930). HOWEVER, DURING VARIOUS DISEASES SUCH AS METABOLIC SYNDROME, INFLAMMATORY BOWEL DISEASE, DIABETES, OBESITY, AND HYPERTENSION THE DYSBIOTIC GUT ENVIRONMENT TENDS TO PREVAIL. OUR RESEARCH FOCUSES ON HOMOCYSTEINE (HCY) METABOLISM THAT OCCUPIES A CENTER-STAGE IN MANY BIOCHEMICALLY RELEVANT EPIGENETIC MECHANISMS. FOR EXAMPLE, DYSBIOTIC BACTERIA METHYLATE PROMOTERS TO INHIBIT GENE ACTIVITIES. INTERESTINGLY, THE PRODUCT OF THE 1-CARBON METABOLISM IS HCY, UNEQUIVOCALLY. EMERGING STUDIES SHOW THAT HOST RESISTANCE TO VARIOUS ANTIBIOTICS OCCURS DUE TO INVERTON PROMOTER INHIBITION, PRESUMABLY BECAUSE OF PROMOTER METHYLATION. THIS RESULTS FROM MODIFICATION OF HOST PROMOTERS BY BACTERIAL PRODUCTS LEADING TO LOSS OF HOST'S ABILITY TO DRUG COMPATIBILITY AND SYSTEM SENSITIVITY. IN THIS STUDY, WE FOCUS ON THE ROLE OF HIGH METHIONINE DIET (HMD), AN INGREDIENT RICH IN RED MEAT AND MEASURE THE EFFECTS OF A PROBIOTIC ON CARDIAC MUSCLE REMODELING AND ITS FUNCTIONS. WE EMPLOYED WILD TYPE (WT) AND CYSTATHIONINE BETA-SYNTHASE HETEROZYGOTE KNOCKOUT (CBS(+/-) ) MICE WITH AND WITHOUT HMD AND WITH AND WITHOUT A PROBIOTIC; PB (LACTOBACILLUS) IN DRINKING WATER FOR 16 WEEKS. RESULTS INDICATE THAT MATRIX METALLOPROTEINASE-2 (MMP-2) ACTIVITY WAS ROBUST IN CBS(+/-) FED WITH HMD AND THAT IT WAS SUCCESSFULLY ATTENUATED BY THE PB TREATMENT. CARDIOMYOCYTE CONTRACTILITY AND ECHO DATA REVEALED MITIGATION OF THE CARDIAC DYSFUNCTION IN CBS(+/-) + HMD MICE TREATED WITH PB. IN CONCLUSION, OUR DATA SUGGEST THAT PROBIOTICS CAN POTENTIALLY REVERSE THE HCY-MEDITATED CARDIAC DYSFUNCTION. 2020 3 4052 29 MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET) CHARACTERIZED BY GENOME-WIDE METHYLATION ANALYSIS. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET) ARE CONSIDERED TO BE RARE, BENIGN, AND ASSOCIATED WITH CHRONIC EPILEPSY. WE PRESENT THE CASE OF A 28-YEAR-OLD MAN WITH A HISTORY OF EPILEPSY SINCE AGE 12. SURGERY OF AN OCCIPITAL CORTICAL LESION IN 2009 REVEALED A DNET. FIVE YEARS LATER, A RECURRENT TUMOR AT THE EDGE OF THE RESECTION CAVITY WAS REMOVED, AND THE TISSUE UNDERWENT AN INTENSIVE DIAGNOSTIC WORKUP. THE FIRST TUMOR WAS UNEQUIVOCALLY CHARACTERIZED AS A DNET, BUT NEUROPATHOLOGICAL DIAGNOSTICS OF THE RECURRENT TUMOR REVEALED A GLIOBLASTOMA. AFTER 6 MONTHS, ANOTHER RECURRENT TUMOR WAS DETECTED NEXT TO THE LOCATION OF THE ORIGINAL TUMOR, AND THIS WAS ALSO RESECTED. AN ILLUMINA 450 K BEADCHIP METHYLATION ARRAY WAS PERFORMED TO CHARACTERIZE ALL OF THE TUMORS. THE METHYLATION PROFILE OF THESE TUMORS SIGNIFICANTLY DIFFERED FROM OTHER GLIOBLASTOMA AND EPILEPSY-ASSOCIATED TUMOR PROFILES AND REVEALED A DNET-LIKE METHYLATION PROFILE. THUS, MOLECULAR CHARACTERIZATION OF THESE RECURRENT TUMORS SUGGESTS MALIGNANT TRANSFORMATION OF A PREVIOUSLY BENIGN DNET. WE FOUND INCREASED COPY NUMBER CHANGES IN THE RECURRENT DNET TUMORS AFTER MALIGNANT TRANSFORMATION. MODERN HIGH-THROUGHPUT ANALYSIS ADDS ESSENTIAL MOLECULAR INFORMATION IN ADDITION TO STANDARD HISTOPATHOLOGY FOR PROPER IDENTIFICATION OF RARE BRAIN TUMORS THAT PRESENT WITH AN UNUSUAL CLINICAL COURSE. 