1  865 146 CHRONIC ACRYLAMIDE EXPOSURE IN MALE MICE RESULTS IN ELEVATED DNA DAMAGE IN THE GERMLINE AND HERITABLE INDUCTION OF CYP2E1 IN THE TESTES. ACUTE ACRYLAMIDE EXPOSURE IN MALE RODENTS RESULTS IN REDUCED REPRODUCTIVE PERFORMANCE AND DOMINANT LETHALITY. HOWEVER, THE REPRODUCTIVE EFFECTS OF LOW DOSE CHRONIC EXPOSURE, WHICH BETTER REFLECTS THE NATURE OF HUMAN EXPOSURE, REMAIN FAR LESS CERTAIN. HUMAN DIETARY CONSUMPTION OF ACRYLAMIDE HAS BEEN ESTIMATED AT AN AVERAGE OF 1-4 MICROG/KG BW/DAY. IN ORDER TO SIMULATE THIS EXPOSURE, MALE MICE WERE PROVIDED WITH ACRYLAMIDE (1 MICROG/ML) VIA THEIR DRINKING WATER CONTINUOUSLY FOR SIX MONTHS, WHICH WAS EQUIVALENT TO A HUMAN DOSE OF 10.5 MICROG/ KG BW/DAY. THIS EXPOSURE REGIME INCREASED DNA DAMAGE IN THE SPERMATOZOA, WITHOUT AFFECTING A CONCOMITANT REDUCTION IN OVERALL FERTILITY. THE OFFSPRING OF ACRYLAMIDE TREATED MICE DID NOT HAVE AN INCREASED INCIDENCE OF SKIN PAPILLOMA FORMATION FOLLOWING THE TWO-STAGE TUMOR INDUCTION PROTOCOL. HOWEVER, THE MALE OFFSPRING OF ACRYLAMIDE TREATED FATHERS HAD SIGNIFICANTLY INCREASED LEVELS OF DNA DAMAGE IN THEIR SPERMATOZOA, DESPITE HAVING HAD NO DIRECT TOXICANT EXPOSURE. IT WAS ALSO FOUND THAT THE F0, AND MOST CRUCIALLY, F1 MICE HAD INCREASED LEVELS OF CYP2E1 PROTEIN IN THEIR GERM CELLS. THIS IS SIGNIFICANT AS CYP2E1 IS THE SOLE ENZYME RESPONSIBLE FOR CONVERSION OF ACRYLAMIDE TO ITS HARMFUL METABOLITE GLYCIDAMIDE. THIS ALTERED EXPRESSION MAY BE DUE TO EPIGENETIC ALTERATIONS. ADDITIONALLY, THE F0 AND F1 MICE HAD INCREASED OXIDATIVE ADDUCTS IN THE DNA OF THEIR GERM CELLS, WHICH WAS HYPOTHESIZED TO ARISE AS A BYPRODUCT OF INCREASED CYP2E1 ACTIVITY. THEREFORE, CHRONIC PATERNAL ACRYLAMIDE EXPOSURE IN MICE HAS CONSEQUENCES FOR THEIR OFFSPRING, AND RAISES CONCERNS FOR THE EFFECTS OF ACRYLAMIDE EXPOSURE IN THE HUMAN POPULATION AND THE ACCUMULATED EFFECTS WITH MULTIPLE GENERATIONS OF EXPOSURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  904  48 CHRONIC EXPOSURE TO CADMIUM INDUCES DIFFERENTIAL METHYLATION IN MICE SPERMATOZOA. CADMIUM EXPOSURE IS UBIQUITOUS AND HAS BEEN LINKED TO DISEASES INCLUDING CANCERS AND REPRODUCTIVE DEFECTS. SINCE CADMIUM IS NONMUTAGENIC, IT IS THOUGHT TO EXERT ITS GENE DYSREGULATORY EFFECTS THROUGH EPIGENETIC REPROGRAMMING. SEVERAL STUDIES HAVE IMPLICATED GERMLINE EXPOSURE TO CADMIUM IN DEVELOPMENTAL REPROGRAMMING. HOWEVER, MOST OF THESE STUDIES HAVE FOCUSED ON MATERNAL EXPOSURE, WHILE THE IMPACT ON SPERM FERTILITY AND DISEASE SUSCEPTIBILITY HAS RECEIVED LESS ATTENTION. IN THIS STUDY, WE USED REDUCED REPRESENTATION BISULFITE SEQUENCING TO COMPREHENSIVELY INVESTIGATE THE IMPACT OF CHRONIC CADMIUM EXPOSURE ON MOUSE SPERMATOZOA DNA METHYLATION. ADULT MALE C57BL/J6 MICE WERE PROVIDED WATER WITH OR WITHOUT CADMIUM CHLORIDE FOR 9 WEEKS. SPERM, TESTES, LIVER, AND KIDNEY TISSUES WERE COLLECTED AT THE END OF THE TREATMENT PERIOD. CADMIUM EXPOSURE WAS CONFIRMED THROUGH GENE EXPRESSION ANALYSIS OF METALLOTHIONEIN-1 AND 2, 2 WELL-KNOWN CADMIUM-INDUCED GENES. ANALYSIS OF SPERM DNA METHYLATION CHANGES REVEALED 1788 DIFFERENTIALLY METHYLATED SITES PRESENT AT REGULATORY REGIONS IN SPERM OF MICE EXPOSED TO CADMIUM COMPARED WITH VEHICLE (CONTROL) MICE. FURTHERMORE, MOST OF THESE DIFFERENTIAL METHYLATION CHANGES POSITIVELY CORRELATED WITH CHANGES IN GENE EXPRESSION AT BOTH THE TRANSCRIPTION INITIATION STAGE AS WELL AS THE SPLICING LEVELS. INTERESTINGLY, THE GENES TARGETED BY CADMIUM EXPOSURE ARE INVOLVED IN SEVERAL CRITICAL DEVELOPMENTAL PROCESSES. OUR RESULTS PRESENT A COMPREHENSIVE ANALYSIS OF THE SPERM METHYLOME IN RESPONSE TO CHRONIC CADMIUM EXPOSURE. THESE DATA, THEREFORE, HIGHLIGHT A FOUNDATIONAL FRAMEWORK TO STUDY GENE EXPRESSION PATTERNS THAT MAY AFFECT FERTILITY IN THE EXPOSED INDIVIDUAL AS WELL AS THEIR OFFSPRING, THROUGH PATERNAL INHERITANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3 1511  43 DNA METHYLATION AND POTENTIAL MULTIGENERATIONAL EPIGENETIC EFFECTS LINKED TO URANIUM CHRONIC LOW-DOSE EXPOSURE IN GONADS OF MALES AND FEMALES RATS. INTRODUCTION: AN INCREASED HEALTH PROBLEM IN INDUSTRIALISED COUNTRIES IS THE CONTEMPORARY CONCERN OF PUBLIC AND SCIENTIFIC COMMUNITY AS WELL. THIS HAS BEEN ATTRIBUTED IN PART TO ACCUMULATED ENVIRONMENTAL POLLUTANTS ESPECIALLY RADIOACTIVE SUBSTANCES AND THE USE OF NUCLEAR POWER PLANTS WORLDWIDE. HOWEVER, THE OUTCOME OF CHRONIC EXPOSURE