1 1816 89 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 2 6484 13 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 3 227 22 ADAPTATION OF AN OUTBREAKING INSECT DEFOLIATOR TO CHRONIC NUTRITIONAL STRESS. DURING INSECT OUTBREAKS, THE HIGH NUMBER OF INDIVIDUALS FEEDING ON ITS HOST PLANT CAUSES A DEPLETION OF THE FOOD SOURCE. REDUCED AVAILABILITY AND DECREASED QUALITY OF NUTRIENTS NEGATIVELY INFLUENCE LIFE-HISTORY TRAITS OF INSECTS DRIVING THEM TO DEVELOP ADAPTIVE STRATEGIES TO PERSIST IN THE ENVIRONMENT. IN A LABORATORY EXPERIMENT WITH THREE REPETITIONS, WE TESTED THE EFFECT OF CHRONIC NUTRITIONAL STRESS ON SPRUCE BUDWORM PERFORMANCE DURING THREE GENERATIONS TO DETERMINE THE ADAPTIVE STRATEGIES EMPLOYED BY THE INSECT TO DEAL WITH A SELECTION PRESSURE PRODUCED BY LOW-QUALITY DIET. OUR RESULTS SHOW THAT ALL TESTED LIFE-HISTORY TRAITS (MORTALITY, DEVELOPMENTAL TIME, PUPAL MASS, GROWTH RATE AND FEMALE FECUNDITY) BUT FEMALE FERTILITY WERE NEGATIVELY INFLUENCED BY THE LOW-QUALITY DIET SIMULATING FOOD DEPLETION DURING OUTBREAK CONDITIONS. HOWEVER, ESPECIALLY FEMALES IN THE THIRD GENERATION UNDER CHRONIC NUTRITIONAL STRESS SHOW AN ADAPTIVE RESPONSE IN LIFE-HISTORY TRAITS WHEN COMPARED TO THOSE REARED ONLY ONE GENERATION ON LOW-QUALITY DIET. LARVAL DEVELOPMENTAL TIME SIGNIFICANTLY DECREASED AND PUPAL MASS, GROWTH RATE AND FECUNDITY SIGNIFICANTLY INCREASED. THE STUDY DEMONSTRATES THE CAPACITY OF SPRUCE BUDWORM TO REACT TO CHRONIC NUTRITIONAL STRESS WITH ADAPTATIONS THAT MAY BE CAUSED BY EPIGENETIC PARENTAL EFFECTS. THIS INFORMATION CAN HELP TO UNDERSTAND THE COURSE OF AN OUTBREAK ESPECIALLY AT PEAK DENSITIES AND DURING THE COLLAPSE. 2015 4 491 22 ASSESSING THE IMPACT OF POLYETHYLENE NANO/MICROPLASTIC EXPOSURE ON HUMAN VAGINAL KERATINOCYTES. THE GLOBAL RISE OF SINGLE-USE THROW-AWAY PLASTIC PRODUCTS HAS ELICITED A MASSIVE INCREASE IN THE NANO/MICROPLASTICS (N/MPLS) EXPOSURE BURDEN IN HUMANS. RECENTLY, IT HAS BEEN DEMONSTRATED THAT DISPOSABLE PERIOD PRODUCTS MAY RELEASE N/MPLS WITH USAGE, WHICH REPRESENTS A POTENTIAL THREAT TO WOMEN'S HEALTH WHICH HAS NOT BEEN SCIENTIFICALLY ADDRESSED YET. BY USING POLYETHYL ENE (PE) PARTICLES (200 NM TO 9 MUM), WE SHOWED THAT ACUTE EXPOSURE TO A HIGH CONCENTRATION OF N/MPLS INDUCED CELL TOXICITY IN VAGINAL KERATINOCYTES AFTER EFFECTIVE CELLULAR UPTAKE, AS VIABILITY AND APOPTOSIS DATA SUGGEST, ALONG WITH TRANSMISSION ELECTRON MICROSCOPY (TEM) OBSERVATIONS. THE INTERNALISED N/MPLS ALTERED THE EXPRESSION OF JUNCTIONAL AND ADHERENCE PROTEINS AND THE ORGANISATION OF THE ACTIN CORTEX, INFLUENCING THE LEVEL OF GENES INVOLVED IN OXIDATIVE STRESS SIGNALLING PATHWAYS AND THAT OF MIRNAS RELATED TO EPITHELIAL BARRIER FUNCTION. WHEN THE EXPOSURE TO PE N/MPLS WAS DISCONTINUED OR BECAME CHRONIC, CELLS WERE ABLE TO RECOVER FROM THE NEGATIVE EFFECTS ON VIABILITY AND DIFFERENTIATION/PROLIFERATION GENE EXPRESSION IN A FEW DAYS. HOWEVER, IN ALL CASES, PE N/MPL EXPOSURE PROMPTED A SUSTAINED ALTERATION OF DNA METHYLTRANSFERASE AND DNA DEMETHYLASE EXPRESSION, WHICH MIGHT IMPACT EPIGENETIC REGULATION PROCESSES, LEADING TO ACCELERATED CELL AGEING AND INFLAMMATION, OR THE OCCURRENCE OF MALIGNANT TRANSFORMATION. 2023 5 3657 27 INDUCTION AND RECOVERY OF CPG SITE SPECIFIC METHYLATION CHANGES IN HUMAN BRONCHIAL CELLS AFTER LONG-TERM EXPOSURE TO CARBON NANOTUBES AND ASBESTOS. INTRODUCTION: INHALATION OF ASBESTOS INDUCES LUNG CANCER VIA DIFFERENT CELLULAR MECHANISMS. TOGETHER WITH THE INCREASED PRODUCTION OF CARBON NANOTUBES (CNTS) GROWS THE CONCERN ABOUT ADVERSE EFFECTS ON THE LUNGS GIVEN THE SIMILARITIES WITH ASBESTOS. WHILE IT HAS BEEN ESTABLISHED THAT CNT AND ASBESTOS INDUCE EPIGENETIC ALTERATIONS, IT IS CURRENTLY NOT KNOWN WHETHER ALTERATIONS AT EPIGENETIC LEVEL REMAIN STABLE AFTER WITHDRAWAL OF THE EXPOSURE. IDENTIFICATION OF DNA METHYLATION CHANGES AFTER A LOW DOSE OF CNT AND ASBESTOS EXPOSURE AND