2016 4 4341 44 MIGRATION TEST OF BISPHENOL A FROM POLYCARBONATE CUPS USING EXCITATION-EMISSION FLUORESCENCE DATA WITH PARALLEL FACTOR ANALYSIS. BISPHENOL A (BPA) IS ONE OF THE MOST LARGELY PRODUCED CHEMICAL IN THE WORLD; IT IS USED TO MAKE PLASTICS AND EPOXY RESINS. THE ENDOCRINE DISRUPTOR POTENTIAL OF BPA IS WELL KNOWN, BUT RECENT RESEARCHES SUGGEST A RELATIONSHIP BETWEEN CHRONIC EXPOSURE TO BPA, GENOTOXIC ACTIVITY AND EPIGENETIC MODIFICATIONS. THE MAIN SOURCE OF EXPOSURE TO BPA INCLUDES FOOD CONTACT MATERIALS (FCM). THUS SIMPLE AND ROBUST TEST METHODS ARE NEEDED TO IMPROVE THE MIGRATION TEST OF BPA. IN THIS WORK, A NON-SEPARATIVE, EASY, FAST AND INEXPENSIVE SPECTROFLUORIMETRIC METHOD BASED ON THE SECOND ORDER CALIBRATION OF EXCITATION-EMISSION FLUORESCENCE MATRICES (EEMS) WAS PROPOSED FOR THE DETERMINATION OF BPA. FOR THE FIRST TIME, MOLECULAR FLUORESCENCE WAS USED TO IDENTIFY UNEQUIVOCALLY AND QUANTIFY BPA. TRILINEARITY OF THE DATA TENSOR GUARANTEES THE UNIQUENESS OF THE SOLUTION OBTAINED THROUGH PARALLEL FACTOR ANALYSIS (PARAFAC), SO ONE FACTOR OF THE DECOMPOSITION MATCHES UP WITH BPA EVEN IF OTHER FLUOROPHORES ARE IN THE TEST SAMPLE. THE EFFECT OF FOUR EXPERIMENTAL FACTORS OF THE PROCEDURE ON THE FIGURES OF MERIT AND THE UNEQUIVOCALLY IDENTIFICATION WAS INVESTIGATED BY MEANS OF A D-OPTIMAL DESIGN AND PARAFAC CALIBRATION. THE METHOD IS LINEAR AND ACCURATE IN THE RANGE 0-720MICROGL(-1). THE DECISION LIMIT CCALPHA AND DETECTION CAPABILITY CCBETA ARE 6.63MICROGL(-1) AND 18.85MICROGL(-1) RESPECTIVELY (WITH PROBABILITIES OF FALSE POSITIVE AND FALSE NEGATIVE FIXED AT 0.05). FINALLY THE PROPOSED METHOD WAS APPLIED TO CARRY OUT A MIGRATION TEST FROM TWO POLYCARBONATE CUPS, USING 3% (W/V) ACETIC ACID IN AQUEOUS SOLUTION AS FOOD SIMULANT. THE MIGRATED AMOUNT OF BPA WAS FOUND TO BE 688.7MICROGL(-1) (N=5) FOR THE FIRST CUP AND 710.5MICROGL(-1) (N=4) FOR THE SECOND ONE, ABOVE THE SPECIFIC MIGRATION LIMIT SET BY EFSA (EUROPEAN FOOD SAFETY AUTHORITY). 2017 5 2539 37 EPIGENETICS IN HYPERHOMOCYSTEINEMIC STATES. A SPECIAL FOCUS ON UREMIA. AIM OF THIS ARTICLE IS TO REVIEW THE TOPIC OF EPIGENETIC CONTROL OF GENE EXPRESSION, ESPECIALLY REGARDING DNA METHYLATION, IN CHRONIC KIDNEY DISEASE AND UREMIA. HYPERHOMOCYSTEINEMIA IS CONSIDERED AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ALTHOUGH THE MOST RECENT INTERVENTION STUDIES UTILIZING FOLIC ACID ARE NEGATIVE. THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH IS ITSELF CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. THE EXTENT OF METHYLATION INHIBITION OF EACH INDIVIDUAL METHYLTRANSFERASE DEPENDS ON THE METHYL DONOR S-ADENOSYLMETHIONINE (ADOMET) AVAILABILITY, ON THE [ADOMET]/[ADOHCY] RATIO, AND ON THE INDIVIDUAL KM VALUE FOR ADOMET AND KI FOR ADOHCY. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, ALMOST UNEQUIVOCALLY SHOW. IN VIVO, DNA METHYLATION MAY BE ALSO INFLUENCED BY VARIOUS FACTORS IN DIFFERENT TISSUES, FOR EXAMPLE BY RATE OF CELL GROWTH, FOLATE STATUS, ETC. AND IMPORTANTLY INFLAMMATION. IN CHRONIC KIDNEY DISEASE AND IN UREMIA, HYPERHOMOCYSTEINEMIA IS COMMONLY SEEN, AND CAN BE ASSOCIATED WITH GLOBAL DNA HYPOMETHYLATION, AND WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION. THIS ALTERATION IS SUSCEPTIBLE OF REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. IF THIS ABNORMALITY WILL TRANSLATE ITSELF IN ALTERATIONS OF EXPRESSION OF GENES RELEVANT TO THE PATHOGENESIS OF THIS DISEASE STILL REMAINS TO BE ESTABLISHED. IN ADDITION, THESE RESULTS ESTABLISH A LINK BETWEEN THE EPIGENETIC CONTROL OF GENE EXPRESSION AND XENOBIOTIC INFLUENCES, SUCH AS FOLATE THERAPY. 