TO LOW DOSES OF A RADIONUCLIDE SUCH AS URANIUM REMAINS UNKNOWN. RECENTLY, A PARADIGM SHIFT IN THE PERCEPTION OF RISK OF RADIOTOXICOLOGY HAS EMERGED THROUGH INVESTIGATING THE POSSIBILITY OF TRANSMISSION OF BIOLOGICAL EFFECTS OVER GENERATIONS, IN PARTICULAR BY EPIGENETIC PATHWAYS. THESE PROCESSES ARE KNOWN FOR THEIR CRUCIAL ROLES ASSOCIATED WITH THE DEVELOPMENT OF SEVERAL DISEASES. OBJECTIVE: THE CURRENT WORK INVESTIGATES THE EPIGENETIC EFFECT OF CHRONIC EXPOSURE TO LOW DOSES OF URANIUM AND ITS INHERITANCE ACROSS GENERATIONS. MATERIALS AND METHODS TO TEST THIS PROPOSITION, A RODENT MULTIGENERATIONAL MODEL, MALES AND FEMALES, WERE EXPOSED TO A NON-TOXIC CONCENTRATION OF URANIUM (40MGL(-1) DRINKING WATER) FOR NINE MONTHS. THE URANIUM EFFECTS ON WERE EVALUATED OVER THREE GENERATIONS (F0, F1 AND F2) BY ANALYSING THE DNA METHYLATION PROFILE AND DNMT GENES EXPRESSION IN OVARIES AND TESTES TISSUES. RESULTS: HERE WE REPORT A SIGNIFICANT HYPERMETHYLATION OF TESTES DNA (P <0.005) WHEREAS OVARIES SHOWED HYPOMETHYLATED DNA (P <0.005). INTERESTINGLY, THIS DNA METHYLATION PROFILE WAS SIGNIFICANTLY MAINTAINED ACROSS GENERATIONS F0, F1 AND F2. FURTHERMORE, QPCR RESULTS OF BOTH TISSUES IMPLY A SIGNIFICANT CHANGE IN THE EXPRESSION OF DNA METHYLTRANSFERASE GENES (DNMT 1 AND DNMT3A/B) AS WELL. CONCLUSION: ALTOGETHER, OUR WORK DEMONSTRATES FOR THE FIRST TIME A SEX-DEPENDANCE AND INHERITANCE OF EPIGENETIC MARKS, DNA METHYLATION, AS A BIOLOGICAL RESPONSE TO THE EXPOSURE TO LOW DOSES OF URANIUM. HOWEVER, IT IS NOT CLEAR WHICH TYPE OF REPRODUCTIVE CELL TYPE IS MORE RESPONSIVE IN THIS CONTEXT.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                
4 3042  39 GENOME-WIDE ALTERATION OF HISTONE METHYLATION PROFILES ASSOCIATED WITH COGNITIVE CHANGES IN RESPONSE TO DEVELOPMENTAL ARSENIC EXPOSURE IN MICE. INORGANIC ARSENIC IS A XENOBIOTIC ENTERING THE BODY PRIMARILY THROUGH CONTAMINATED DRINKING WATER AND FOOD. THERE ARE DEFINED MECHANISMS THAT DESCRIBE ARSENIC'S ASSOCIATION WITH INCREASED CANCER INCIDENCE, HOWEVER MECHANISMS EXPLAINING ARSENIC EXPOSURE AND NEURODEVELOPMENTAL OR AGING DISORDERS ARE POORLY DEFINED. IN RECENT YEARS, ARSENIC EFFECTS ON EPIGENOME HAVE BECOME A PARTICULAR FOCUS. WE HYPOTHESIZE THAT HUMAN RELEVANT ARSENIC EXPOSURE DURING PARTICULAR DEVELOPMENTAL WINDOWS, OR LONG-TERM EXPOSURE LATER IN LIFE INDUCE PATHOPHYSIOLOGICAL NEURAL CHANGES THROUGH EPIGENOMIC ALTERATIONS, IN PARTICULAR HISTONE METHYLATION PROFILE, MANIFESTING AS COGNITIVE DECLINE. C57BL/6 WILD-TYPE MICE WERE CONTINUALLY EXPOSED TO SODIUM ARSENITE (100 MICROG/L) IN DRINKING WATER PRIOR TO MATING THROUGH WEANING OF THE EXPERIMENTAL PROGENY. A SECOND COHORT OF AGED APP/PS MICE WERE CHRONICALLY EXPOSED TO THE SAME LEVEL OF ARSENIC. COGNITIVE TESTING, HISTOLOGICAL EXAMINATION OF BRAINS AND GENOME-WIDE METHYLATION LEVELS OF H3K4ME3 AND H3K27ME3 EXAMINED AFTER CHIP-SEQ WERE USED TO DETERMINE THE EFFECTS OF ARSENIC EXPOSURE. DEVELOPMENTAL ARSENIC EXPOSURE CAUSED SIGNIFICANTLY DIMINISHED COGNITION IN WILD-TYPE MICE. THE ANALYSIS OF CHIP-SEQ DATA AND EXPERIMENTS WITH MOUSE EMBRYONIC STEM CELLS DEMONSTRATED THAT EPIGENETIC CHANGES INDUCED BY ARSENIC EXPOSURE TRANSLATED INTO GENE EXPRESSION ALTERATIONS ASSOCIATED WITH NEURONAL DEVELOPMENT AND NEUROLOGICAL DISEASE. INCREASED HIPPOCAMPAL AMYLOID PLAQUES LEVELS OF APP/PS MICE AND COGNITIVE DECLINE PROVIDED EVIDENCE THAT ARSENIC EXPOSURE AGGRAVATED AN EXISTING ALZHEIMER'S DISEASE-LIKE PHENOTYPE. WE SHOW DEVELOPMENTAL ARSENIC EXPOSURE SIGNIFICANTLY IMPACTS HISTONE MODIFICATIONS IN BRAIN WHICH REMAIN PRESENT INTO ADULTHOOD AND PROVIDE A POTENTIAL MECHANISM BY WHICH DEVELOPMENTAL ARSENIC EXPOSURE INFLUENCES COGNITIVE FUNCTIONS. WE ALSO SHOW THAT HUMAN RELEVANT, CHRONIC ARSENIC EXPOSURE HAS DELETERIOUS EFFECTS ON ADULT APP/PS MICE AND EXACERBATES EXISTING ALZHEIMER'S DISEASE-LIKE SYMPTOMS. THE RESULTS DEMONSTRATE HOW DEVELOPMENTAL ARSENIC EXPOSURE IMPACTS THE BRAIN EPIGENOME, LEADING TO ALTERED GENE EXPRESSION LATER IN LIFE.	2022	
                                                                                                                                              
