1  1325 113 DEPLETED URANIUM INDUCES SEX- AND TISSUE-SPECIFIC METHYLATION PATTERNS IN ADULT ZEBRAFISH. WE EXAMINED THE EFFECTS OF CHRONIC EXPOSURE TO DIFFERENT CONCENTRATIONS (2 AND 20 MUG L(-)(1)) OF ENVIRONMENTALLY RELEVANT WATERBORNE DEPLETED URANIUM (DU) ON THE DNA METHYLATION PATTERNS BOTH AT HPAII RESTRICTION SITES (5'-CCGG-3') AND ACROSS THE WHOLE GENOME IN THE ZEBRAFISH BRAIN, GONADS, AND EYES. WE FIRST IDENTIFIED SEX-DEPENDENT DIFFERENCES IN THE METHYLATION LEVEL OF HPAII SITES AFTER EXPOSURE. IN MALES, THESE EFFECTS WERE PRESENT AS EARLY AS 7 DAYS AFTER EXPOSURE TO 20 MUG L(-)(1) DU, AND WERE EVEN MORE PRONOUNCED IN THE BRAIN, GONADS, AND EYES AFTER 24 DAYS. HOWEVER, IN FEMALES, HYPOMETHYLATION WAS ONLY OBSERVED IN THE GONADS AFTER EXPOSURE TO 20 MUG L(-)(1) DU FOR 24 DAYS. SEX-SPECIFIC EFFECTS OF DU WERE ALSO APPARENT AT THE WHOLE-GENOME LEVEL, BECAUSE IN MALES, EXPOSURE TO 20 MUG L(-)(1) DU FOR 24 DAYS RESULTED IN CYTOSINE HYPERMETHYLATION IN THE BRAIN AND EYES AND HYPOMETHYLATION IN THE GONADS. IN CONTRAST, IN FEMALES, HYPERMETHYLATION WAS OBSERVED IN THE BRAIN AFTER EXPOSURE TO BOTH CONCENTRATIONS OF DU FOR 7 DAYS. BASED ON OUR CURRENT KNOWLEDGE OF URANIUM TOXICITY, SEVERAL HYPOTHESES ARE PROPOSED TO EXPLAIN THESE FINDINGS, INCLUDING THE INVOLVEMENT OF OXIDATIVE STRESS, ALTERATION OF DEMETHYLATION ENZYMES AND THE CALCIUM SIGNALING PATHWAY. THIS STUDY REPORTS, FOR THE FIRST TIME, THE SEX- AND TISSUE-SPECIFIC EPIGENETIC CHANGES THAT OCCUR IN A NONHUMAN ORGANISM AFTER EXPOSURE TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF URANIUM, WHICH COULD INDUCE TRANSGENERATIONAL EPIGENETIC EFFECTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  6681  35 USING ZEBRAFISH EMBRYO BIOASSAYS TO IDENTIFY CHEMICALS MODULATING THE REGULATION OF THE EPIGENOME: A CASE STUDY WITH SIMVASTATIN. CONTAMINANTS OF EMERGING CONCERN HAVE BEEN INCREASINGLY ASSOCIATED WITH THE MODULATION OF THE EPIGENOME, LEADING TO POTENTIALLY INHERITED AND PERSISTENT IMPACTS ON APICAL ENDPOINTS. HERE, WE ADDRESS THE PERFORMANCE OF THE OECD TEST NO. 236 FET (FISH EMBRYO ACUTE TOXICITY) IN THE IDENTIFICATION OF CHEMICALS ABLE TO MODULATE THE EPIGENOME. USING ZEBRAFISH (DANIO RERIO) EMBRYOS, ACUTE AND CHRONIC EXPOSURES WERE PERFORMED WITH THE PHARMACEUTICAL, SIMVASTATIN (SIM), A WIDELY PRESCRIBED HYPOCHOLESTEROLEMIC DRUG REPORTED TO INDUCE INTER AND TRANSGENERATIONAL EFFECTS. IN THE PRESENT STUDY, THE EPIGENETIC EFFECTS OF ENVIRONMENTALLY RELEVANT CONCENTRATIONS OF SIM (FROM 8 NG/L TO 2000 NG/L) WERE ADDRESSED FOLLOWING (1) AN ACUTE