2009 6 653 34 BISPHENOL A, HYPERTENSION, AND CARDIOVASCULAR DISEASES: EPIDEMIOLOGICAL, LABORATORY, AND CLINICAL TRIAL EVIDENCE. BISPHENOL A (BPA) EXPOSURE HAS BECOME ONE OF THE MOST COMMON ENVIRONMENTAL CHEMICAL EXPOSURES IN HUMANS. THERE IS GROWING EVIDENCE REGARDING AN ASSOCIATION BETWEEN BPA EXPOSURE, HYPERTENSION, AND CARDIOVASCULAR DISEASES (CVD). IF BPA EXPOSURE IS INDEED ASSOCIATED WITH RAISED BLOOD PRESSURE AND CVD, IT WOULD BE A MAJOR PUBLIC HEALTH PROBLEM. THEREFORE, WE REVIEWED THE EPIDEMIOLOGICAL, LABORATORY, AND CLINICAL TRIAL EVIDENCE FOR AN ASSOCIATION BETWEEN BPA EXPOSURE, CVD, AND HYPERTENSION, AND DISCUSSED THE POSSIBLE MECHANISMS IN THIS ARTICLE. CROSS-SECTIONAL STUDIES IN VARIOUS ETHNICITIES SUGGESTED A POSSIBLE ASSOCIATION BETWEEN BPA EXPOSURE AND HYPERTENSION; THIS ASSOCIATION WAS SUPPORTED BY A PANEL STUDY AND A RANDOMIZED CLINICAL TRIAL. DESPITE THE DISCORDANCE AMONG CROSS-SECTIONAL STUDIES ABOUT AN ASSOCIATION BETWEEN BPA EXPOSURE AND CVD, A LONGITUDINAL STUDY SHOWS THAT BPA EXPOSURE IS A RISK FACTOR FOR CVD. THE EFFECTS OF BPA EXPOSURE SUCH AS ENDOCRINAL DISTURBANCE, INDUCTION OF OXIDATIVE STRESS AND INFLAMMATION, EPIGENETIC CHANGE, AND LINKS WITH OTHER CHRONIC DISEASES MAY HIGHLIGHT A POSSIBLE MECHANISM BETWEEN BPA EXPOSURE, CVD, AND HYPERTENSION. TO CLARIFY THE CAUSAL RELATIONSHIP, WELL-DESIGNED STUDIES ARE NEEDED IN THE FUTURE. 2016 7 3438 43 HYPERHOMOCYSTEINEMIA IN UREMIA--A RED FLAG IN A DISRUPTED CIRCUIT. HYPERHOMOCYSTEINEMIA IS AN INDEPENDENT CARDIOVASCULAR RISK FACTOR, ACCORDING TO MOST OBSERVATIONAL STUDIES AND TO STUDIES USING THE MENDELIAN RANDOMIZATION APPROACH, UTILIZING THE COMMON POLYMORPHISM C677T OF METHYLENE TETRAHYDROFOLATE REDUCTASE. IN CONTRAST, THE MOST RECENT SECONDARY PREVENTIVE INTERVENTION STUDIES, IN THE GENERAL POPULATION AND IN CHRONIC KIDNEY DISEASE (CKD) AND UREMIA, WHICH ARE ALL NEGATIVE (WITH THE POSSIBLE NOTABLE EXCEPTION OF STROKE), POINT TO OTHER DIRECTIONS. HOWEVER, ALL TRIALS USE FOLIC ACID IN VARIOUS DOSAGES AS A MEANS TO REDUCE HOMOCYSTEINE LEVELS, WITH THE ADDITION OF VITAMINS B6 AND B12. IT IS POSSIBLE THAT FOLIC ACID HAS NEGATIVE EFFECTS, WHICH OFFSET THE BENEFITS; ALTERNATIVELY, HOMOCYSTEINE COULD BE AN INNOCENT BY-STANDER, OR A SURROGATE OF THE REAL CULPRIT. THE LATTER POSSIBILITY LEADS US TO THE SEARCH FOR POTENTIAL CANDIDATES. FIRST, THE ACCUMULATION OF HOMOCYSTEINE IN BLOOD LEADS TO AN INTRACELLULAR INCREASE OF S-ADENOSYLHOMOCYSTEINE (ADOHCY), A POWERFUL COMPETITIVE METHYLTRANSFERASE INHIBITOR, WHICH BY ITSELF IS CONSIDERED A PREDICTOR OF CARDIOVASCULAR EVENTS. DNA METHYLTRANSFERASES ARE AMONG THE PRINCIPAL TARGETS OF HYPERHOMOCYSTEINEMIA, AS STUDIES IN SEVERAL CELL CULTURE AND ANIMAL MODELS, AS WELL AS IN HUMANS, SHOW. IN CKD AND IN UREMIA, HYPERHOMOCYSTEINEMIA AND HIGH INTRACELLULAR ADOHCY ARE PRESENT AND ARE ASSOCIATED WITH ABNORMAL ALLELIC EXPRESSION OF GENES REGULATED THROUGH METHYLATION, SUCH AS IMPRINTED GENES, AND PSEUDOAUTOSOMAL GENES, THUS POINTING TO EPIGENETIC DYSREGULATION. THESE ALTERATIONS ARE SUSCEPTIBLE TO REVERSAL UPON HOMOCYSTEINE-LOWERING THERAPY OBTAINED THROUGH FOLATE ADMINISTRATION. SECOND, IT HAS TO BE KEPT IN MIND THAT HOMOCYSTEINE IS MAINLY PROTEIN-BOUND, AND ITS EFFECTS COULD BE LINKED THEREFORE TO PROTEIN HOMOCYSTEINYLATION. IN THIS RESPECT, INCREASED PROTEIN HOMOCYSTEINYLATION HAS BEEN FOUND IN UREMIA, LEADING TO ALTERATIONS IN PROTEIN FUNCTION. 2009 8 108 31 A REVIEW OF THE PROTECTIVE EFFECT OF MELATONIN IN PESTICIDE-INDUCED TOXICITY. PESTICIDES ARE AMONG THE MOST IMPORTANT CHEMICALS USED IN AGRICULTURE SECTOR. HOWEVER, THEIR EXTENSIVE USE HAS POLLUTED THE ENVIRONMENT AND INCREASED HUMAN VULNERABILITY TO VARIOUS CHRONIC DISEASES. PESTICIDE EXPOSURE CAUSES GENETIC AND EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS. AREAS COVERED: THIS REVIEW IS BASED ON THE LITERATURE STUDIES CURRENTLY REPORTED ON PESTICIDE-INDUCED TOXICITY AND THE PROTECTIVE ROLE OF MELATONIN. SCIENTIFIC