5 5166  35 PRECONCEPTION PATERNAL ALCOHOL EXPOSURE EXERTS SEX-SPECIFIC EFFECTS ON OFFSPRING GROWTH AND LONG-TERM METABOLIC PROGRAMMING. BACKGROUND: ALTHOUGH CLINICAL DATA SUPPORT AN ASSOCIATION BETWEEN PATERNAL ALCOHOL USE AND DEFICITS IN CHILD NEUROCOGNITIVE DEVELOPMENT, THE RELATIONSHIP BETWEEN PATERNAL DRINKING AND ALCOHOL-INDUCED GROWTH PHENOTYPES REMAINS CHALLENGING TO DEFINE. USING AN ESTABLISHED MOUSE MODEL OF CHRONIC EXPOSURE, PREVIOUS WORK BY OUR GROUP HAS LINKED PRECONCEPTION PATERNAL ALCOHOL USE TO SEX-SPECIFIC PATTERNS OF FETAL GROWTH RESTRICTION AND PLACENTAL DYSFUNCTION. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE THE LONG-TERM IMPACT OF CHRONIC PRECONCEPTION PATERNAL ALCOHOL USE ON OFFSPRING GROWTH AND METABOLIC PROGRAMMING. RESULTS: PRECONCEPTION PATERNAL ALCOHOL EXPOSURE INDUCED A PROLONGED PERIOD OF FETAL GESTATION AND AN INCREASED INCIDENCE OF INTRAUTERINE GROWTH RESTRICTION, WHICH AFFECTED THE MALE OFFSPRING TO A GREATER EXTENT THAN THE FEMALES. WHILE THE FEMALE OFFSPRING OF ETHANOL-EXPOSED MALES WERE ABLE TO MATCH THE BODY WEIGHTS OF THE CONTROLS WITHIN THE FIRST 2 WEEKS OF POSTNATAL LIFE, MALE OFFSPRING CONTINUED TO DISPLAY AN 11% REDUCTION IN WEIGHT AT 5 WEEKS OF AGE AND A 6% REDUCTION AT 8 WEEKS OF AGE. THE OBSERVED GROWTH DEFICITS ASSOCIATED WITH INSULIN HYPERSENSITIVITY IN THE MALE OFFSPRING, WHILE IN CONTRAST, FEMALES DISPLAYED A MODEST LAG IN THEIR GLUCOSE TOLERANCE TEST. THESE METABOLIC DEFECTS WERE ASSOCIATED WITH AN UP-REGULATION OF GENES WITHIN THE PRO-FIBROTIC TGF-BETA SIGNALING PATHWAY AND INCREASED LEVELS OF CELLULAR HYDROXYPROLINE WITHIN THE LIVERS OF THE MALE OFFSPRING. WE OBSERVED SUPPRESSED CYTOKINE PROFILES WITHIN THE LIVER AND PANCREAS OF BOTH THE MALE AND FEMALE OFFSPRING, WHICH CORRELATED WITH THE UP-REGULATION OF GENES IN THE LIVERX/RETINOIDX/FARNESOIDX RECEPTOR PATHWAYS. HOWEVER, PATTERNS OF GENE EXPRESSION WERE HIGHLY VARIABLE BETWEEN THE OFFSPRING OF ALCOHOL-EXPOSED SIRES. IN THE ADULT OFFSPRING OF ALCOHOL-EXPOSED MALES, WE DID NOT OBSERVE ANY DIFFERENCES IN THE ALLELIC EXPRESSION OF IGF2 OR ANY OTHER IMPRINTED GENES. CONCLUSIONS: THE IMPACT OF PATERNAL ALCOHOL USE ON CHILD DEVELOPMENT IS POORLY EXPLORED AND REPRESENTS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THE TERATOGENIC EFFECTS OF ETHANOL. OUR STUDIES IMPLICATE PATERNAL EXPOSURE HISTORY AS AN ADDITIONAL AND IMPORTANT MODIFIER OF ALCOHOL-INDUCED GROWTH PHENOTYPES AND CHALLENGE THE CURRENT MATERNAL-CENTRIC EXPOSURE PARADIGM.	2019	

6 4008  38 LOW DOSE OF URANIUM INDUCES MULTIGENERATIONAL EPIGENETIC EFFECTS IN RAT KIDNEY. PURPOSE: A PROTOCOL OF CHRONIC EXPOSURE TO LOW DOSE OF URANIUM WAS ESTABLISHED IN ORDER TO DISTINGUISH THE SEXUAL DIFFERENCES AND THE DEVELOPMENTAL PROCESS THAT ARE CRITICAL WINDOWS FOR EPIGENETIC EFFECTS OVER GENERATIONS. METHODS: BOTH MALE AND FEMALE RATS WERE CONTAMINATED THROUGH THEIR DRINKING WATER WITH A NON-TOXIC SOLUTION OF URANYL NITRATE FOR 9 MONTHS. THE EXPOSED GENERATION (F0) AND THE FOLLOWING TWO GENERATIONS (F1 AND F2) WERE EXAMINED. CLINICAL MONITORING, GLOBAL DNA METHYLATION PROFILE AND DNA METHYLTRANSFERASES (DNMTS) GENE EXPRESSION WERE ANALYZED IN KIDNEYS. RESULTS: WHILE THE BODY WEIGHT OF F1 MALES INCREASED, A SMALL DECREASE IN KIDNEY AND BODY WEIGHT WAS OBSERVED IN F2 MALES. IN ADDITION, GLOBAL DNA HYPERMETHYLATION PROFILE IN KIDNEY CELLS WAS OBSERVED IN F1 AND F2 MALES. QPCR RESULTS REVEAL A SIGNIFICANT INCREASE OF METHYLTRANSFERASE GENES EXPRESSION (DNMT1 AND DNMT3A) FOR F2 FEMALES. CONCLUSIONS: IN THE FIELD OF PUBLIC HEALTH POLICY AND TO RAISE ATTENTION TO GENERATIONAL EFFECTS FOR THE RISK ASSESSMENT OF THE ENVIRONMENTAL EXPOSURES, LOW DOSES OF URANIUM DO NOT IMPLY CLINICAL EFFECTS ON ADULT EXPOSED RATS. HOWEVER, OUR RESULTS CONFIRM THE IMPORTANCE OF THE DEVELOPMENTAL WINDOWS' SENSITIVITY IN ADDITION TO THE SEXUAL DIMORPHISMS OF THE OFFSPRING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7 6553  32 TRANSGENERATIONAL EFFECTS IN DNA METHYLATION, GENOTOXICITY AND REPRODUCTIVE PHENOTYPE BY CHRONIC ARSENIC EXPOSURE. AN EMERGING CONCERN IS THE INFLUENCES OF EARLY LIFE EXPOSURE TO ENVIRONMENTAL TOXICANTS ON OFFSPRING CHARACTERISTICS IN LATER LIFE. SINCE RECENT EVIDENCE SUGGESTS A TRANSGENERATIONAL TRANSFERENCE OF ABERRANT PHENOTYPES FROM EXPOSED-PARENTS TO NON-EXPOSED OFFSPRING RELATED TO ADULT-ONSET DISEASES INCLUDING REPRODUCTIVE PHENOTYPE. THE TRANSGENERATIONAL POTENTIAL OF ARSENIC A WELL KNOW GENOTOXIC AND EPIGENETIC MODIFIER AGENT HAS NOT BEEN ASSESSED IN MAMMALS UNTIL NOW. IN THIS EXPERIMENTAL