RECOVERY CAN BE USEFUL TO DETERMINE THE FIBRE/PARTICLE TOXICITY AND ADVERSE OUTCOME. METHODS: HUMAN BRONCHIAL EPITHELIAL CELLS (16HBE) WERE TREATED WITH A LOW AND NON-CYTOTOXIC DOSE (0.25 MICROG/ML) OF MULTI-WALLED CARBON NANOTUBES (MWCNTS-NM400) OR SINGLE-WALLED CARBON NANOTUBES (SWCNTS-SRM2483) AND 0.05 MICROG/ML AMOSITE (BROWN) ASBESTOS FOR THE COURSE OF FOUR WEEKS (SUB-CHRONIC EXPOSURE). AFTER THIS TREATMENT, THE CELLS WERE FURTHER INCUBATED (WITHOUT PARTICLE/FIBRE) FOR TWO WEEKS, ALLOWING RECOVERY FROM THE EXPOSURE (RECOVERY PERIOD). NUCLEAR DEPOSITIONS OF THE CNTS WERE ASSESSED USING FEMTOSECOND PULSED LASER MICROSCOPY IN A LABEL-FREE MANNER. DNA METHYLATION ALTERATIONS WERE ANALYSED USING MICROARRAYS THAT ASSESS MORE THAN 850 THOUSAND CPG SITES IN THE WHOLE GENOME. RESULTS: AT NON-CYTOTOXIC DOSES, CNTS WERE NOTED TO BE INCORPORATED WITH IN THE NUCLEUS AFTER A FOUR WEEKS PERIOD. EXPOSURE TO MWCNTS INDUCED A SINGLE HYPOMETHYLATION AT A CPG SITE AND GENE PROMOTER REGION. NO CHANGE IN DNA METHYLATION WAS OBSERVED AFTER THE RECOVERY PERIOD FOR MWCNTS. EXPOSURE TO SWCNTS OR AMOSITE INDUCED HYPERMETHYLATION AT CPG SITES AFTER SUB-CHRONIC EXPOSURE WHICH MAY INVOLVE IN 'TRANSCRIPTION FACTOR ACTIVITY' AND 'SEQUENCE-SPECIFIC DNA BINDING' GENE ONTOLOGIES. AFTER THE RECOVERY PERIOD, HYPERMETHYLATION AND HYPOMETHYLATION WERE NOTED FOR BOTH SWCNTS AND AMOSITE. HIPPOCALCINLIKE 1 (HPCAL1), PROTEASE SERINE 3 (PRSS3), KALLIKREIN-RELATED PEPTIDASE 3 (KLK3), KRUPPEL LIKE FACTOR 3 (KLF3) GENES WERE HYPERMETHYLATED AT DIFFERENT TIME POINTS IN EITHER SWCNT-EXPOSED OR AMOSITE-EXPOSED CELLS. CONCLUSION: THESE RESULTS SUGGEST THAT THE SPECIFIC SWCNT (SRM2483) AND AMOSITE FIBRES STUDIED INDUCE HYPO- OR HYPERMETHYLATION ON CPG SITES IN DNA AFTER VERY LOW-DOSE EXPOSURE AND RECOVERY PERIOD. THIS EFFECT WAS NOT SEEN FOR THE STUDIED MWCNT (NM400). 2020 6 6835 23 [INFLUENCE OF AGE OF PATIENTS WITH BRONCHOPULMONARY PATHOLOGY ON LOW-MOLECULAR DNA CONCENTRATION IN BLOOD PLASMA.]. THE AIM OF THE WORK WAS TO DETERMINE THE CONCENTRATION OF LOW-MOLECULAR-WEIGHT PLASMA DNA (LMDNA) IN PATIENTS WITH COPD AND CHRONIC NON-OBSTRUCTIVE BRONCHITIS (CNONB) OF TWO AGE GROUPS - 34-59 AND 60-80 YEARS. THE LEVELS OF LMDNA IN HEALTHY DONORS, PATIENTS WITH CNONB, HEALTHY RELATIVES OF PATIENTS WITH COPD DID NOT DIFFER, WHILE THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD WAS SIGNIFICANTLY LOWER. IN COPD PATIENTS AGED 34-59 YEARS, THE LEVEL OF LMDNA WAS REDUCED BY MORE THAN 7 TIMES, AND IN COPD PATIENTS WHO SURVIVED TO 60-80 YEARS, IT WAS 3 TIMES LOWER COMPARED TO THE VALUE OF THIS BIOCHEMICAL INDICATOR IN HEALTHY DONORS OF THE SAME AGE. THE REDUCTION OF LMDNA REFLECTED A REDUCED SYSTEMIC APOPTOTIC ACTIVITY IN THE BODY OF PATIENTS WITH COPD. A SIGNIFICANT DIFFERENCE IN THE CONCENTRATION OF LMDNA IN PATIENTS WITH COPD AND CNONB IN REMISSION CAN BE USED FOR DIFFERENTIAL DIAGNOSIS OF THE DEVELOPMENT OF THESE PATHOLOGICAL PROCESSES. AN INCREASE IN THE LOW LEVEL OF LMDNA IN COPD PATIENTS DURING AGING MAY INDICATE THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LIFE EXTENSION. 2022 7 1109 19 COMMERCIAL PROCESSED SOY-BASED FOOD PRODUCT CONTAINS GLYCATED AND GLYCOXIDATED LUNASIN PROTEOFORMS. NUTRACEUTICALS HAVE BEEN PROPOSED TO EXERT POSITIVE EFFECTS ON HUMAN HEALTH AND CONFER PROTECTION AGAINST MANY CHRONIC DISEASES. A MAJOR BIOACTIVE COMPONENT OF SOY-BASED FOODS IS LUNASIN PEPTIDE, WHICH HAS POTENTIAL TO EXERT A MAJOR IMPACT ON THE HEALTH OF HUMAN CONSUMERS WORLDWIDE, BUT THE BIOCHEMICAL FEATURES OF DIETARY LUNASIN STILL REMAIN POORLY CHARACTERIZED. IN THIS STUDY, LUNASIN WAS PURIFIED FROM A SOY-BASED FOOD PRODUCT VIA STRONG ANION EXCHANGE SOLID PHASE EXTRACTION AND THEN SUBJECTED TO TOP-DOWN MASS SPECTROMETRY ANALYSIS THAT REVEALED IN DETAIL THE MOLECULAR DIVERSITY OF LUNASIN IN PROCESSED SOYBEAN FOODS. WE DETECTED MULTIPLE GLYCATED PROTEOFORMS