DATABASES SUCH AS PUBMED, SCOPUS AND WEB OF SCIENCE WERE SEARCHED USING KEYWORDS 'PESTICIDE' AND 'MELATONIN' UP TO JANUARY 2016. FULL LENGTH ARTICLES RELATED TO ANIMAL AND HUMAN EXPOSURE WERE RETRIEVED. A TOTAL NUMBER OF 181 RECORDS WERE OBTAINED, AND AFTER EXCLUDING THE DUPLICATES, 97 PAPERS WERE FURTHER SCREENED ON THE BASIS OF RELEVANCE TO THE TOPIC. EXPERT OPINION: MELATONIN AS A BROAD-SPECTRUM ANTIOXIDANT IS ABLE TO PENETRATE CELLULAR COMPARTMENTS SPECIFICALLY THE MITOCHONDRIA. IT IS A POTENT FREE RADICAL SCAVENGER WITH LOW TOXICITY AND DESIRABLE SOLUBILITY IN ORGANIC AND AQUEOUS PHASES. WE ARE OF THE OPINION THAT MELATONIN IS A PROMISING AGENT IN MINIMIZING ORGAN INJURIES INDUCED BY PESTICIDES. 2017 9 1140 25 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT. 2020 10 4182 34 MESOAMERICAN NEPHROPATHY (MEN): WHAT WE KNOW SO FAR. IN 2002, A REPORT FROM EL SALVADOR DESCRIBED A HIGH INCIDENCE OF CHRONIC KIDNEY DISEASE (CKD) OF UNKNOWN CAUSE, MOSTLY IN YOUNG MALES FROM SPECIFIC COASTAL AREAS. SIMILAR SITUATIONS WERE OBSERVED ALONG THE PACIFIC OCEAN COASTLINE OF OTHER CENTRAL AMERICAN COUNTRIES AND SOUTHERN MEXICO (MESOAMERICA). THIS NEW FORM OF CKD HAS BEEN DENOMINATED MESOAMERICAN ENDEMIC NEPHROPATHY (MEN). THE TYPICAL PRESENTATION OF MEN IS A YOUNG MALE FROM AN ENDEMIC AREA WITH A FAMILY HISTORY OF CKD, LOW EGFR, HIGH SERUM CREATININE, LOW LEVEL OF ALBUMINURIA, HYPOKALEMIA, HYPERURICEMIA, AND URINE URATE CRYSTALS. KIDNEY BIOPSY DEMONSTRATING TUBULOINTERSTITIAL NEPHRITIS REMAINS THE GOLD STANDARD FOR DIAGNOSIS BUT IS AVAILABLE ONLY FOR A MINORITY. COMMONLY PROPOSED CAUSES INCLUDE THERMAL STRESS/DEHYDRATION AND/OR EXPOSURE TO ENVIRONMENTAL POLLUTANTS. HOWEVER, LIKELY, A THIRD FACTOR, WHICH COULD BE GENETIC OR EPIGENETIC, COULD CONTRIBUTE TO THE CAUSE AND DEVELOPMENT OF THE DISEASE, ALONG WITH SOCIAL DETERMINANTS. CURRENTLY, PREVENTIVE MEASURES FOCUS ON MINIMIZING WORKERS EXPOSURE TO THERMAL STRESS/DEHYDRATION. THERE ARE MANY RESEARCH OPPORTUNITIES AND PRIORITIES SHOULD INCLUDE CLINICAL TRIALS TO EVALUATE THE EFFICACY AND SAFETY OF THE CURRENT TREATMENT PROTOCOLS, ALONG WITH ETIOLOGICAL AND GENETIC STUDIES, AND THE DEVELOPMENT OF KIDNEY DISEASE DATA SYSTEMS. ALTHOUGH THERE IS SCANT AND CONTROVERSIAL LITERATURE WITH REGARD S TO THE ETIOLOGY, DIAGNOSIS AND MANAGEMENT OF THE DISEASE, OUR AIM IS TO PROVIDE THE READER A VISION OF THE DISEASE BASED ON OUR EXPERIENCE. 2020 11 5113 30 POPULATION-LEVEL IMPACTS OF PESTICIDE-INDUCED CHRONIC EFFECTS ON INDIVIDUALS DEPEND MORE ON ECOLOGY THAN TOXICOLOGY. THE CURRENT METHOD FOR ASSESSING LONG-TERM RISK OF PESTICIDES TO MAMMALS IN THE EU IS BASED ON THE INDIVIDUAL RATHER THAN THE POPULATION-LEVEL AND LACKS ECOLOGICAL REALISM. HENCE THERE IS LITTLE POSSIBILITY FOR REGULATORY AUTHORITIES TO INCREASE ECOLOGICAL REALISM AND UNDERSTANDING OF RISKS AT THE POPULATION-LEVEL. HERE WE DEMONSTRATE HOW, USING ABM MODELLING, ASSESSMENTS AT THE POPULATION-LEVEL CAN BE OBTAINED EVEN FOR A PESTICIDE WITH COMPLEX LONG-TERM EFFECTS SUCH AS EPIGENETIC TRANSMISSION OF REPRODUCTIVE DEPRESSION. BY OBJECTIVELY FITTING NONLINEAR MODELS TO THE SIMULATION OUTPUTS IT WAS POSSIBLE TO COMPARE POPULATION DEPRESSION AND RECOVERY RATES FOR A RANGE OF SCENARIOS IN WHICH TOXICITY AND EXPOSURE FACTORS WERE VARIED. THE SYSTEM WAS DIFFERENTIALLY SENSITIVE TO THE VARIOUS FACTORS, BUT VOLE ECOLOGY AND BEHAVIOUR WERE AT LEAST AS IMPORTANT PREDICTORS OF POPULATION-LEVEL EFFECTS AS TOXICOLOGY. THIS EMPHASISES THE NEED FOR GREATER FOCUS ON ANIMAL ECOLOGY IN RISK ASSESSMENTS. 