STUDY, WE EVALUATED THE TRANSGENERATIONAL EFFECTS OF ARSENIC IN A RAT MODEL WITH CHRONIC EXPOSURE TO ARSENIC. RATS CHRONICALLY EXPOSED TO ARSENIC IN DRINKING WATER (1 MG AS(2)O(3)/ML) (F0) WERE MATED TO PRODUCE THE ARSENIC LINEAGE (F1, F2, AND F3). THE ARSENIC TOXIC EFFECTS ON WERE EVALUATED OVER THE FOUR GENERATIONS BY ANALYZING THE DNA METHYLATION PERCENTAGE, GENOTOXICITY IN WBC AND PHYSICAL AND REPRODUCTIVE PARAMETERS, INCLUDING SPERM QUALITY PARAMETERS AND HISTOPATHOLOGICAL EVALUATION OF THE GONADS. CHRONIC EXPOSURE TO ARSENIC CAUSED GENOTOXIC DAMAGE (F0-F3) DIFFERENT METHYLATION PATTERNS, ALTERATIONS IN PHYSICAL AND REPRODUCTIVE PARAMETERS, ABERRANT MORPHOLOGY IN THE OVARIES (F0 AND F1) AND TESTICLES (F1-F3), AND A DECREASE IN THE QUALITY OF SPERM (F0-F3, EXCEPT F2). PARENTAL CHRONIC ARSENIC EXPOSURE CAUSES TRANSGENERATIONAL GENOTOXICITY AND CHANGES IN GLOBAL DNA METHYLATION WHICH MIGHT BE ASSOCIATED WITH REPRODUCTIVE DEFECTS IN RATS. COMBINED WITH RECENT STUDIES REVEAL THAT DISTURBANCES IN THE EARLY LIFE OF AN INDIVIDUAL CAN AFFECT THE HEALTH OF LATER GENERATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 4224  35 METHYLATION CHANGES IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE EXPOSED TO ACUTE AND CHRONIC LOW-DOSE X-RAY-IRRADIATION. THE BIOLOGICAL AND GENETIC EFFECTS OF CHRONIC LOW-DOSE RADIATION (LDR) EXPOSURE AND ITS RELATIONSHIP TO CARCINOGENESIS HAVE RECEIVED A LOT OF ATTENTION IN THE RECENT YEARS. FOR EXAMPLE, RADIATION-INDUCED GENOME INSTABILITY, WHICH IS THOUGHT TO BE A PRECURSOR OF TUMOROGENESIS, WAS SHOWN TO HAVE A TRANSGENERATIONAL NATURE. THIS INDICATES A POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LDR-INDUCED GENOME INSTABILITY. GENOMIC DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MECHANISMS. EXISTING DATA ON RADIATION EFFECTS ON DNA METHYLATION PATTERNS IS LIMITED, AND NO ONE HAS SPECIFICALLY STUDIED THE EFFECTS OF THE LDR. WE REPORT THE FIRST STUDY OF THE EFFECTS OF WHOLE-BODY LDR EXPOSURE ON GLOBAL GENOME METHYLATION IN MUSCLE AND LIVER TISSUES OF MALE AND FEMALE MICE. IN PARALLEL, WE EVALUATED CHANGES IN PROMOTER METHYLATION AND EXPRESSION OF THE TUMOR SUPPRESSOR GENE P16(INKA) AND DNA REPAIR GENE O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT). WE OBSERVED DIFFERENT PATTERNS OF RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION IN THE LIVER AND MUSCLE OF EXPOSED MALES AND FEMALES. WE ALSO FOUND SEX AND TISSUE-SPECIFIC DIFFERENCES IN P16(INKA) PROMOTER METHYLATION UPON LDR EXPOSURE. IN MALE LIVER TISSUE, P16(INKA) PROMOTER METHYLATION WAS MORE PRONOUNCED THAN IN FEMALE TISSUE. IN CONTRAST, NO SIGNIFICANT RADIATION-INDUCED CHANGES IN P16(INKA) PROMOTER METHYLATION WERE NOTED IN THE MUSCLE TISSUE OF EXPOSED MALES AND FEMALES. RADIATION ALSO DID NOT SIGNIFICANTLY AFFECT METHYLATION STATUS OF MGMT PROMOTER. WE ALSO OBSERVED SUBSTANTIAL SEX DIFFERENCES IN ACUTE AND CHRONIC RADIATION-INDUCED EXPRESSION OF P16(INKA) AND MGMT GENES. ANOTHER IMPORTANT OUTCOME OF OUR STUDY WAS THE FACT THAT CHRONIC LOW-DOSE RADIATION EXPOSURE PROVED TO BE A MORE POTENT INDUCER OF EPIGENETIC EFFECTS THAN THE ACUTE EXPOSURE. THIS SUPPORTS PREVIOUS FINDINGS THAT CHRONIC EXPOSURE LEADS TO GREATER GENOME DESTABILIZATION THAN ACUTE EXPOSURE.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                      
9 6078  45 THE EFFECT OF CHRONIC ARSENIC EXPOSURE IN ZEBRAFISH. ARSENIC IS A PREVALENT ENVIRONMENTAL TOXIN AND A GROUP ONE HUMAN CARCINOGENIC AGENT. CHRONIC ARSENIC EXPOSURE HAS BEEN ASSOCIATED WITH MANY HUMAN DISEASES. THE AIM OF THIS STUDY IS TO EVALUATE ZEBRAFISH AS AN ANIMAL MODEL TO ASSESS ARSENIC TOXICITY IN ELEVATED LONG-TERM ARSENIC EXPOSURE. WITH PROLONGED EXPOSURE (6 MONTHS) TO VARIOUS CONCENTRATIONS OF ARSENIC FROM 50 PPB TO 300 PPB, EFFECTS OF ARSENIC ACCUMULATION IN ZEBRAFISH TISSUES, AND PHENOTYPES WERE INVESTIGATED. RESULTS SHOWED THAT THERE ARE NO SIGNIFICANT CHANGES OF ARSENIC RETENTION IN ZEBRAFISH TISSUES, AND ZEBRAFISH DID NOT EXHIBIT ANY VISIBLE TUMOR FORMATION UNDER ARSENIC EXPOSURE CONDITIONS. HOWEVER, THE ZEBRAFISH DEMONSTRATE A DYSFUNCTION IN THEIR NEUROLOGICAL SYSTEM, WHICH IS REFLECTED BY A REDUCTION OF LOCOMOTIVE ACTIVITY. MOREOVER, ELEVATED LEVELS OF THE SUPEROXIDE DISMUTASE (SOD2) PROTEIN WERE DETECTED IN THE EYE AND LIVER, SUGGESTING INCREASED OXIDATIVE STRESS. IN ADDITION, THE PROGENIES