EMBRYO ASSAY BASED ON OECD TEST NO. 236 FET, (2) A CHRONIC PARTIAL LIFE-CYCLE EXPOSURE USING ADULT ZEBRAFISH (90 DAYS), AND (3) F1 EMBRYOS OBTAINED FROM PARENTAL EXPOSED ANIMALS. SIMVASTATIN INDUCED SIGNIFICANT EFFECTS IN GENE EXPRESSION OF KEY EPIGENETIC BIOMARKERS (DNA METHYLATION AND HISTONE ACETYLATION/DEACETYLATION) IN THE GONADS OF EXPOSED ADULT ZEBRAFISH AND IN 80 HPF ZEBRAFISH EMBRYOS (ACUTE AND CHRONIC PARENTAL INTERGENERATIONAL EXPOSURE), ALBEIT WITH DISTINCT EFFECT PROFILES BETWEEN BIOLOGICAL SAMPLES. IN THE CHRONIC EXPOSURE, SIM IMPACTED PARTICULARLY DNA METHYLTRANSFERASE GENES IN MALES AND FEMALE GONADS, WHEREAS IN F1 EMBRYOS SIM AFFECTED MOSTLY GENES ASSOCIATED WITH HISTONE ACETYLATION/DEACETYLATION. IN THE EMBRYO ACUTE DIRECT EXPOSURE, SIM MODULATED THE EXPRESSION OF BOTH GENES INVOLVED IN DNA METHYLATION AND HISTONE DEACETYLASE. THESE FINDINGS FURTHER SUPPORT THE USE OF EPIGENETIC BIOMARKERS IN ZEBRAFISH EMBRYOS IN A HIGH THROUGHPUT APPROACH TO IDENTIFY AND PRIORITIZE EPIGENOME-MODULATING CHEMICALS.	2023	
                                                                                                                                                                                                                                                                                           
3  2366  29 EPIGENETIC REGULATION OF STEROIDOGENIC ENZYMES EXPRESSED IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM HEALTHY INDIVIDUALS AND FROM PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. SEX HORMONE SYNTHESIS OCCURS IN VARIOUS ORGANS AND TISSUES BESIDES THE GONADS, SUCH AS ADRENAL GLANDS, BRAIN, INTESTINES, SKIN, FAT, BONE, AND CELLS OF THE IMMUNE SYSTEM. REGARDING THE LATTER, IT IS STILL NOT CLEAR WHICH PATHWAYS ARE ACTIVE, AND IF THEY ARE MODIFIED IN CASE OF ILLNESS OF THE IMMUNE SYSTEM. OUR GOAL IN THIS STUDY WAS TO DETERMINE MRNA EXPRESSION OF DIFFERENT STEROIDOGENIC ENZYMES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY INDIVIDUALS OF BOTH SEXES AND OF DIFFERENT AGES, AND THEN TO COMPARE THEIR EXPRESSION BETWEEN HEALTHY INDIVIDUALS AND PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). FURTHERMORE, TO ELUCIDATE POSSIBLE MECHANISMS THAT REGULATE ENZYME EXPRESSION, WE ANALYZED EPIGENETIC EVENTS LIKE PROMOTER METHYLATION. WE DETERMINED THAT NORMAL CELLS OF THE IMMUNE SYSTEM, REGARDLESS OF SEX AND AGE, EXPRESSED P450 SIDE CHAIN CLEAVAGE (P450SCC), CYTOCHROME P450 17ALPHA-HYDROXYLASE/C17,20-LYASE (P45017ALPHA), 3BETA-HYDROXYSTEROID DEHYDROGENASE/DELTA5-DELTA4-ISOMERASE (3BETA-HSD), STEROID 5 ALPHA REDUCTASE (5ALPHA-R) TYPES 1, 2 AND 3, 3ALPHA-HYDROXYSTEROID DEHYDROGENASE (3ALPHA-HSD) TYPE 3, AND 17BETA-HYDROXYSTEROID DEHYDROGENASE (17BETA-HSD) TYPES 1, 3 AND 5. WE ALSO ESTABLISHED THAT 5ALPHA-R 1, 5ALPHA-R 3, 3ALPHA-HSD 3, 17BETA-HSD 1 AND 17BETA-HSD 5 EXPRESSION WAS ALTERED IN CLL PATIENTS, AND THAT PROMOTER REGIONS OF 5ALPHA-R 1, 17BETA-HSD 1 AND 17BETA-HSD 5 WERE DIFERENTIALLY METHYLATED. THESE RESULTS SUGGEST THAT STEROIDOGENIC PATHWAYS MAY BE AFFECTED IN CLL CELLS, AND THIS COULD BE RELATED TO DISEASE PATHOGENESIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  1511  41 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	
                                                                                             
5  6553  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  4923  26 PARENTAL DIURON EXPOSURE CAUSES LOWER HATCHABILITY AND ABNORMAL OVARIAN DEVELOPMENT IN OFFSPRING OF MEDAKA (ORYZIAS MELASTIGMA). DIURON IS ONE OF THE MOST WIDELY USED HERBICIDES WORLDWIDE. IT HAS BEEN WIDELY DETECTED IN VARIOUS AQUATIC ENVIRONMENTS, ESPECIALLY IN MARINE ECOSYSTEMS. ALTHOUGH DIRECT EFFECTS OF DIURON EXPOSURE ON VARIOUS ORGANISMS HAVE BEEN REPORTED, LITTLE IS KNOWN ABOUT ITS EFFECTS ON MARINE FISHES INCLUDING MULTIGENERATIONAL EFFECTS. HEREIN, THE FILIAL GENERATION (F1) OF DIURON-EXPOSED MARINE MEDAKA (ORYZIAS MELASTIGMA) (F0) WAS RAISED IN CLEAN SEAWATER FROM FERTILIZED EGGS TO ADULTHOOD AND USED AS A MARINE FISH MODEL TO STUDY THE POTENTIAL MULTIGENERATIONAL EFFECTS OF DIURON. WE FOUND THAT THE SUCCESSFUL HATCHING OF F1 LARVAE WAS SIGNIFICANTLY REDUCED AND THAT OVARIAN DEVELOPMENT IN F1 FEMALES WAS RETARDED. A SIGNIFICANT INCREASE IN THE PERCENTAGE OF PREVITELLOGENIC OOCYTES, ALONG WITH A VISUAL DECREASE IN THE PERCENTAGE OF VITELLOGENIC AND MATURE OOCYTES IN THE F1 OVARY, WERE OBSERVED. THE HORMONE LEVELS OF THE HYPOTHALAMUS-PITUITARY-GONAD-LIVER AXIS AND VITELLOGENIN-RELATED TRANSCRIPTION WERE DOWNREGULATED. IN ADDITION, THE MRNA LEVELS OF DNA METHYLTRANSFERASE IN THE BRAIN, OVARY AND LIVER OF F1 ADULT FISH EXHIBITED SIGNIFICANT UPREGULATION, SUGGESTING THAT THE PROBABLE UNDERLYING MULTIGENERATIONAL MECHANISM MIGHT BE ASSOCIATED WITH EPIGENETIC MODIFICATIONS. TAKEN TOGETHER, THESE RESULTS DEMONSTRATED THAT CHRONIC ENVIRONMENTAL DIURON EXPOSURE IN F0 MARINE MEDAKA CAN INHIBIT F1 OVARY DEVELOPMENT AND SUGGESTED THAT DIURON MAY AFFECT MARINE FISH THRIVING IN THE OCEAN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  4008  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8   166  23 ABNORMAL OVARIAN DNA METHYLATION PROGRAMMING DURING GONAD MATURATION IN WILD CONTAMINATED FISH. THERE IS INCREASING EVIDENCE THAT POLLUTANTS MAY CAUSE DISEASES VIA EPIGENETIC MODIFICATIONS. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION PARTICIPATE IN THE REGULATION OF GENE TRANSCRIPTION. SURPRISINGLY, EPIGENETICS RESEARCH IS STILL LIMITED IN ECOTOXICOLOGY. IN THIS STUDY, WE INVESTIGATED WHETHER CHRONIC EXPOSURE TO CONTAMINANTS EXPERIENCED BY WILD FEMALE FISH (ANGUILLA ANGUILLA) THROUGHOUT THEIR JUVENILE PHASE CAN AFFECT THE DNA METHYLATION STATUS OF THEIR OOCYTES DURING GONAD MATURATION. THUS, FISH WERE SAMPLED IN TWO LOCATIONS PRESENTING A LOW OR A HIGH CONTAMINATION LEVEL. THEN, FISH WERE TRANSFERRED TO THE LABORATORY AND ARTIFICIALLY MATURED. BEFORE HORMONAL TREATMENT, THE DNA METHYLATION LEVELS OF THE GENES ENCODING FOR THE AROMATASE AND THE RECEPTOR OF THE FOLLICLE STIMULATING HORMONE WERE HIGHER IN CONTAMINATED FISH THAN IN FISH FROM THE CLEAN SITE. FOR THE HORMONE RECEPTOR, THIS HYPERMETHYLATION WAS POSITIVELY CORRELATED WITH THE CONTAMINATION LEVEL OF FISH AND WAS ASSOCIATED WITH A DECREASE IN ITS TRANSCRIPTION LEVEL. IN ADDITION, WHEREAS GONAD GROWTH WAS ASSOCIATED WITH AN INCREASE IN DNA METHYLATION IN FISH FROM THE CLEAN SITE, NO CHANGES WERE OBSERVED IN CONTAMINATED FISH IN RESPONSE TO HORMONAL TREATMENT. FINALLY, A HIGHER GONAD GROWTH WAS OBSERVED IN FISH FROM THE REFERENCE SITE IN COMPARISON TO CONTAMINATED FISH.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9  6526  27 TRANSCRIPTIONAL CHANGES IN THE OVARIES OF PERCH FROM CHERNOBYL. FISH HAVE BEEN HIGHLY EXPOSED TO RADIATION IN FRESHWATER SYSTEMS AFTER THE CHERNOBYL NUCLEAR POWER PLANT (NPP) ACCIDENT IN 1986 AND IN FRESHWATER AND MARINE SYSTEMS AFTER THE MORE RECENT FUKUSHIMA NPP ACCIDENT IN 2011. IN THE YEARS AFTER THE ACCIDENT, THE RADIOACTIVITY LEVELS RAPIDLY DECLINED DUE TO RADIOACTIVE DECAY AND ENVIRONMENTAL PROCESSES, BUT CHRONIC LOWER DOSE EXPOSURES PERSISTED. TO GAIN INSIGHTS INTO THE LONG-TERM EFFECTS OF ENVIRONMENTAL LOW DOSE RADIATION ON FISH OVARIES DEVELOPMENT, A HIGH-THROUGHPUT TRANSCRIPTOMIC APPROACH INCLUDING A DE NOVO ASSEMBLY WAS APPLIED TO DIFFERENT GONAD PHENOTYPES OF FEMALE PERCH: DEVELOPED GONADS FROM REFERENCE LAKES, DEVELOPED/IRRADIATED FROM MEDIUM CONTAMINATED LAKE, AND BOTH DEVELOPED/IRRADIATED AND UNDEVELOPED FROM MORE HIGHLY CONTAMINATED LAKES. THIS IS THE MOST COMPREHENSIVE ANALYSIS TO DATE OF THE GENE RESPONSES IN WILDLIFE REPRODUCTIVE SYSTEM TO RADIATION. SOME GENE RESPONSES