2009 12 3901 39 LEAD (PB) AND NEURODEVELOPMENT: A REVIEW ON EXPOSURE AND BIOMARKERS OF EFFECT (BDNF, HDL) AND SUSCEPTIBILITY. LEAD (PB) IS A UBIQUITOUS ENVIRONMENTAL POLLUTANT AND A POTENT TOXIC COMPOUND. HUMANS ARE EXPOSED TO PB THROUGH INHALATION, INGESTION, AND SKIN CONTACT VIA FOOD, WATER, TOBACCO SMOKE, AIR, DUST, AND SOIL. PB ACCUMULATES IN BONES, BRAIN, LIVER AND KIDNEY. FETAL EXPOSURE OCCURS VIA TRANSPLACENTAL TRANSMISSION. THE MOST CRITICAL HEALTH EFFECTS ARE DEVELOPMENTAL NEUROTOXICITY IN INFANTS AND CARDIOVASCULAR EFFECTS AND NEPHROTOXICITY IN ADULTS. PB EXPOSURE HAS BEEN STEADILY DECREASING OVER THE PAST DECADES, BUT THERE ARE FEW RECENT EXPOSURE DATA FROM THE GENERAL EUROPEAN POPULATION; MOREOVER, NO SAFE PB LIMIT HAS BEEN SET. SENSITIVE BIOMARKERS OF EXPOSURE, EFFECT AND SUSCEPTIBILITY, THAT RELIABLY AND TIMELY INDICATE PB-ASSOCIATED TOXICITY ARE REQUIRED TO ASSESS HUMAN EXPOSURE-HEALTH RELATIONSHIPS IN A SITUATION OF LOW TO MODERATE EXPOSURE. THEREFORE, A SYSTEMATIC LITERATURE REVIEW BASED ON PUBMED ENTRIES PUBLISHED BEFORE JULY 2019 THAT ADDRESSED PB EXPOSURE AND BIOMARKERS OF EFFECT AND SUSCEPTIBILITY, NEURODEVELOPMENTAL TOXICITY, EPIGENETIC MODIFICATIONS, AND TRANSCRIPTOMICS WAS CONDUCTED. FINALLY INCLUDED WERE 58 ORIGINAL PAPERS ON PB EXPOSURE AND 17 STUDIES ON BIOMARKERS. THE BIOMARKERS THAT ARE LINKED TO PB EXPOSURE AND NEURODEVELOPMENT WERE GROUPED INTO EFFECT BIOMARKERS (SERUM BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND SERUM/SALIVA CORTISOL), SUSCEPTIBILITY MARKERS (EPIGENETIC MARKERS AND GENE SEQUENCE VARIANTS) AND OTHER BIOMARKERS (SERUM HIGH-DENSITY LIPOPROTEIN (HDL), MATERNAL IRON (FE) AND CALCIUM (CA) STATUS). SERUM BDNF AND PLASMA HDL ARE POTENTIAL CANDIDATES TO BE FURTHER VALIDATED AS EFFECT MARKERS FOR ROUTINE USE IN HBM STUDIES OF PB, COMPLEMENTED BY MARKERS OF FE AND CA STATUS TO ALSO ADDRESS NUTRITIONAL INTERACTIONS RELATED TO NEURODEVELOPMENTAL DISORDERS. FOR SEVERAL MARKERS, A CAUSAL RELATIONSHIP WITH PB-INDUCED NEURODEVELOPMENTAL TOXICITY IS LIKELY. RESULTS ON BDNF ARE DISCUSSED IN RELATION TO ADVERSE OUTCOME PATHWAY (AOP) 13 ("CHRONIC BINDING OF ANTAGONIST TO N-METHYL-D-ASPARTATE RECEPTORS (NMDARS) DURING BRAIN DEVELOPMENT INDUCES IMPAIRMENT OF LEARNING AND MEMORY ABILITIES") OF THE AOP-WIKI. FURTHER STUDIES ARE NEEDED TO VALIDATE SENSITIVE, RELIABLE, AND TIMELY EFFECT BIOMARKERS, ESPECIALLY FOR LOW TO MODERATE PB EXPOSURE SCENARIOS. 2021 13 537 33 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020 14 6384 41 THE ROLE OF POLYCARBONATE MONOMER BISPHENOL-A IN INSULIN RESISTANCE. BISPHENOL A (BPA) IS A SYNTHETIC UNIT OF POLYCARBONATE POLYMERS AND EPOXY RESINS, THE TYPES OF PLASTICS THAT COULD BE FOUND IN ESSENTIALLY EVERY HUMAN POPULATION AND INCORPORATED INTO ALMOST EVERY ASPECT OF THE MODERN HUMAN SOCIETY. BPA POLYMERS APPEAR IN A WIDE RANGE OF PRODUCTS, FROM LIQUID STORAGES (PLASTIC BOTTLES, CAN AND GLASS LININGS, WATER PIPES AND TANKS) AND FOOD STORAGES (PLASTICS WRAPS AND CONTAINERS), TO MEDICAL AND DENTAL DEVICES. BPA POLYMERS COULD BE HYDROLYZED SPONTANEOUSLY OR IN A PHOTO- OR TEMPERATURE-CATALYZED PROCESS, PROVIDING WIDESPREAD ENVIRONMENTAL DISTRIBUTION AND CHRONIC EXPOSURE TO THE BPA MONOMER IN CONTEMPORARY HUMAN POPULATIONS. BISPHENOL A IS ALSO A XENOESTROGEN, AN ENDOCRINE-DISRUPTING CHEMICAL (EDC) THAT INTERFERES WITH THE ENDOCRINE SYSTEM MIMICKING THE EFFECTS OF AN ESTROGEN AND COULD POTENTIALLY KEEP OUR ENDOCRINE SYSTEM IN A CONSTANT PERTURBATION THAT PARALLELS ENDOCRINE DISRUPTION ARISING DURING PREGNANCY, SUCH AS INSULIN