OF ARSENIC-TREATED PARENTS DISPLAYED A SMALLER BIOMASS (FOUR-FOLD REDUCTION IN BODY WEIGHT) COMPARED WITH THOSE FROM THEIR PARENTAL CONTROLS. THIS RESULT INDICATES THAT ARSENIC MAY INDUCE GENETIC OR EPIGENETIC CHANGES THAT ARE THEN PASSED ON TO THE NEXT GENERATION. OVERALL, THIS STUDY DEMONSTRATES THAT ZEBRAFISH IS A CONVENIENT VERTEBRATE MODEL WITH ADVANTAGES IN THE EVALUATION OF ARSENIC-ASSOCIATED NEUROLOGICAL DISORDERS AS WELL AS ITS INFLUENCES ON THE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 1655  26 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11 1815  27 EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN ON EPIGENETIC REGULATORY GENES EXPRESSION AND EPIGENETIC CODE IN HUMAN PROSTATE EPITHELIAL CELLS. CHRONIC EXPOSURES TO ARSENIC AND ESTROGEN ARE KNOWN RISK FACTORS FOR PROSTATE CANCER. THOUGH THE EVIDENCE SUGGESTS THAT EXPOSURE TO ARSENIC OR ESTROGENS CAN DISRUPT NORMAL DNA METHYLATION PATTERNS AND HISTONE MODIFICATIONS, THE MECHANISMS BY WHICH THESE CHEMICALS INDUCE EPIGENETIC CHANGES ARE NOT FULLY UNDERSTOOD. MOREOVER, THE EPIGENETIC EFFECTS OF CO-EXPOSURE TO THESE TWO CHEMICALS ARE NOT KNOWN. THEREFORE, THE OBJECTIVE OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF CHRONIC EXPOSURE TO ARSENIC AND ESTROGEN, BOTH ALONE AND IN COMBINATION, ON THE EXPRESSION OF EPIGENETIC REGULATORY GENES, THEIR CONSEQUENCES ON DNA METHYLATION, AND HISTONE MODIFICATIONS. HUMAN PROSTATE EPITHELIAL CELLS, RWPE-1, CHRONICALLY EXPOSED TO ARSENIC AND ESTROGEN ALONE AND IN COMBINATION WERE USED FOR ANALYSIS OF EPIGENETIC REGULATORY GENES EXPRESSION, GLOBAL DNA METHYLATION CHANGES, AND HISTONE MODIFICATIONS AT PROTEIN LEVEL. THE RESULT OF THIS STUDY REVEALED THAT EXPOSURE TO ARSENIC, ESTROGEN, AND THEIR COMBINATION ALTERS THE EXPRESSION OF EPIGENETIC REGULATORY GENES AND CHANGES GLOBAL DNA METHYLATION AND HISTONE MODIFICATION PATTERNS IN RWPE-1 CELLS. THESE CHANGES WERE SIGNIFICANTLY GREATER IN ARSENIC AND ESTROGEN COMBINATION TREATED GROUP THAN INDIVIDUALLY TREATED GROUP. THE FINDINGS OF THIS STUDY WILL HELP EXPLAIN THE EPIGENETIC MECHANISM OF ARSENIC- AND/OR ESTROGEN-INDUCED PROSTATE CARCINOGENESIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12 5628  33 SEMEN ABNORMALITIES, SPERM DNA DAMAGE AND GLOBAL HYPERMETHYLATION IN HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION. BACKGROUND: CYTOGENETIC STUDIES HAVE DEMONSTRATED THAT LOW LEVELS OF CHRONIC RADIATION EXPOSURE CAN POTENTIALLY INCREASE THE FREQUENCY OF CHROMOSOMAL ABERRATIONS AND ANEUPLOIDY IN SOMATIC CELLS. EPIDEMIOLOGICAL STUDIES HAVE SHOWN THAT HEALTH WORKERS OCCUPATIONALLY EXPOSED TO IONIZING RADIATION BEAR AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES. OBJECTIVES: TO FIND THE INFLUENCE OF OCCUPATIONAL RADIATION EXPOSURE ON SEMEN CHARACTERISTICS, INCLUDING GENETIC AND EPIGENETIC INTEGRITY OF SPERMATOZOA IN A CHRONICALLY EXPOSED POPULATION. METHODS: THIS CROSS SECTIONAL STUDY INCLUDED 134 MALE VOLUNTEERS OF WHICH 83 WERE OCCUPATIONALLY EXPOSED TO IONIZING RADIATION AND 51 WERE NON-EXPOSED CONTROL SUBJECTS. SEMEN CHARACTERISTICS, SPERM DNA FRAGMENTATION, ANEUPLOIDY AND INCIDENCE OF GLOBAL HYPERMETHYLATION IN THE SPERMATOZOA WERE DETERMINED AND COMPARED BETWEEN THE NON-EXPOSED AND THE EXPOSED GROUP. RESULTS: DIRECT COMPARISON OF THE SEMEN CHARACTERISTICS BETWEEN THE NON-EXPOSED AND THE EXPOSED POPULATION REVEALED SIGNIFICANT DIFFERENCES IN MOTILITY CHARACTERISTICS, VIABILITY, AND MORPHOLOGICAL ABNORMALITIES (P<0.05-0.0001). ALTHOUGH, THE LEVEL OF SPERM DNA FRAGMENTATION WAS SIGNIFICANTLY HIGHER IN THE EXPOSED GROUP AS COMPARED TO THE NON-EXPOSED GROUP (P<0.05-0.0001), THE INCIDENCE OF SPERM ANEUPLOIDY WAS NOT STATISTICALLY DIFFERENT BETWEEN THE TWO GROUPS. HOWEVER, A SIGNIFICANT NUMBER OF HYPERMETHYLATED SPERMATOZOA WERE OBSERVED IN THE EXPOSED GROUP IN COMPARISON TO NON-EXPOSED GROUP (P<0.05). CONCLUSIONS: WE PROVIDE THE FIRST EVIDENCE ON THE DETRIMENTAL EFFECTS OF OCCUPATIONAL RADIATION EXPOSURE ON FUNCTIONAL, GENETIC AND EPIGENETIC INTEGRITY OF SPERM IN HEALTH WORKERS. HOWEVER, FURTHER STUDIES ARE REQUIRED TO CONFIRM THE POTENTIAL DETRIMENTAL EFFECTS OF IONIZING RADIATION IN THESE SUBJECTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  457  35 APPLYING A MULTISCALE SYSTEMS BIOLOGY APPROACH TO STUDY THE EFFECT OF CHRONIC LOW-DOSE EXPOSURE TO URANIUM IN RAT