TOGETHER WITH POTENTIALLY TOXIC ADVANCED GLYCATION END PRODUCTS (AGES) DERIVED FROM LUNASIN. IN BOTH CASES, MODIFICATION SITES WERE LYS24 AND LYS29 LOCATED AT THE HELICAL REGION THAT SHOWS STRUCTURAL HOMOLOGY WITH A CONSERVED REGION OF CHROMATIN-BINDING PROTEINS. THE IDENTIFIED POST-TRANSLATIONAL MODIFICATIONS MAY HAVE AN IMPORTANT REPERCUSSION ON LUNASIN EPIGENETIC REGULATORY CAPACITY. TAKING TOGETHER, OUR RESULTS DEMONSTRATE THE IMPORTANCE OF PROPER CHEMICAL CHARACTERIZATION OF COMMERCIAL PROCESSED FOOD PRODUCTS TO ASSESS THEIR IMPACT ON CONSUMER'S HEALTH AND RISK OF CHRONIC DISEASES. 2016 8 6777 15 [ASSOCIATION OF P-MOBILE ELEMENT ACTIVITY AND DNA METHYLATION PATTERN CHANGES IN THE CONDITIONS OF DROSOPHILA MELANOGASTER PROLONGED IRRADIATION]. ASSOCIATION OF THE RADIOSENSITIVITY AND EPIGENETIC PATTERN DNA CHANGES AT THE CONDITIONS OF PROLONGED IRRADIATION WAS INVESTIGATED. TWO LABORATORY DROSOPHILA MELANOGASTER STRAINS (CANTON-S AND RI) IRRADIATED FOR 20 GENERATIONS TO LOW DOSES RATE (1.2 X 10(-1), 0.8 X 10(-8) AND 0.12 X 10(-8) GY/S) WERE USED AS EXPERIMENTAL OBJECTS. DNA FOR THE ANALYSIS WAS EXTRACTED SEPARATELY FOR THE FLIES OF MALES AND FEMALES. RESTRICTION ENDONUCLEASES GLUL, GLAL WERE USED. RESTRICTION ANALYSIS HAS SHOWN THAT THERE ARE DIFFERENT DNA METHYLATED PATTERNS FOR MALES AND FEMALES AS FOR CONTROL AND EXPOSED VARIANTS. AT THE CHRONIC IRRADIATION THERE WAS THE DECLINE OF METHYLATION LEVEL AT THE ENZYMES GLUL, GLAL SITES RECOGNITION. 2010 9 3074 18 GENOME-WIDE DNA METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INORGANIC NANOPARTICLES IN HUMAN KIDNEY CELLS AFTER CHRONIC EXPOSURE. THE UNIQUE PHYSICOCHEMICAL PROPERTIES MAKE INORGANIC NANOPARTICLES (INPS) AN EXCITING TOOL IN DIAGNOSIS AND DISEASE MANAGEMENT. HOWEVER, AS INPS ARE RELATIVELY DIFFICULT TO FULLY DEGRADE AND EXCRETE, THEIR UNINTENDED ACCUMULATION IN THE TISSUE MIGHT RESULT IN ADVERSE HEALTH EFFECTS. HEREIN, WE PROVIDE A METHYLOME-TRANSCRIPTOME FRAMEWORK FOR CHRONIC EFFECTS OF INPS, COMMONLY USED IN BIOMEDICAL APPLICATIONS, IN HUMAN KIDNEY TH-1 CELLS. RENAL CLEARANCE IS ONE OF THE MOST IMPORTANT ROUTES OF NANOPARTICLE EXCRETION; THEREFORE, A DETAILED EVALUATION OF NANOPARTICLE-MEDIATED NEPHROTOXICITY IS AN IMPORTANT TASK. INTEGRATED ANALYSIS OF METHYLOME AND TRANSCRIPTOME CHANGES INDUCED BY INPS (PEG-AUNPS, FE(3)O(4)NPS, SIO(2)NPS, AND TIO(2)NPS) REVEALED SIGNIFICANTLY DEREGULATED GENES WITH FUNCTIONAL CLASSIFICATION IN IMMUNE RESPONSE, DNA DAMAGE, AND CANCER-RELATED PATHWAYS. ALTHOUGH MOST DEREGULATED GENES WERE UNIQUE TO INDIVIDUAL INPS, A RELATIVELY HIGH PROPORTION OF THEM ENCODED THE TRANSCRIPTION FACTORS. INTERESTINGLY, FOS HYPERMETHYLATION INVERSELY CORRELATING WITH GENE EXPRESSION WAS ASSOCIATED WITH ALL INPS EXPOSURES. OUR STUDY EMPHASIZES THE NEED FOR A MORE COMPREHENSIVE INVESTIGATION OF INPS' BIOLOGICAL SAFETY, ESPECIALLY AFTER CHRONIC EXPOSURE. 2022 10 1429 25 DIFFERENTIAL EXPRESSION OF MICRORNAS IN THE HIPPOCAMPI OF MALE AND FEMALE RODENTS AFTER CHRONIC ALCOHOL ADMINISTRATION. BACKGROUND: WOMEN ARE MORE VULNERABLE THAN MEN TO THE NEUROTOXICITY AND SEVERE BRAIN DAMAGE CAUSED BY CHRONIC HEAVY ALCOHOL USE. IN ADDITION, BRAIN DAMAGE DUE TO CHRONIC HEAVY ALCOHOL USE MAY BE ASSOCIATED WITH SEX-DEPENDENT EPIGENETIC MODIFICATIONS. THIS STUDY AIMED TO IDENTIFY MICRORNAS (MIRNAS) AND THEIR TARGET GENES THAT ARE DIFFERENTIALLY EXPRESSED IN THE HIPPOCAMPI OF MALE AND FEMALE ANIMAL MODELS IN RESPONSE TO ALCOHOL. METHODS: AFTER CHRONIC ALCOHOL ADMINISTRATION (3~3.5 G/KG/DAY) IN MALE (CONTROL, N = 10; ALCOHOL, N = 12) OR FEMALE (CONTROL, N = 10; ALCOHOL, N = 12) SPRAGUE-DAWLEY RATS FOR 6 WEEKS, WE MEASURED BODY WEIGHTS AND DOUBLECORTIN (DCX; A NEUROGENESIS MARKER) CONCENTRATIONS AND ANALYZED UP- OR DOWNREGULATED MIRNAS USING GENECHIP MIRNA 4.0 ARRAYS. THE DIFFERENTIALLY EXPRESSED MIRNAS AND THEIR PUTATIVE TARGET GENES WERE VALIDATED