RESISTANCE (IR). GESTATIONAL INSULIN RESISTANCE REPRESENTS A NATURAL BIOLOGICAL PHENOMENON OF HIGHER INSULIN RESISTANCE IN PERIPHERAL TISSUES OF THE PREGNANT FEMALES, WHEN NUTRIENTS ARE INCREASINGLY BEING DIRECTED TO THE EMBRYO INSTEAD OF BEING STORED IN PERIPHERAL TISSUES. GESTATIONAL DIABETES MELLITUS MAY APPEAR IN HEALTHY NON-DIABETIC FEMALES, DUE TO GESTATIONAL INSULIN RESISTANCE THAT LEADS TO INCREASED BLOOD SUGAR LEVELS AND HYPERINSULINEMIA (INCREASED INSULIN PRODUCTION FROM THE PANCREATIC BETA CELLS). THE HYPOTHESIS STATES THAT UNNOTICED AND CONSTANT EXPOSURE TO THIS ENVIRONMENTAL CHEMICAL MIGHT POTENTIALLY LEAD TO THE FORMATION OF CHRONIC LOW-LEVEL ENDOCRINE DISRUPTIVE STATE THAT RESEMBLES GESTATIONAL INSULIN RESISTANCE, WHICH MIGHT CONTRIBUTE TO THE DEVELOPMENT OF DIABETES. THE INCREASING BODY OF EVIDENCE SUPPORTS THE MAJOR PREMISES OF THIS HYPOTHESIS, AS EXEMPLIFIED BY THE NUMEROUS PUBLICATIONS EXAMINING THE ASSOCIATION OF BPA AND INSULIN RESISTANCE, BOTH EPIDEMIOLOGICAL AND MECHANISTIC. HOWEVER, TO WHAT EXTENT BPA MIGHT CONTRIBUTE TO THE DEVELOPMENT OF DIABETES IN THE MODERN SOCIETIES STILL REMAINS UNKNOWN. IN THIS REVIEW, I DISCUSS THE CHEMICAL PROPERTIES OF BPA AND THE SOURCES OF BPA CONTAMINATION FOUND IN THE ENVIRONMENT AND IN HUMAN TISSUES. I PROVIDE AN OVERVIEW OF MECHANISMS FOR THE PROPOSED ROLE OF BISPHENOL A IN INSULIN RESISTANCE AND DIABETES, AS WELL AS OTHER RELATED DISEASES, SUCH AS CARDIOVASCULAR DISEASES. I DESCRIBE THE TRANSMISSION OF BPA EFFECTS TO THE OFFSPRING AND POSTULATE THAT GENDER RELATED DIFFERENCES MIGHT ORIGINATE FROM DIFFERENCES IN LIVER ENZYME LEVELS, SUCH AS UDP-GLUCURONOSYLTRANSFERASE, WHICH IS INVOLVED IN BPA PROCESSING AND ITS ELIMINATION FROM THE ORGANISM. I DISCUSS THE MOLECULAR MECHANISMS OF BPA ACTION THROUGH NUCLEAR AND MEMBRANE-BOUND ER RECEPTORS, NON-MONOTONIC DOSE RESPONSE, EPIGENETIC MODIFICATIONS OF THE DNA AND PROPOSE THAT CHRONIC EXPOSURE TO WEAK BINDERS, SUCH AS BPA, MAY MIMIC THE EFFECTS OF STRONG BINDERS, SUCH AS ESTROGENS. 2017 15 6305 49 THE QUESTION IS WHETHER INTAKE OF FOLIC ACID FROM DIET ALONE DURING PREGNANCY IS SUFFICIENT. PREGNANCY AND FOLIC ACID: PREGNANCY IS THE MOST IMPORTANT PERIOD IN LIFE OF EVERY WOMAN, PARTIALLY FOR THE NUMBER OF PHYSIOLOGICAL ADAPTATIONS SHE IS GOING THROUGH, PARTIALLY FOR THE EXPECTANCE OF NEW LIFE. IN ADDITION, PREGNANCY IS THE "CRITICAL WINDOW" FOR DEVELOPMENT LATER IN CHILDHOOD, AS A PERIOD OF FOETAL PROGRAMMING DURING WHICH NUTRITION PLAYS ONE OF CRUCIAL ROLES. DESPITE THE GENERAL BELIEF THAT NUTRITION THROUGH PREGNANCY IS ADEQUATE AND CHARACTERIZED BY BETTER NUTRITIONAL HABITS, A NUMBER OF STUDIES DO NOT CORROBORATE THIS BELIEF. ROLE OF FOLIC ACID: AN ADEQUATE FOLATE BLOOD LEVEL IS NECESSARY FOR NORMAL CELL GROWTH, SYNTHESIS OF SEVERAL COMPOUNDS INCLUDING DEOXYRIBONUCLEIC ACID AND RIBONUCLEIC ACID, PROPER BRAIN AND NEUROLOGIC FUNCTIONS; IT IS INCLUDED IN THE REGULATION OF HOMOCYSTEINE LEVEL, AND CLOSELY RELATED TO THE VITAMIN B12 METABOLISM. FOLATE DEFICIENCY IN PREGNANCY IS RELATED TO NEURAL TUBE DEFECTS, OTHER NEUROLOGICAL DISORDERS, PRETERM DELIVERY AND LOW BIRTH WEIGHT. FOOD SOURCES: A CORRELATION BETWEEN FOLATE AND THE PREVENTION OF BROAD SPECTRUM OF CHRONIC DISEASES HAS BEEN CONFIRMED. EMERGING EVIDENCE FROM THE EPIGENETIC STUDIES IS NOW BRINGING EVEN MORE LIGHT ON THE LEVEL OF SIGNIFICANCE OF FOLIC ACID. A WIDE RANGE OF PLANT AND ANIMAL FOODS ARE THE NATURAL SOURCES OF FOLATE; LIVER, YEAST, MUSHROOMS, AND GREEN LEAFY VEGETABLES BEING THE MOST SIGNIFICANT. DIFFERENT WAYS OF