KIDNEYS. PURPOSE: TO EXAMINE THE EFFECTS OF LOW-DOSE EXPOSURE TO URANIUM WITH A SYSTEMS BIOLOGY APPROACH, A MULTISCALE HIGH-THROUGHPUT MULTI-OMICS ANALYSIS WAS APPLIED WITH A PROTOCOL FOR CHRONIC EXPOSURE TO THE RAT KIDNEY. METHODS: MALE AND FEMALE RATS WERE CONTAMINATED FOR NINE MONTHS THROUGH THEIR DRINKING WATER WITH A NONTOXIC SOLUTION OF URANYL NITRATE. A MULTISCALE APPROACH ENABLED CLINICAL MONITORING ASSOCIATED WITH METABOLOMIC AND TRANSCRIPTOMIC (MRNA AND MICRORNA) ANALYSES. RESULTS: A SEX-INTERACTION EFFECT WAS OBSERVED IN THE KIDNEY, URINE, AND PLASMA METABOLOMES OF CONTAMINATED RATS. MOREOVER, URINE AND KIDNEY METABOLIC PROFILES CORRELATED AND CONFIRMED THAT THE PRIMARY DYSREGULATED METABOLISMS ARE THOSE OF NICOTINATE-NICOTINAMIDE AND OF UNSATURATED FATTY ACID BIOSYNTHESIS. UPSTREAM OF THE METABOLIC PATHWAYS, TRANSCRIPTOMIC PROFILES OF THE KIDNEY REVEAL GENE ACTIVITY FOCUSED ON GENE REGULATION MECHANISMS, CELL SIGNALING, CELL STRUCTURE, DEVELOPMENTAL PROCESSES, AND CELL PROLIFERATION. EXAMINATION OF EPIGENETIC POST-TRANSCRIPTIONAL GENE REGULATION PROCESSES SHOWED SIGNIFICANT DYSREGULATION OF 70 MICRO-RNAS. THE MULTI-OMICS APPROACH HIGHLIGHTED THE ACTIVITIES OF THE CELLS' BIOLOGICAL PROCESSES ON MULTIPLE SCALES THROUGH ANALYSIS OF GENE EXPRESSION, CONFIRMED BY CHANGES OBSERVED IN THE METABOLOME. CONCLUSION: OUR RESULTS SHOWED CHANGES IN MULTI-OMIC PROFILES OF RATS EXPOSED TO LOW DOSES OF URANIUM CONTAMINATION, COMPARED WITH CONTROLS. THESE CHANGES INVOLVED GENE EXPRESSION AS WELL AS MODIFICATIONS IN THE TRANSCRIPTOME AND THE METABOLOME. THE METABOLOMIC PROFILE CONFIRMED THAT THE MAIN MOLECULAR TARGETS OF URANIUM IN KIDNEY CELLS ARE THE METABOLISM OF NICOTINATE-NICOTINAMIDE AND THE BIOSYNTHESIS OF UNSATURATED FATTY ACIDS. ADDITIONALLY, GENE EXPRESSION ANALYSIS SHOWED THAT THE METABOLISM OF FATTY ACIDS IS TARGETED BY PROCESSES ASSOCIATED WITH CELL FUNCTION. THESE RESULTS DEMONSTRATE THAT MULTISCALE SYSTEMS BIOLOGY IS USEFUL IN ELUCIDATING THE MOST DISCRIMINATIVE PATHWAYS FROM GENOMIC TO METABOLOMIC LEVELS FOR ASSESSING THE BIOLOGICAL IMPACT OF THIS LOW-LEVEL ENVIRONMENTAL EXPOSURE, I.E. THE EXPOSOME.	2019	
                                                                                                                                                                                                         
14  126  50 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	
                                                                                                                                                                                                          
15 5397  36 REDUCED LEVELS OF MIRNAS 449 AND 34 IN SPERM OF MICE AND MEN EXPOSED TO EARLY LIFE STRESS. EXPOSURE OF MALE MICE TO EARLY LIFE STRESS ALTERS THE LEVELS OF SPECIFIC SPERM MIRNAS THAT PROMOTE STRESS-ASSOCIATED BEHAVIORS IN THEIR OFFSPRING. TO BEGIN TO EVALUATE WHETHER SIMILAR PHENOMENA OCCUR IN MEN, WE SEARCHED FOR SPERM MIRNA CHANGES THAT OCCUR IN BOTH MICE AND MEN EXPOSED TO EARLY LIFE STRESSORS THAT HAVE LONG-LASTING EFFECTS. FOR MEN, WE USED THE ADVERSE CHILDHOOD EXPERIENCE (ACE) QUESTIONNAIRE. IT REVEALS THE DEGREE OF ABUSIVE AND/OR DYSFUNCTIONAL FAMILY EXPERIENCES WHEN YOUNG, WHICH INCREASES RISKS OF DEVELOPING FUTURE PSYCHOLOGICAL AND PHYSICAL DISORDERS. FOR MALE MICE, WE USED ADOLESCENT CHRONIC SOCIAL INSTABILITY (CSI) STRESS, WHICH NOT ONLY ENHANCES SOCIABILITY DEFECTS FOR >1 YEAR, BUT ALSO ANXIETY AND DEFECTIVE SOCIABILITY IN FEMALE OFFSPRING FOR MULTIPLE GENERATIONS THROUGH THE MALE LINEAGE. HERE WE FOUND A STATISTICALLY SIGNIFICANT INVERSE CORRELATION BETWEEN LEVELS OF MULTIPLE MIRNAS OF THE MIR-449/34 FAMILY AND ACE SCORES OF CAUCASIAN MALES. REMARKABLY, WE FOUND MEMBERS OF THE SAME SPERM MIRNA FAMILY ARE ALSO REDUCED IN MICE EXPOSED TO CSI STRESS. THUS, FUTURE STUDIES SHOULD BE DESIGNED TO DIRECTLY TEST WHETHER REDUCED LEVELS OF THESE MIRNAS COULD BE USED AS UNBIASED INDICATORS OF CURRENT AND/OR EARLY LIFE EXPOSURE TO SEVERE STRESS. MOREOVER, AFTER MATING STRESSED MALE MICE, THESE SPERM MIRNA REDUCTIONS PERSIST IN BOTH EARLY EMBRYOS THROUGH AT LEAST THE MORULA STAGE AND IN SPERM OF MALES DERIVED FROM THEM, SUGGESTING THESE MIRNA CHANGES CONTRIBUTE TO TRANSMISSION OF STRESS PHENOTYPES ACROSS GENERATIONS. SINCE OFFSPRING OF MEN EXPOSED TO EARLY LIFE TRAUMA HAVE ELEVATED RISKS FOR PSYCHOLOGICAL DISORDERS, THESE FINDINGS RAISE THE POSSIBILITY THAT A PORTION OF THIS RISK MAY BE DERIVED FROM EPIGENETIC REGULATION OF THESE SPERM MIRNAS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