BY RT-QPCR. RESULTS: ALCOHOL ATTENUATED BODY WEIGHT GAIN ONLY IN THE MALE GROUP. ON THE OTHER HAND, ALCOHOL LED TO INCREASED SERUM AST IN FEMALE RATS AND DECREASED SERUM TOTAL CHOLESTEROL CONCENTRATIONS IN MALE RATS. THE EXPRESSION OF DCX WAS SIGNIFICANTLY REDUCED IN THE HIPPOCAMPI OF MALE ALCOHOL-TREATED RATS. NINE MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN MALE ALCOHOL-TREATED RATS, INCLUDING UPREGULATION OF MIR-125A-3P, LET-7A-5P, AND MIR-3541, AND DOWNREGULATION OF THEIR TARGET GENES (PRDM5, SUV39H1, PTPRZ1, MAPK9, ING4, WT1, NKX3-1, DAB2IP, RNF152, RIPK1, LIN28A, APBB3, NRAS, AND ACVR1C). ON THE OTHER HAND, 7 MIRNAS WERE SIGNIFICANTLY UP- OR DOWNREGULATED IN ALCOHOL-TREATED FEMALE RATS, INCLUDING DOWNREGULATION OF MIR-881-3P AND MIR-504 AND UPREGULATION OF THEIR TARGET GENES (NAA50, CLOCK, CBFB, ARIH1, UBE2G1, AND GNG7). CONCLUSIONS: THESE RESULTS SUGGEST THAT CHRONIC HEAVY ALCOHOL USE PRODUCES SEX-DEPENDENT EFFECTS ON NEUROGENESIS AND MIRNA EXPRESSION IN THE HIPPOCAMPUS AND THAT SEX DIFFERENCES SHOULD BE CONSIDERED WHEN DEVELOPING MIRNA BIOMARKERS TO DIAGNOSE OR TREAT ALCOHOLICS. 2020 11 3552 16 IMMUNOSUPPRESSION BY CHRONIC EXPOSURE TO N-NITROSODIMETHYLAMINE (NDMA) IN MICE. IMMUNOSUPPRESSION OF HUMORAL AND CELLULAR RESPONSES FOLLOWING CHRONIC ORAL EXPOSURE TO 1, 5, 10, AND 20 PPM N-NITROSODIMETHYLAMINE (NDMA) WAS EXAMINED IN CD-1 MICE. MONITORING OF CUMULATIVE MORTALITY AND THE INCIDENCE OF PERITONEAL ASCITES IN ANIMALS SHOWED AN NDMA DOSE-RELATED MORTALITY AND HEPATOTOXICITY. NO VISIBLE CHANGES IN IMMUNOLOGICAL PARAMETERS WERE NOTED AT THE 1 PPM NDMA DOSE. IMMUNOSUPPRESSION OF IMMUNOGLOBULIN M (IGM) ANTIBODY RESPONSE BY NDMA TO SHEEP RED BLOOD CELLS (SRBC) WAS TIME-RELATED, DOSE-RELATED, AND COULD BE REVERSED WITHIN 30 D BY REMOVAL OF THE CHEMICAL FROM THE DRINKING WATER. CELLULAR IMMUNE RESPONSE, MONITORED BY ALLOGENEIC STIMULATION OF CELLS IN MIXED LYMPHOCYTE REACTION (MLR), WAS MARKEDLY SUPPRESSED BY 10 AND 20 PPM NDMA. THUS, CHRONIC EXPOSURE TO NDMA, EXCEPT FOR THE LOW-HEPATOTOXIC DOSES OF NITROSAMINE, RESULTED IN A MARKED AND PERSISTENT IMMUNOSUPPRESSION OF CELLULAR AND HUMORAL RESPONSES IN CD-1 MICE. IN CONCLUSION, CHRONIC EXPOSURE TO THE HEPATOTOXIC (ASCITE-INDUCING) DOSES OF NDMA SUPPRESSED HUMORAL AND CELLULAR IMMUNITY. THE PERSISTENT IMMUNOSUPPRESSION COULD BE REVERSED AFTER THE REMOVAL OF NDMA FROM THE DRINKING WATER. ALTHOUGH NO DIRECT NDMA-RELATED CANCER WAS REPORTED IN HUMANS, OUR DATA POINT TO A POTENTIAL EPIGENETIC CARCINOGENICITY OF NITROSAMINES DUE TO CHRONIC IMMUNOSUPPRESSION. 1992 12 2758 15 EXPRESSION OF HORMONAL CARCINOGENESIS GENES AND RELATED REGULATORY MICRORNAS IN UTERUS AND OVARIES OF DDT-TREATED FEMALE RATS. THE INSECTICIDE DICHLORODIPHENYLTRICHLOROETHANE (DDT) IS A NONMUTAGENIC XENOBIOTIC COMPOUND ABLE TO EXERT ESTROGEN-LIKE EFFECTS RESULTING IN ACTIVATION OF ESTROGEN RECEPTOR-ALPHA (ERALPHA) FOLLOWED BY CHANGED EXPRESSION OF ITS DOWNSTREAM TARGET GENES. IN ADDITION, STUDIES PERFORMED OVER RECENT YEARS SUGGEST THAT DDT MAY ALSO INFLUENCE EXPRESSION OF MICRORNAS. HOWEVER, AN IMPACT OF DDT ON EXPRESSION OF ER, MICRORNAS, AND RELATED TARGET GENES HAS NOT BEEN FULLY ELUCIDATED. HERE, USING REAL-TIME PCR, WE ASSESSED CHANGES IN EXPRESSION OF KEY GENES INVOLVED IN HORMONAL CARCINOGENESIS AS WELL AS POTENTIALLY RELATED REGULATORY ONCOGENIC/TUMOR SUPPRESSOR MICRORNAS AND THEIR TARGET GENES IN THE UTERUS AND OVARIES OF FEMALE WISTAR RATS DURING SINGLE AND CHRONIC MULTIPLE-DOSE DDT EXPOSURE. WE FOUND THAT APPLYING DDT RESULTS IN ALTERED EXPRESSION OF MICRORNAS-221, -222, -205, -126A, AND -429, THEIR TARGET GENES (PTEN, DICER1), AS WELL AS GENES INVOLVED IN HORMONAL CARCINOGENESIS (ESR1, PGR, CCND1, CYP19A1). NOTABLY, CYP19A1 EXPRESSION SEEMS TO BE ALSO REGULATED BY MICRORNAS-221, -222, AND -205. THE DATA SUGGEST THAT EPIGENETIC EFFECTS INDUCED BY DDT AS A POTENTIAL