FOOD PREPARATION INFLUENCE THE FOLATE STABILITY AND ITS BIOAVAILABILITY VARIES FROM 25 TO 50% FROM FOODS, 85% FROM ENRICHED FOODS OR 100% FROM SUPPLEMENTS. CONCLUSION: A GREAT AMOUNT OF SCIENTIFIC RESULTS HAS LED TO OFFICIAL RECOMMENDATIONS FOR FOLIC ACID SUPPLEMENTATION IN PREGNANT WOMEN AS WELL AS IN A NUMBER OF OBLIGATORY OR VOLUNTARY FORTIFICATION PROGRAMMES IN ORDER TO PREVENT THE FOLATE DEFICIENCY ON THE LEVEL OF DIFFERENT POPULATION GROUPS. NEVERTHELESS, THERE MUST BE A CERTAIN LEVEL OF PRECAUTION FOR ELDERLY BECAUSE FOLATE CAN MASK THE VITAMIN B12 DEFICIENCY WITH POSSIBLE FATAL OUTCOMES. 2014 16 2900 39 GENDER BIAS IN THERAPEUTIC EFFORT: FROM RESEARCH TO HEALTH CARE. THERE ARE RELEVANT DIMENSIONS FROM A GENDER PERSPECTIVE RELATED TO THERAPEUTIC EFFORT. TO ILLUSTRATE AND DISCUSS POSSIBLE GENDER BIAS RELATED TO MEDICINES, THROUGH THE CONSUMPTION ANALYSIS IN WOMEN, THE PRESCRIPTION OF BIOLOGICAL DRUGS ACCORDING TO SEX, THE POTENTIAL GENDER INEQUALITY IN ADVERSE DRUG REACTIONS, AND RESEARCH WITH CLINICAL TRIALS, AS WELL AS THE DECISIONS OF INTERNATIONAL INSTITUTIONS IN THE MARKETING OF MEDICINAL PRODUCTS. THERE IS GREATER TENDENCY TO PRESCRIBE PAIN RELIEVERS, REGARDLESS OF PAIN, AND DRUGS FOR LOW INTENSITY DEPRESSIVE SYMPTOMS IN WOMEN THAN IN MEN. THE OPPOSITE OCCURS IN THE PRESCRIPTION OF STATINS AND ADEQUATE DOSES, AND WITH THE GREATER PROBABILITY OF PRESCRIBING ANTI-TUMOR NECROSIS FACTOR IN MEN THAN IN WOMEN WITH ANKYLOSING SPONDYLITIS, DESPITE A SIMILAR DISEASE BURDEN. ADVERSE DRUG REACTIONS ARE OBSERVED MORE FREQUENTLY IN WOMEN THAN IN MEN, WHERE DETERMINANTS SUCH AS BODY WEIGHT ARE HAVING LITTLE INFLUENCE ON THE DOSAGE. IT IS CURRENTLY SCARCELY CONSIDERED IN THE PRESCRIPTION THAT WOMEN HAVE DIFFERENCES IN THE ACTIVITY OF CYTOCHROME CYPP450 ENZYMES, WHICH CAN AFFECT THE LIVER'S METABOLISM RATE. THERE ARE EVEN IMMUNOLOGICAL, GENETIC AND EPIGENETIC EFFECTS (DUE TO HEREDITY AND UNEVEN GENE DOSING LOCATED IN THE X AND Y CHROMOSOMES) THAT CAN INFLUENCE THESE DIFFERENCES BY SEX. FINALLY, THROUGH CASES OF HORMONAL THERAPY CLINICAL TRIALS, A DRUG FOR WOMEN'S INHIBITED SEXUAL DESIRE AND A CONTRACEPTIVE FOR MEN, GENDER BIAS AND STEREOTYPES ARE SHOWN TO INFLUENCE A POTENTIAL GENERATION OF INEQUALITIES, ESPECIALLY IN ADVERSE DRUG REACTIONS TO THE DETRIMENT OF WOMEN. IN CONCLUSION, HEALTH PROFESSIONALS FREQUENTLY ATTRIBUTE PHYSICAL SYMPTOMS TO WOMEN'S EMOTIONALITY, INFLUENCING THEIR GREATER PRESCRIPTION OF SYMPTOMATIC DRUGS. WHETHER THE SAME REASON INFLUENCES THE LOWER PRESCRIPTION OF THERAPEUTIC DRUGS IN WOMEN THAN IN MEN SHOULD BE ANALYZED. THERE ARE BIOLOGICAL DETERMINANTS TO CONSIDER DUE TO THEIR INFLUENCE ON A GREATER PHARMACOLOGICAL TOXICITY IN WOMEN. CLINICAL TRIALS SHOULD IMPROVE ACCORDING TO THE GENDER RECOMMENDATIONS BY THE FOOD AND DRUGS ADMINISTRATION. 2020 17 3452 25 HYPERTENSIVE DISORDERS OF PREGNANCY SHARE COMMON CFDNA METHYLATION PROFILES. HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) CONTRIBUTE SUBSTANTIALLY TO PERINATAL MORBIDITY AND MORTALITY. EPIGENETIC CHANGES POINT TOWARDS CARDIO-METABOLIC DYSREGULATION FOR THESE VASCULAR DISORDERS. IN EARLY PREGNANCY, EPIGENETIC CHANGES USING CELL FREE DNA (CFDNA) ARE LARGELY UNEXPLORED. WE AIMED TO INVESTIGATE THESE IN HDP BETWEEN 11 AND 14 WEEKS OF GESTATION BY ANALYSIS OF CFDNA METHYLATION PROFILES IN PATIENTS WITH HYPERTENSIVE DISORDERS. WE IDENTIFIED PATIENTS WITHOUT CHRONIC HYPERTENSION BUT WITH SUBSEQUENT DEVELOPMENT OF PREECLAMPSIA (PE) (N = 11), WITH CHRONIC HYPERTENSION (HT) BUT WITHOUT PE DEVELOPMENT (N = 