16 2472  28 EPIGENETIC TRANSMISSION OF THE IMPACT OF EARLY STRESS ACROSS GENERATIONS. BACKGROUND: TRAUMATIC EXPERIENCES IN EARLY LIFE ARE RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL AND EMOTIONAL DISORDERS. SUCH DISORDERS CAN PERSIST THROUGH ADULTHOOD AND HAVE OFTEN BEEN REPORTED TO BE TRANSMITTED ACROSS GENERATIONS. METHODS: TO INVESTIGATE THE TRANSGENERATIONAL EFFECT OF EARLY STRESS, MICE WERE EXPOSED TO CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION FROM POSTNATAL DAY 1 TO 14. RESULTS: WE SHOW THAT CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION INDUCES DEPRESSIVE-LIKE BEHAVIORS AND ALTERS THE BEHAVIORAL RESPONSE TO AVERSIVE ENVIRONMENTS IN THE SEPARATED ANIMALS WHEN ADULT. MOST OF THE BEHAVIORAL ALTERATIONS ARE FURTHER EXPRESSED BY THE OFFSPRING OF MALES SUBJECTED TO MATERNAL SEPARATION, DESPITE THE FACT THAT THESE MALES ARE REARED NORMALLY. CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION ALSO ALTERS THE PROFILE OF DNA METHYLATION IN THE PROMOTER OF SEVERAL CANDIDATE GENES IN THE GERMLINE OF THE SEPARATED MALES. COMPARABLE CHANGES IN DNA METHYLATION ARE ALSO PRESENT IN THE BRAIN OF THE OFFSPRING AND ARE ASSOCIATED WITH ALTERED GENE EXPRESSION. CONCLUSIONS: THESE FINDINGS HIGHLIGHT THE NEGATIVE IMPACT OF EARLY STRESS ON BEHAVIORAL RESPONSES ACROSS GENERATIONS AND ON THE REGULATION OF DNA METHYLATION IN THE GERMLINE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17 5773  43 SPERM MICRORNA CONTENT IS ALTERED IN A MOUSE MODEL OF MALE OBESITY, BUT THE SAME SUITE OF MICRORNAS ARE NOT ALTERED IN OFFSPRING'S SPERM. THE PREVALENCE OF OBESITY IS INCREASING WORLDWIDE AND HAS TRIPLED IN MEN OF REPRODUCTIVE AGE SINCE THE 1970S. CONCERNINGLY, OBESITY IS NOT ONLY COMORBID WITH OTHER CHRONIC DISEASES, BUT THERE IS MOUNTING EVIDENCE THAT IT INCREASES THE NON-COMMUNICABLE DISEASE LOAD IN THEIR CHILDREN (EG MORTALITY, OBESITY, AUTISM). ANIMAL STUDIES HAVE DEMONSTRATED THAT PATERNAL OBESITY INCREASES THE RISK OF METABOLIC (EG GLUCOSE METABOLISM DEFECTS, OBESITY) AND REPRODUCTIVE DISORDERS IN OFFSPRING. EPIGENETIC CHANGES WITHIN SPERM ARE CLEAR MECHANISTIC CANDIDATES THAT ARE ASSOCIATED WITH BOTH CHANGES TO THE FATHER'S ENVIRONMENT AND OFFSPRING PHENOTYPE. SPECIFICALLY THERE IS EMERGING EVIDENCE THAT A FATHER'S SPERM MICRORNA CONTENT BOTH RESPONDS TO PATERNAL ENVIRONMENTAL CUES AND ALTERS THE GENE EXPRESSION PROFILE AND SUBSEQUENT DEVELOPMENT OF THE EARLY EMBRYO. WE USED A MOUSE MODEL OF HIGH FAT DIET (HFD) INDUCED OBESITY TO INVESTIGATE WHETHER MALE OBESITY COULD MODULATE SPERM MICRORNA CONTENT. WE ALSO INVESTIGATED WHETHER THIS ALTERATION TO A FATHER'S SPERM MICRORNA CONTENT LEAD TO A SIMILAR CHANGE IN THE SPERM OF MALE OFFSPRING. OUR INVESTIGATIONS WERE INITIALLY GUIDED BY A TAQMAN PCR ARRAY, WHICH INDICATED THE DIFFERENTIAL ABUNDANCE OF 28 SPERM BORNE MICRORNAS IN HFD MICE. QPCR CONFIRMATION IN A MUCH LARGER COHORT OF FOUNDER MALES DEMONSTRATED THAT 13 OF THESE MICRORNAS WERE DIFFERENTIALLY ABUNDANT (11 UP-REGULATED; 2 DOWN-REGULATED) DUE TO HFD FEEDING. DESPITE METABOLIC AND REPRODUCTIVE PHENOTYPES ALSO BEING OBSERVED IN GRAND-OFFSPRING FATHERED VIA THE MALE OFFSPRING LINEAGE, THERE WAS NO EVIDENCE THAT ANY OF THE 13 MICRORNAS WERE ALSO DYSREGULATED IN MALE OFFSPRING SPERM. THIS WAS PRESUMABLY DUE TO THE VARIATION SEEN WITHIN BOTH GROUPS OF OFFSPRING AND SUGGESTS OTHER MECHANISMS MIGHT ACT BETWEEN OFFSPRING AND GRAND-OFFSPRING. THUS 13 SPERM BORNE MICRORNAS ARE MODULATED BY A FATHER'S HFD AND THE PRESUMED TRANSFER OF THIS ALTERED MICRORNA PAYLOAD TO THE EMBRYO AT FERTILISATION POTENTIALLY ACTS TO ALTER THE EMBRYONIC MOLECULAR MAKEUP POST-FERTILISATION, ALTERING ITS GROWTH TRAJECTORY, ULTIMATELY AFFECTING ADULT OFFSPRING PHENOTYPE AND MAY CONTRIBUTE TO PATERNAL PROGRAMMING.	2016	
                                                                                                                                  