CARCINOGEN MAY BE BASED ON AT LEAST TWO MECHANISMS: (I) ACTIVATION OF ERALPHA FOLLOWED BY ALTERED EXPRESSION OF THE TARGET GENES ENCODING RECEPTOR PGR AND CCND1 AS WELL AS IMPAIRED EXPRESSION OF CYP19A1, AFFECTING, THEREBY, CELL HORMONE BALANCE; AND (II) CHANGED EXPRESSION OF MICRORNAS RESULTING IN IMPAIRED EXPRESSION OF RELATED TARGET GENES INCLUDING REDUCED LEVEL OF CYP19A1 MRNA. 2017 13 2674 24 ETHOSUXIMIDE REDUCES EPILEPTOGENESIS AND BEHAVIORAL COMORBIDITY IN THE GAERS MODEL OF GENETIC GENERALIZED EPILEPSY. PURPOSE: ETHOSUXIMIDE (ESX) IS A DRUG OF CHOICE FOR THE SYMPTOMATIC TREATMENT OF ABSENCE SEIZURES. CHRONIC TREATMENT WITH ESX HAS BEEN REPORTED TO HAVE DISEASE-MODIFYING ANTIEPILEPTOGENIC ACTIVITY IN THE WAG/RIJ RAT MODEL OF GENETIC GENERALIZED EPILEPSY (GGE) WITH ABSENCE SEIZURES. HERE WE EXAMINED WHETHER CHRONIC TREATMENT WITH ESX (1) POSSESSES ANTIEPILEPTOGENIC EFFECTS IN THE GENETIC ABSENCE EPILEPSY RATS FROM STRASBOURG (GAERS) MODEL OF GGE, (2) IS ASSOCIATED WITH A MITIGATION OF BEHAVIORAL COMORBIDITIES, AND (3) INFLUENCES GENE EXPRESSION IN THE SOMATOSENSORY CORTEX REGION WHERE SEIZURES ARE THOUGHT TO ORIGINATE. METHODS: GAERS AND NONEPILEPTIC CONTROL (NEC) RATS WERE CHRONICALLY TREATED WITH ESX (IN DRINKING WATER) OR CONTROL (TAP WATER) FROM 3 TO 22 WEEKS OF AGE. SUBSEQUENTLY, ALL ANIMALS RECEIVED TAP WATER ONLY FOR ANOTHER 12 WEEKS TO ASSESS ENDURING EFFECTS OF TREATMENT. SEIZURE FREQUENCY AND ANXIETY-LIKE BEHAVIORS WERE SERIALLY ASSESSED THROUGHOUT THE EXPERIMENTAL PARADIGM. TREATMENT EFFECTS ON THE EXPRESSION OF KEY COMPONENTS OF THE EPIGENETIC MOLECULAR MACHINERY, THE DNA METHYLTRANSFERASE ENZYMES, WERE ASSESSED USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR). KEY FINDINGS: ESX TREATMENT SIGNIFICANTLY REDUCED SEIZURES IN GAERS DURING THE TREATMENT PHASE, AND THIS EFFECT WAS MAINTAINED DURING THE 12-WEEK POSTTREATMENT PHASE (P < 0.05). FURTHERMORE, THE ANXIETY-LIKE BEHAVIORS PRESENT IN GAERS WERE REDUCED BY ESX TREATMENT (P < 0.05). MOLECULAR ANALYSIS REVEALED THAT ESX TREATMENT WAS ASSOCIATED WITH INCREASED EXPRESSION OF DNA METHYLTRANSFERASE ENZYME MESSENGER RNA (MRNA) IN CORTEX. SIGNIFICANCE: CHRONIC ESX TREATMENT HAS DISEASE-MODIFYING EFFECTS IN THE GAERS MODEL OF GGE, WITH ANTIEPILEPTOGENIC EFFECTS AGAINST ABSENCE SEIZURES AND MITIGATION OF BEHAVIORAL COMORBIDITIES. THE CELLULAR MECHANISM FOR THESE EFFECTS MAY INVOLVE EPIGENETIC MODIFICATIONS. 2013 14 1622 22 DNA METHYLTRANSFERASES IN MALAR MELASMA AND THEIR MODIFICATION BY SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. BACKGROUND: MALAR MELASMA HAS A CHRONIC AND RECURRENT CHARACTER THAT MAY BE RELATED TO EPIGENETIC CHANGES. OBJECTIVE: TO RECOGNIZE THE EXPRESSION AND DNA METHYLATION OF DNA METHYLTRANSFERASES (DNMTS) IN MALAR MELASMA AND PERILESIONAL SKIN, AS WELL AS THE CHANGES IN DNMTS AFTER THEIR TREATMENT WITH SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. METHODS: THIRTY FEMALE PATIENTS WERE CLINICALLY EVALUATED FOR THE EXPRESSION OF DNMT1 AND DNMT3B USING REAL-TIME PCR AND IMMUNOFLUORESCENCE. THESE INITIAL RESULTS WERE COMPARED TO RESULTS AFTER EIGHT WEEKS OF TREATMENT WITH SUNSCREEN IN COMBINATION WITH NIACINAMIDE, RETINOIC ACID, OR PLACEBO. RESULTS: THE RELATIVE EXPRESSION OF DNMT1 WAS SIGNIFICANTLY ELEVATED IN MELASMA COMPARED WITH UNAFFECTED SKIN IN ALL SUBJECTS, INDICATING DNA HYPERMETHYLATION. AFTER TREATMENT, IT WAS DECREASED IN ALL GROUPS: NIACINAMIDE (7 VERSUS 1; P<0.01), RETINOIC ACID (7 VERSUS 2; P<0.05), AND PLACEBO (7 VERSUS 3; P<0.05), WHICH CORRELATES WITH CLINICAL IMPROVEMENT. DNMT3B WAS NOT OVEREXPRESSED IN LESIONAL SKIN BUT REDUCED IN ALL GROUPS. CONCLUSIONS: WE FOUND DNA HYPERMETHYLATION IN MELASMA LESIONS. ENVIRONMENTAL FACTORS SUCH AS SOLAR RADIATION MAY INDUCE CELLULAR CHANGES THAT TRIGGER HYPERPIGMENTATION THROUGH THE ACTIVATION OF PATHWAYS REGULATED BY EPIGENETIC MODIFICATIONS. HOWEVER, LIMITING