14), AND LACKING BOTH PE AND HT (N = 422). WE MATCHED PATIENTS ACCORDING TO PE RISK FACTORS INTO THREE GROUPS (N = 5 EACH GROUP): (1) PE: NO HT BUT PE DEVELOPMENT, (2) HT: CHRONIC HYPERTENSION BUT NO PE AND (3) CONTROL: NO PE OR HT. WE SUCCESSFULLY OPTIMIZED OUR CFDNA ISOLATION PROCESS PRIOR TO WHOLE GENOME BISULFITE SEQUENCING. ANALYSIS OF CFDNA METHYLATION CHANGES INDICATE A COMMON PREDISPOSITION IN PE AND HT GROUPS, CHIEFLY OF MATERNAL ORIGIN. ASSESSMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS AND ANNOTATED GENES POINT TOWARDS A COMMON CARDIOVASCULAR PREDISPOSITION IN PREECLAMPSIA AND HYPERTENSION GROUPS IN THE FIRST TRIMESTER. WE POSTULATE THE PIVOTAL ROLE OF THE MATERNAL CARDIOVASCULAR SYSTEM IN HDP, WHICH IS ALREADY EVIDENT IN THE FIRST TRIMESTER. 2022 18 4819 37 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 19 4363 50 MIRNA AS MARKERS FOR THE DIAGNOSTIC SCREENING OF COLON CANCER. EARLY SCREENING FOR COLON CANCER (CC) ALLOWS FOR EARLY STAGE DIAGNOSIS OF THE MALIGNANCY AND POTENTIALLY REDUCES DISEASE MORTALITY AS THE CANCER IS MOST LIKELY CURABLE AT ITS EARLIEST STAGES. EARLY DETECTION WOULD BE DESIRABLE IF ACCURATE, PRACTICAL AND COST-EFFECTIVE DIAGNOSTIC MEASURES FOR THIS CANCER WERE AVAILABLE. MORTALITY AND MORBIDITY FROM CC REPRESENT A MAJOR HEALTH PROBLEM INVOLVING A MALIGNANT DISEASE THAT IS THEORETICALLY PREVENTABLE THROUGH SCREENING. CURRENT SCREENING METHODS (E.G., THE CONVENIENT AND INEXPENSIVE IMMUNOLOGICAL FECAL OCCULT BLOOD TEST, FOBTI, OBTAINED FROM PATIENTS' MEDICAL RECORDS) EITHER LACK SENSITIVITY AND REQUIRE DIETARY RESTRICTION, WHICH IMPEDES COMPLIANCE AND USE; ARE COSTLY (E.G., COLONOSCOPY), WHICH DECREASES COMPLIANCE; OR COULD RESULT IN MORTALITY. IN COMPARISON WITH THE FOBT TEST, A NON-INVASIVE SENSITIVE SCREEN FOR WHICH THERE IS NO REQUIREMENT FOR DIETARY RESTRICTION WOULD BE A MORE CONVENIENT TEST. COLORECTAL CANCER IS THE ONLY CANCER FOR WHICH COLONOSCOPY IS RECOMMENDED AS A SCREENING METHOD. ALTHOUGH COLONOSCOPY IS A RELIABLE SCREENING TOOL, THE INVASIVE NATURE, ABDOMINAL PAIN, POTENTIAL COMPLICATIONS AND HIGH COST HAVE HAMPERED THE APPLICATION OF THIS PROCEDURE WORLDWIDE. A SCREENING APPROACH USING THE STABLE MIRNA MOLECULES, WHICH ARE RELATIVELY NON-DEGRADABLE WHEN EXTRACTED FROM NON-INVASIVE STOOL AND SEMI-INVASIVE BLOOD SAMPLES BY COMMERCIALLY AVAILABLE KITS AND MANIPULATED THEREAFTER, WOULD BE PREFERABLE TO A TRANSCRIPTOMIC MRNA-, A MUTATION DNA-, AN EPIGENETIC- OR A PROTEOMIC-BASED TEST. THE APPROACH USES REVERSE TRANSCRIPTASE, MODIFIED REAL-TIME QUANTITATIVE PCR. ALTHOUGH EXOSOMAL RNA WOULD BE MISSED, USING A RESTRICTED EXTRACTION OF TOTAL RNA FROM STOOL OR BLOOD, A PARALLEL TEST COULD ALSO BE CARRIED OUT ON RNA OBTAINED FROM STOOL OR PLASMA SAMPLES, AND APPROPRIATE CORRECTIONS FOR EXSOSOMAL LOSS CAN BE MADE FOR ACCURATE AND QUANTITATIVE TEST RESULT. EVENTUALLY, A CHIP CAN BE DEVELOPED TO FACILITATE DIAGNOSIS, AS HAS BEEN DONE FOR THE QUANTIFICATION OF GENETICALLY MODIFIED ORGANISMS IN FOODS. THE GOLD STANDARD TO WHICH THE MOLECULAR MIRNA TEST IS COMPARED IS COLONOSCOPY, WHICH CAN BE OBTAINED FROM PATIENTS' MEDICAL RECORDS. IF PERFORMANCE CRITERIA ARE MET, AS DETAILED HEREIN, A MIRNA TEST IN HUMAN STOOL OR BLOOD SAMPLES BASED ON HIGH-THROUGHPUT AUTOMATED TECHNOLOGIES AND QUANTITATIVE EXPRESSION MEASUREMENTS COMMONLY USED IN THE DIAGNOSTIC CLINICAL LABORATORY SHOULD BE ADVANCED TO THE CLINICAL SETTING, WHICH WILL MAKE A SIGNIFICANT IMPACT ON CC PREVENTION. 2014 20 3623 58 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