18 6562  30 TRANSIENT AND PERMANENT CHANGES IN DNA METHYLATION PATTERNS IN INORGANIC ARSENIC-MEDIATED EPITHELIAL-TO-MESENCHYMAL TRANSITION. CHRONIC LOW DOSE INORGANIC ARSENIC EXPOSURE CAUSES CELLS TO TAKE ON AN EPITHELIAL-TO-MESENCHYMAL PHENOTYPE, WHICH IS A CRUCIAL PROCESS IN CARCINOGENESIS. INORGANIC ARSENIC IS NOT A MUTAGEN AND THUS EPIGENETIC ALTERATIONS HAVE BEEN IMPLICATED IN THIS PROCESS. INDEED, DURING THE EPITHELIAL-TO-MESENCHYMAL TRANSITION, MORPHOLOGIC CHANGES TO CELLS CORRELATE WITH CHANGES IN CHROMATIN STRUCTURE AND GENE EXPRESSION, ULTIMATELY DRIVING THIS PROCESS. HOWEVER, STUDIES ON THE EFFECTS OF INORGANIC ARSENIC EXPOSURE/WITHDRAWAL ON THE EPITHELIAL-TO-MESENCHYMAL TRANSITION AND THE IMPACT OF EPIGENETIC ALTERATIONS IN THIS PROCESS ARE LIMITED. IN THIS STUDY WE USED HIGH-RESOLUTION MICROARRAY ANALYSIS TO MEASURE THE CHANGES IN DNA METHYLATION IN CELLS UNDERGOING INORGANIC ARSENIC-INDUCED EPITHELIAL-TO-MESENCHYMAL TRANSITION, AND ON THE REVERSAL OF THIS PROCESS, AFTER REMOVAL OF THE INORGANIC ARSENIC EXPOSURE. WE FOUND THAT CELLS EXPOSED TO CHRONIC, LOW-DOSE INORGANIC ARSENIC EXPOSURE SHOWED 30,530 SITES WERE DIFFERENTIALLY METHYLATED, AND WITH INORGANIC ARSENIC WITHDRAWAL SEVERAL DIFFERENTIAL METHYLATED SITES WERE REVERSED, ALBEIT NOT COMPLETELY. FURTHERMORE, THESE CHANGES IN DNA METHYLATION MAINLY CORRELATED WITH CHANGES IN GENE EXPRESSION AT MOST SITES TESTED BUT NOT AT ALL. THIS STUDY SUGGESTS THAT DNA METHYLATION CHANGES ON GENE EXPRESSION ARE NOT CLEAR-CUT AND PROVIDE A PLATFORM TO BEGIN TO UNCOVER THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION, SPECIFICALLY WITHIN THE CONTEXT OF INORGANIC ARSENIC TREATMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 3837  29 IONIZING RADIATION-INDUCED OXIDATIVE STRESS, EPIGENETIC CHANGES AND GENOMIC INSTABILITY: THE PIVOTAL ROLE OF MITOCHONDRIA. PURPOSE: TO REVIEW THE DATA CONCERNING THE ROLE OF ENDOGENOUSLY GENERATED REACTIVE OXYGEN SPECIES (ROS) IN THE NON-TARGETED IONIZING RADIATION (IR) EFFECTS AND IN DETERMINATION OF THE CELL POPULATION'S FATE, BOTH EARLY AFTER EXPOSURE AND AFTER MANY GENERATIONS. CONCLUSIONS: THE SHORT-TERM AS WELL AS CHRONIC OXIDATIVE STRESS RESPONSES MAINLY ARE PRODUCED DUE TO ROS GENERATION BY THE ELECTRON TRANSPORT CHAIN (ETC) OF THE MITOCHONDRIA AND BY THE CYTOPLASMIC NADPH OXIDASES. WHETHER THE INDUCTION OF THE OXIDATIVE STRESS AND ITS CONSEQUENCES OCCUR OR ARE HAMPERED IN A SINGLE CELL LARGELY DEPENDS ON THE INTERACTION BETWEEN THE NUCLEUS AND THE CELLULAR POPULATION OF SEVERAL HUNDRED OR THOUSANDS OF MITOCHONDRIA THAT ARE GENETICALLY HETEROGENEOUS. HIGH INTRA-MITOCHONDRIAL ROS LEVEL IS DAMAGING THE MITOCHONDRIAL (MT) DNA AND ITS MUTATIONS AFFECT THE EPIGENETIC CONTROL MECHANISMS OF THE NUCLEAR (N) DNA, BY DECREASING THE ACTIVITY OF METHYLTRANSFERASES AND THUS, CAUSING GLOBAL DNA HYPOMETHYLATION. THESE CHANGES ARE TRANSMITTED TO THE PROGENY OF THE IRRADIATED CELLS. THE CHRONIC OXIDATIVE STRESS IS THE MAIN CAUSE OF THE LATE POST-RADIATION EFFECTS, INCLUDING CANCER, AND THIS MAKES IT AN IMPORTANT ADVERSE EFFECT OF EXPOSURE TO IR AND A TARGET FOR RADIOLOGICAL PROTECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20 4767  28 NUCLEAR AND MITOCHONDRIAL DNA ALTERATIONS IN NEWBORNS WITH PRENATAL EXPOSURE TO CIGARETTE SMOKE. NEWBORNS EXPOSED TO MATERNAL CIGARETTE SMOKE (CS) IN UTERO HAVE AN INCREASED RISK OF DEVELOPING CHRONIC DISEASES, CANCER, AND ACQUIRING DECREASED COGNITIVE FUNCTION IN ADULTHOOD. ALTHOUGH THE LITERATURE REPORTS MANY DELETERIOUS EFFECTS ASSOCIATED WITH MATERNAL CIGARETTE SMOKING ON THE FETUS, THE MOLECULAR ALTERATIONS AND MECHANISMS OF ACTION ARE NOT YET CLEAR. SMOKING MAY ACT DIRECTLY ON NUCLEAR DNA BY INDUCING MUTATIONS OR EPIGENETIC MODIFICATIONS. RECENT STUDIES ALSO INDICATE THAT SMOKING MAY ACT ON MITOCHONDRIAL DNA BY INDUCING A CHANGE IN THE NUMBER OF COPIES TO MAKE UP FOR THE DAMAGE CAUSED BY SMOKING ON THE RESPIRATORY CHAIN AND LACK OF ENERGY. IN ADDITION, INDIVIDUAL GENETIC SUSCEPTIBILITY PLAYS A SIGNIFICANT ROLE IN DETERMINING THE EFFECTS OF SMOKING DURING DEVELOPMENT. FURTHERMORE, PRIOR EXPOSURE OF PATERNAL AND MATERNAL GAMETES TO CIGARETTE SMOKE MAY AFFECT THE HEALTH OF THE DEVELOPING INDIVIDUAL, NOT ONLY THE IN UTERO EXPOSURE. THIS REVIEW EXAMINES THE GENETIC AND EPIGENETIC ALTERATIONS IN NUCLEAR AND MITOCHONDRIAL DNA ASSOCIATED WITH SMOKE EXPOSURE DURING THE MOST SENSITIVE PERIODS OF DEVELOPMENT (PRIOR TO CONCEPTION, PRENATAL AND EARLY POSTNATAL) AND ASSESSES HOW SUCH CHANGES MAY HAVE CONSEQUENCES FOR BOTH FETAL GROWTH AND DEVELOPMENT.	2015