OR DECREASING DNA METHYLATION THROUGH SUNSCREEN, NIACINAMIDE, AND RETINOIC ACID TREATMENTS THAT PROVIDE PHOTOPROTECTION AND GENETIC TRANSCRIPTION CAN COUNTERACT THIS. 2019 15 3505 25 IDENTIFICATION OF SEX-SPECIFIC DNA METHYLATION CHANGES DRIVEN BY SPECIFIC CHEMICALS IN CORD BLOOD IN A FAROESE BIRTH COHORT. FAROE ISLANDERS CONSUME MARINE FOODS CONTAMINATED WITH METHYLMERCURY (MEHG), POLYCHLORINATED BIPHENYLS (PCBS), AND OTHER TOXICANTS ASSOCIATED WITH CHRONIC DISEASE RISKS. DIFFERENTIAL DNA METHYLATION AT SPECIFIC CPG SITES IN CORD BLOOD MAY SERVE AS A SURROGATE BIOMARKER OF HEALTH IMPACTS FROM CHEMICAL EXPOSURES. WE AIMED TO IDENTIFY KEY ENVIRONMENTAL CHEMICALS IN CORD BLOOD ASSOCIATED WITH DNA METHYLATION CHANGES IN A POPULATION WITH ELEVATED EXPOSURE TO CHEMICAL MIXTURES. WE STUDIED 72 PARTICIPANTS OF A FAROESE BIRTH COHORT RECRUITED BETWEEN 1986 AND 1987 AND FOLLOWED UNTIL ADULTHOOD. THE CORD BLOOD DNA METHYLOME WAS PROFILED USING INFINIUM HUMANMETHYLATION450 BEADCHIPS. WE DETERMINED THE ASSOCIATIONS OF CPG SITE CHANGES WITH CONCENTRATIONS OF MEHG, MAJOR PCBS, OTHER ORGANOCHLORINE COMPOUNDS [HEXACHLOROBENZENE (HCB), P,P'-DICHLORODIPHENYLDICHLOROETHYLENE (P,P'-DDE) AND P,P'-DICHLORODIPHENYLTRICHLOROETHANE], AND PERFLUOROALKYL SUBSTANCES. IN A COMBINED SEX ANALYSIS, AMONG THE 16 CHEMICALS STUDIED, PCB CONGENER 105 (CB-105) EXPOSURE WAS ASSOCIATED WITH THE MAJORITY OF DIFFERENTIALLY METHYLATED CPG SITES (214 OUT OF A TOTAL OF 250). IN FEMALE-ONLY ANALYSIS, ONLY 73 CB-105 ASSOCIATED CPG SITES WERE DETECTED, 44 OF WHICH WERE MAPPED TO GENES IN THE ELAV1-ASSOCIATED CANCER NETWORK. IN MALES-ONLY, METHYLATION CHANGES WERE SEEN FOR PERFLUOROOCTANE SULFONATE, HCB, AND P,P'-DDE IN 10,598, 1,238, AND 1,473 CPG SITES, RESPECTIVELY, 15% OF WHICH WERE ENRICHED IN CYTOBANDS OF THE X-CHROMOSOME ASSOCIATED WITH NEUROLOGICAL DISORDERS. IN THIS MULTIPLE-POLLUTANT AND GENOME-WIDE STUDY, WE IDENTIFIED KEY EPIGENETIC TOXICANTS. THE SIGNIFICANT ENRICHMENT OF SPECIFIC X-CHROMOSOME SITES IN MALES IMPLIES POTENTIAL SEX-SPECIFIC EPIGENOME RESPONSES TO PRENATAL CHEMICAL EXPOSURES. 2018 16 2666 22 ESTABLISHMENT OF AN INTERMITTENT COLD STRESS MODEL USING TUPAIA BELANGERI AND EVALUATION OF COMPOUND C737 TARGETING NEURON-RESTRICTIVE SILENCER FACTOR. PREVIOUS STUDIES HAVE SHOWN THAT INTERMITTENT COLD STRESS (ICS) INDUCES DEPRESSION-LIKE BEHAVIORS IN MAMMALS. TUPAIA BELANGERI (THE TREE SHREW) IS THE ONLY EXPERIMENTAL ANIMAL OTHER THAN THE CHIMPANZEE THAT HAS BEEN SHOWN TO BE SUSCEPTIBLE TO INFECTION BY HEPATITIS B AND C VIRUSES. MOREOVER, FULL GENOME SEQUENCE ANALYSIS HAS REVEALED STRONG HOMOLOGY BETWEEN HOST PROTEINS IN TUPAIA AND IN HUMANS AND OTHER PRIMATES. TUPAIA NEUROMODULATOR RECEPTOR PROTEINS ARE ALSO KNOWN TO HAVE A HIGH DEGREE OF HOMOLOGY WITH THEIR CORRESPONDING PRIMATE PROTEINS. BASED ON THESE SIMILARITIES, WE HYPOTHESIZED THAT INDUCTION OF ICS IN TUPAIA WOULD PROVIDE A USEFUL ANIMAL MODEL OF STRESS RESPONSES. WE EXPOSED YOUNG ADULT TUPAIA TO ICS AND OBSERVED DECREASES IN BODY TEMPERATURE AND BODY WEIGHT IN BOTH FEMALE AND MALE TUPAIA, SUGGESTING THAT TUPAIA ARE AN APPROPRIATE ANIMAL MODEL FOR ICS STUDIES. WE FURTHER EXAMINED THE EFFICACY OF A NEW SMALL-MOLECULE COMPOUND, C737, AGAINST THE EFFECTS OF ICS. C737 MIMICS THE HELICAL STRUCTURE OF NEURON-RESTRICTIVE SILENCER FACTOR (NRSF/REST), WHICH REGULATES A WIDE RANGE OF TARGET GENES INVOLVED IN NEURONAL FUNCTION AND PAIN MODULATION. TREATMENT WITH C737 SIGNIFICANTLY REDUCED STRESS-INDUCED WEIGHT LOSS IN FEMALE TUPAIA; THESE EFFECTS WERE STRONGER THAN THOSE ELICITED BY THE ANTIDEPRESSANT AGOMELATINE. THESE RESULTS SUGGEST THAT TUPAIA REPRESENTS A USEFUL NON-RODENT ICS MODEL. OUR DATA ALSO PROVIDE NEW INSIGHTS INTO THE FUNCTION OF NRSF/REST IN STRESS-INDUCED DEPRESSION AND OTHER DISORDERS WITH EPIGENETIC INFLUENCES OR THOSE WITH HIGH PREVALENCE IN WOMEN. 