THAT WERE MODULATED IN IRRADIATED GONADS WERE FOUND TO BE INVOLVED IN BIOLOGICAL PROCESSES INCLUDING CELL DIFFERENTIATION AND PROLIFERATION (GGNB2, MOD5, RERGL), CYTOSKELETON ORGANIZATION (K1C18, MTPN), GONAD DEVELOPMENT (NELL2, TCP4), LIPID METABOLISM (LDAH, AT11B, NLTP), REPRODUCTION (CYB5, CYP17A, OVOS), DNA DAMAGE REPAIR (WDHD1, RAD51, HUS1), AND EPIGENETIC MECHANISMS (DMAP1). IDENTIFICATION OF THESE GENES PROVIDES A BETTER UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS UNDERPINNING THE DEVELOPMENT OF THE GONAD PHENOTYPES OF WILD PERCH AND HOW FISH MAY RESPOND TO CHRONIC EXPOSURE TO RADIATION IN THEIR NATURAL ENVIRONMENT, THOUGH CAUSAL ATTRIBUTION OF GENE RESPONSES REMAINS UNCLEAR IN THE UNDEVELOPED GONADS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10    73  33 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE.	2014	
                                                                                                                                                                                                             
11   891  30 CHRONIC EFFECTS OF CLOFIBRIC ACID IN ZEBRAFISH (DANIO RERIO): A MULTIGENERATIONAL STUDY. CLOFIBRIC ACID (CA) IS AN ACTIVE METABOLITE OF THE BLOOD LIPID LOWERING AGENT CLOFIBRATE, A PHARMACEUTICAL DESIGNED TO WORK AS AGONIST OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA). IT IS THE MOST COMMONLY REPORTED FIBRATE IN AQUATIC ENVIRONMENTS WITH LOW DEGRADATION RATE AND POTENTIAL ENVIRONMENTAL PERSISTENCE. PREVIOUS FISH EXPOSURES SHOWED THAT CA MAY IMPACT SPERMATOGENESIS, GROWTH AND THE EXPRESSION OF FAT BINDING PROTEIN GENES. HOWEVER, THERE ARE LIMITED DATA ON THE EFFECTS OF CHRONIC MULTIGENERATIONAL CA EXPOSURES. HERE, WE ASSESSED CHRONIC MULTIGENERATIONAL EFFECTS OF CA EXPOSURE USING ZEBRAFISH (DANIO RERIO) AS A TELEOST MODEL. ZEBRAFISH WERE EXPOSED THROUGH THE DIET TO CA (1 AND 10MG/G) DURING THEIR WHOLE LIFETIME. GROWTH, REPRODUCTION-RELATED PARAMETERS AND EMBRYONIC DEVELOPMENT WERE ASSESSED IN THE EXPOSED FISH (F1 GENERATION) AND THEIR OFFSPRING (F2 GENERATION), TOGETHER WITH MUSCLE TRIGLYCERIDE CONTENT AND GONAD HISTOLOGY. IN ORDER TO STUDY THE POTENTIAL UNDERLYING MECHANISMS, THE TRANSCRIPTION LEVELS OF GENES CODING FOR ENZYMES INVOLVED IN LIPID METABOLISM PATHWAYS WERE DETERMINED. THE RESULTS SHOW THAT CHRONIC LIFE-CYCLE EXPOSURE TO CA INDUCED A SIGNIFICANT REDUCTION IN GROWTH OF F1 GENERATION AND LOWERED TRIGLYCERIDE MUSCLE CONTENT (10MG/G GROUP). ALSO, AN IMPACT IN MALE GONAD DEVELOPMENT WAS OBSERVED TOGETHER WITH A DECREASE IN THE FECUNDITY (10MG/G GROUP) AND HIGHER FREQUENCY OF EMBRYO ABNORMALITIES IN THE OFFSPRING OF FISH EXPOSED TO THE LOWEST CA DOSE. THE PROFILE OF THE TARGET GENES WAS SEX- AND TISSUE-DEPENDENT. IN F1 AN UP-REGULATION OF MALE HEPATIC PPARAA, PPARB AND ACOX TRANSCRIPT LEVELS WAS OBSERVED, SUGGESTING AN ACTIVATION OF THE FATTY ACID METABOLISM (PROVIDED THAT TRANSCRIPT LEVEL CHANGE INDICATES ALSO A PROTEIN LEVEL CHANGE). INTERESTINGLY, THE F2 GENERATION, RAISED WITH CONTROL DIET, DISPLAYED A RESPONSE PATTERN DIFFERENT FROM THAT OBSERVED IN F1, SHOWING AN INCREASE IN WEIGHT IN THE DESCENDANTS OF CA EXPOSED FISH, IN COMPARISON WITH CONTROL ANIMALS, WHICH POINTS TO A MULTIGENERATIONAL EFFECT.	2015	
      
12  6552  31 TRANSGENERATIONAL DNA METHYLATION CHANGES IN DAPHNIA MAGNA EXPOSED TO CHRONIC GAMMA IRRADIATION. OUR AIM WAS TO INVESTIGATE EPIGENETIC CHANGES IN DAPHNIA MAGNA AFTER A 25-DAY CHRONIC EXTERNAL GAMMA IRRADIATION (GENERATION F0 EXPOSED TO 6.5 MUGY.H(-1) OR 41.3 MGY.H(-1)) AND THEIR POTENTIAL INHERITANCE BY SUBSEQUENT RECOVERING GENERATIONS, NAMELY, F2 (EXPOSED AS GERMLINE CELLS IN F1 EMBRYOS) AND F3 (THE FIRST TRULY UNEXPOSED GENERATION). EFFECTS ON SURVIVAL, GROWTH, AND REPRODUCTION WERE OBSERVED AND DNA WAS EXTRACTED FOR WHOLE-GENOME BISULFITE SEQUENCING IN ALL GENERATIONS. RESULTS SHOWED EFFECTS ON REPRODUCTION IN F0 BUT NO EFFECT IN THE SUBSEQUENT GENERATIONS F1, F2, AND F3. IN CONTRAST, WE OBSERVED SIGNIFICANT METHYLATION CHANGES AT SPECIFIC CPG POSITIONS IN EVERY GENERATION INDEPENDENT OF DOSE RATE, WITH A MAJORITY OF HYPOMETHYLATION. SOME OF THESE CHANGES WERE SHARED BETWEEN DOSE RATES AND BETWEEN GENERATIONS. ASSOCIATED GENE FUNCTIONS INCLUDED GENE FAMILIES AND GENES THAT WERE PREVIOUSLY SHOWN TO PLAY ROLES DURING EXPOSURE TO IONIZING RADIATION. COMMON METHYLATION CHANGES DETECTED BETWEEN GENERATIONS F2 AND F3 CLEARLY SHOWED THAT EPIGENETIC MODIFICATIONS CAN BE TRANSMITTED TO UNEXPOSED GENERATIONS, MOST LIKELY THROUGH THE GERMLINE, WITH POTENTIAL IMPLICATIONS FOR ENVIRONMENTAL RISK.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  1835  30 EFFECTS OF NON-HUMAN SPECIES IRRADIATION AFTER THE CHERNOBYL NPP ACCIDENT. THE AREA AFFECTED BY THE CHERNOBYL NUCLEAR POWER PLANT ACCIDENT IN 1986 HAS BECOME A UNIQUE TEST SITE WHERE LONG-TERM ECOLOGICAL AND BIOLOGICAL CONSEQUENCES OF A DRASTIC CHANGE IN A RANGE OF ENVIRONMENTAL FACTORS AS WELL AS TRENDS AND INTENSITY OF SELECTION ARE STUDIED IN NATURAL SETTINGS. THE CONSEQUENCES OF THE CHERNOBYL ACCIDENT FOR BIOTA VARIED FROM AN ENHANCED RATE OF MUTAGENESIS TO DAMAGE