2016 17 4360 21 MIR-6769B-5P TARGETS CCND-1 TO REGULATE PROLIFERATION IN CADMIUM-TREATED PLACENTAL TROPHOBLASTS: ASSOCIATION WITH THE IMPAIRMENT OF FETAL GROWTH. ENVIRONMENTAL CADMIUM (CD) IS POSITIVELY ASSOCIATED WITH PLACENTAL IMPAIRMENT AND FETAL GROWTH RETARDATION. NEVERTHELESS, ITS POTENTIAL MECHANISMS REMAIN UNCLEAR. MICRORNAS (MIRNAS) ARE KNOWN TO INFLUENCE PLACENTAL DEVELOPMENT AND FETAL GROWTH. THIS WORK WAS AIMED TO DETERMINE WHICH MIRNAS ARE INVOLVED IN CD-IMPAIRED PLACENTAL AND FETAL DEVELOPMENT BASED ON THE MRNA AND MIRNA EXPRESSION PROFILES ANALYSIS. AS A RESULT, GESTATIONAL CD EXPOSURE DECEASED FETAL AND PLACENTAL WEIGHT, AND REDUCED THE PROTEIN LEVEL OF PCNA IN HUMAN AND MOUSE PLACENTAE. FURTHERMORE, THE RESULTS OF MRNA MICROARRAY SHOWED THAT CD-DOWNREGULATED MRNAS WERE PREDICTIVELY CORRELATED WITH SEVERAL BIOLOGICAL PROCESSES, INCLUDING CELL PROLIFERATION, DIFFERENTIATION AND MOTILITY. IN ADDITION, THE RESULTS OF MIRNA MICROARRAY AND QPCR ASSAY DEMONSTRATED THAT CD SIGNIFICANTLY INCREASED THE LEVEL OF MIR-6769B-5P, MIR-146B-5P AND MIR-452-5P. INTEGRATED ANALYSIS OF CD-UPREGULATED MIRNAS PREDICTED TARGET GENES AND CD-DOWNREGULATED MRNAS FOUND THAT OVERLAPPING MRNAS, SUCH AS CCND1, CDK13, RINT1 AND CDC26 WERE ALSO SIGNIFICANTLY ASSOCIATED WITH CELL PROLIFERATION. FURTHER EXPERIMENTS SHOWED THAT MIR-6769B-5P INHIBITOR, BUT NOT MIR-146B-5P AND MIR-452-5P, MARKEDLY REVERSED CD-DOWNREGULATED THE EXPRESSION OF PROLIFERATION-RELATED MRNAS, AND THEREBY RESTORED CD-DECREASED THE PROTEINS LEVEL OF CCND1 AND PCNA IN HUMAN PLACENTAL TROPHOBLASTS. DUAL LUCIFERASE REPORTER ASSAY FURTHER REVEALED THAT MIR-6769B-5P DIRECTLY TARGETS CCND1. FINALLY, THE CASE-CONTROL STUDY DEMONSTRATED THAT INCREASED MIR-6769B-5P LEVEL AND IMPAIRED CELL PROLIFERATION WERE OBSERVED IN SMALL-FOR-GESTATIONAL-AGE HUMAN PLACENTAE. IN CONCLUSION, MIR-6769B-5P TARGETS CCND-1 TO REGULATE PROLIFERATION IN CD-TREATED PLACENTAL TROPHOBLASTS, WHICH IS ASSOCIATED WITH THE IMPAIRMENT OF FETAL GROWTH. OUR FINDINGS IMPLY THAT PLACENTAL MIR-6769B-5P MAY BE USED AS AN EPIGENETIC MARKER FOR ENVIRONMENTAL POLLUTANTS-CAUSED FETAL GROWTH RESTRICTION AND ITS LATE-ONSET CHRONIC DISEASES. 2021 18 3474 19 IDENTIFICATION OF A RICE METALLOCHAPERONE FOR CADMIUM TOLERANCE BY AN EPIGENETIC MECHANISM AND POTENTIAL USE FOR CLEAN UP IN WETLAND. CADMIUM (CD) IS A TOXIC HEAVY METAL THAT INITIATES DIVERSE CHRONIC DISEASES THROUGH FOOD CHAINS. DEVELOPING A BIOTECHNOLOGY FOR MANIPULATING CD UPTAKE IN PLANTS IS BENEFICIAL TO REDUCE ENVIRONMENTAL AND HEALTH RISKS. HERE, WE IDENTIFIED A NOVEL EPIGENETIC MECHANISM UNDERLYING CD ACCUMULATION REGULATED BY AN UNCHARACTERIZED METALLOCHAPERONE NAMELY HEAVY METAL RESPONSIVE PROTEIN (HMP) IN RICE PLANTS. OSHMP RESIDES IN CYTOPLASM AND NUCLEUS, DOMINANTLY INDUCED BY CD STRESS AND BINDS DIRECTLY TO CD IONS. OSHMP OVEREXPRESSION ENHANCED THE RICE GROWTH UNDER CD STRESS BUT ACCUMULATED MORE CD, WHEREAS KNOCKOUT OR KNOCKDOWN OF OSHMP SHOWED A CONTRASTING EFFECT. THE ENHANCED CD ACCUMULATION IN THE TRANSGENIC LINES WAS CONFIRMED BY A LONG-TERM EXPERIMENT WITH RICE GROWING AT THE ENVIRONMENTALLY REALISTIC CD CONCENTRATION IN SOIL. THE BISULFITE SEQUENCING AND CHROMATIN IMMUNOPRECIPITATION ASSESSMENTS REVEALED THAT CD STRESS REDUCED SIGNIFICANTLY THE DNA METHYLATION AT CPG (CYTOSINE-GUANINE) AND HISTONE H3K9ME2 MARKS IN THE UPSTREAM OF OSHMP. BY IDENTIFYING A COUPLE OF MUTANTS DEFECTIVE IN DNA METHYLATION AND HISTONE MODIFICATION (H3K9ME2) SUCH AS OSMET1 (METHYLATRANSFEASE1) AND OSSDG714 (KRYPTONITE), WE FOUND THAT THE CD-INDUCED EPIGENETIC HYPOMETHYLATION AT THE REGION WAS ASSOCIATED WITH OSHMP OVEREXPRESSION, WHICH CONSEQUENTLY LED TO CD DETOXIFICATION IN RICE. THE CAUSAL RELATIONSHIP WAS CONFIRMED BY THE GUS REPORTER GENE COUPLED WITH OSHMP AND OSMET1 WHEREBY OSMET1 REPRESSED DIRECTLY THE OSHMP EXPRESSION. OUR WORK SIGNIFIES THAT EXPRESSION OF OSHMP IS REQUIRED FOR CD DETOXIFICATION IN RICE PLANTS, AND THE CD-INDUCED HYPOMETHYLATION IN THE SPECIFIC REGION IS RESPONSIBLE FOR THE ENHANCED OSHMP EXPRESSION. IN SUMMARY, THIS STUDY GAINED AN INSIGHT INTO THE EPIGENETIC MECHANISM FOR ADDITIONAL OSHMP EXPRESSION WHICH CONSEQUENTLY ENSURES RICE ADAPTATION TO THE CD-CONTAMINATED ENVIRONMENT. 2021 19 645 20 BIRTH DEFECTS IN GAZA: PREVALENCE, TYPES, FAMILIARITY AND CORRELATION WITH ENVIRONMENTAL FACTORS. THIS IS THE FIRST REPORT OF REGISTRATION AT BIRTH, AND OF INCIDENCE OF MAJOR STRUCTURAL BIRTH DEFECTS (BD) OBTAINED IN GAZA AT AL SHIFA HOSPITAL, WHERE 28% OF TOTAL BIRTHS IN GAZA STRIP OCCUR. DOCTORS REGISTERED 4,027 DELIVERIES, WITH A PROTOCOL COMPREHENSIVE OF CLINICAL, DEMOGRAPHIC, KIN AND ENVIRONMENTAL QUESTIONS. PREVALENCE OF BD IS 14/1,000, WITHOUT ASSOCIATION WITH INTERMARRIAGE OR GENDER OF THE CHILD. PREVALENCE OF LATE MISCARRIAGES AND STILL BIRTHS ARE RESPECTIVELY 23.3/1,000 AND 7.4/1,000, AND OF PREMATURE BIRTHS 19.6/1,000. COUPLES WITH A BD CHILD HAVE ABOUT 10 TIMES HIGHER FREQUENCY OF RECURRENCE OF A BD IN THEIR PROGENY THAN THOSE WITH NORMAL CHILDREN, BUT NONE OF THEIR 694 SIBLINGS AND ONLY 10/1,000 OF THEIR 1,423 PROGENY HAD BD, SIMILAR TO THE FREQUENCY IN GENERAL POPULATION. THESE DATA SUGGEST OCCURRENCE OF NOVEL GENETIC AND EPIGENETIC EVENTS IN DETERMINATION OF BD. CHILDREN WITH BD WERE BORN WITH HIGHER FREQUENCY (P < 0 001) IN FAMILIES WHERE ONE OR BOTH PARENTS WERE UNDER "WHITE PHOSPHORUS" ATTACK, THAT IN THE GENERAL POPULATION. BOMBING OF THE FAMILY HOME AND REMOVAL OF THE RUBBLE WERE ALSO FREQUENTLY REPORTED BY COUPLES WITH BD OCCURRENCE. THESE DATA SUGGESTS A CAUSATIVE/FAVORING ROLE OF ACUTE EXPOSURE OF PARENTS TO THE WEAPONS-ASSOCIATED CONTAMINANTS, AND/OR OF THEIR CHRONIC EXPOSURE FROM THEIR PERSISTENCE IN THE ENVIRONMENT ON THE EMBRYONIC DEVELOPMENT OF THEIR CHILDREN. 2012 20 5353 23 RE-EVALUATION OF POLIHEXANIDE USE IN WOUND ANTISEPSIS IN ORDER TO CLARIFY AMBIGUITIES OF TWO ANIMAL STUDIES. OBJECTIVE: DUE TO CLASSIFICATION OF THE AGENT POLIHEXANIDE (PHMB) IN CATEGORY 2 'MAY CAUSE CANCER' BY THE COMMITTEE FOR RISK ASSESSMENT OF THE EUROPEAN CHEMICALS AGENCY IN 2011, THE USERS OF WOUND ANTISEPTICS MAY BE HIGHLY CONFUSED. IN 2017, THIS STATEMENT WAS UPDATED, DEFINING PHMB UP TO 0.1% AS A PRESERVATIVE SAFE IN ALL COSMETIC PRODUCTS. IN THE INTEREST OF PATIENT SAFETY, A SCIENTIFIC CLARIFICATION OF THE POTENTIAL CARCINOGENICITY OF PHMB IS NECESSARY. METHODS: A MULTIDISCIPLINARY TEAM (MDT) OF MICROBIOLOGISTS, SURGEONS, DERMATOLOGISTS AND BIOCHEMISTS CONDUCTED A BENEFIT-RISK ASSESSMENT TO CLARIFY THE HAZARD OF ANTISEPTIC USE OF PHMB. RESULTS: IN TWO ANIMAL STUDIES, FROM WHICH THE ASSESSMENT OF A CARCINOGENIC RISK WAS DERIVED, PHMB WAS ADMINISTERED ORALLY OVER TWO YEARS IN EXTREMELY HIGH CONCENTRATIONS FAR ABOVE THE NO(A)EL (NO-OBSERVED-(ADVERSE-) EFFECT LEVEL) IN RATS AND MICE. FEEDING IN THE NO(A)EL RANGE RESULTED IN NO ABNORMAL EFFECTS. IN ONE MALE IN THE HIGHEST DOSE GROUP OF 4000PPM PHMB, AN ADENOCARCINOMA WAS FOUND, WHICH THE AUTHOR ATTRIBUTED TO CHRONIC INFLAMMATION OF THE COLON WITH SYSTEMIC ATYPICAL EXPOSURE. THE INCREASING INCIDENCE OF HEMANGIOSARCOMAS HIGHLY PROBABLY RESULTED FROM INCREASED ENDOTHELIAL PROLIFERATION, TRIGGERED BY THE EXCEEDINGLY HIGH DOSAGE FED, BECAUSE PHMB IS NOT GENOTOXIC AND THERE IS NO EVIDENCE FOR EPIGENETIC EFFECTS. DISCUSSION: IT IS WELL KNOWN THAT PHMB IS NOT ABSORBED WHEN APPLIED TOPICALLY. CONSIDERING THE ABSENCE OF GENOTOXICITY AND EPIGENETIC EFFECTS TOGETHER WITH THE INTERPRETATION OF THE ANIMAL STUDIES, IT IS THE CONSENSUS OF THE MULTIDISCIPLINARY EXPERTS THAT A CARCINOGENIC RISK FROM PHMB-USE FOR WOUND ANTISEPSIS CAN BE RULED OUT. CONCLUSION: ON THIS BASIS AND CONSIDERING THEIR EFFECTIVENESS, TOLERABILITY AND CLINICAL EVIDENCE, THE INDICATIONS FOR PHMB BASED WOUND ANTISEPTICS ARE JUSTIFIED. 2019