AT THE ECOSYSTEM LEVEL. THE REVIEW COMPREHENSIVELY BRINGS TOGETHER KEY DATA OF THE LONG-TERM STUDIES OF BIOLOGICAL EFFECTS IN PLANTS AND ANIMALS INHABITING OVER 20 YEARS THE CHERNOBYL NPP ZONE. THE SEVERITY OF RADIATION EFFECTS WAS STRONGLY DEPENDENT ON THE DOSE RECEIVED IN THE EARLY PERIOD AFTER THE ACCIDENT. THE MOST EXPOSED PHYTOCENOSES AND SOIL ANIMALS' COMMUNITIES EXHIBITED DOSE DEPENDENT ALTERATIONS IN THE SPECIES COMPOSITION AND REDUCTION IN BIOLOGICAL DIVERSITY. ON THE OTHER HAND, NO DECREASE IN NUMBERS OR TAXONOMIC DIVERSITY OF SMALL MAMMALS EVEN IN THE MOST RADIOACTIVE HABITAT WAS SHOWN. IN A MAJORITY OF THE STUDIES, IN BOTH PLANT AND ANIMAL POPULATIONS FROM THE CHERNOBYL ZONE, IN THE FIRST YEARS AFTER THE ACCIDENT HIGH INCREASES IN MUTATION RATES WERE DOCUMENTED. IN MOST CASES THE DOSE-EFFECT RELATIONSHIPS WERE NONLINEAR AND THE MUTATION RATES PER UNIT DOSE WERE HIGHER AT LOW DOSES AND DOSE RATES. IN SUBSEQUENT YEARS A DECLINE IN THE RADIATION BACKGROUND RATE OCCURRED FASTER THAN REDUCTION IN THE MUTATION RATE. PLANT AND ANIMAL POPULATIONS HAVE SHOWN SIGNS OF ADAPTATION TO CHRONIC EXPOSURE. IN ADAPTATION TO THE ENHANCED LEVEL OF EXPOSURE AN ESSENTIAL ROLE OF EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION WAS SHOWN. BASED ON THE CHERNOBYL NPP ACCIDENT STUDIES, IN THE PRESENT REVIEW ATTEMPTS WERE MADE TO ASSESS MINIMUM DOSES AT WHICH ECOLOGICAL AND BIOLOGICAL EFFECTS WERE OBSERVED.	2008	
                                                                                                                                                                                                                                                                                      
14  3109  37 GENOTOXIC AND EPIGENETIC EFFECTS OF DIURON IN THE PACIFIC OYSTER: IN VITRO EVIDENCE OF INTERACTION BETWEEN DNA DAMAGE AND DNA METHYLATION. RECENTLY, RESEARCH HAS CONTRIBUTED TO BETTER KNOWLEDGE ON THE OCCURRENCE OF PESTICIDES IN COASTAL WATER BY IDENTIFYING FREQUENTLY DETECTED SUBSTANCES, THEIR CONCENTRATION RANGE AND THEIR ACUTE AND CHRONIC TOXICITY FOR ORGANISMS. PESTICIDE POLLUTION IS OF PARTICULAR CONCERN IN FRANCE DUE TO IMPORTANT AGRICULTURAL ACTIVITIES AND PRESENCE OF SEVERAL EXOREIC CATCHMENT AREAS THAT VEHICLE PESTICIDES UP TO COASTAL WATERS, IMPACTING NON-TARGET MARINE SPECIES. SEVERAL ECOTOXICOLOGY QUESTIONS REMAIN TO BE ADDRESSED CONCERNING THE LONG-TERM EFFECTS OF CHRONIC PESTICIDE EXPOSURE AND THE MECHANISMS INVOLVED IN ADAPTATION TO CHEMICAL STRESS. IN THE PRESENT STUDY, WE BROUGHT NEW INSIGHTS ON THE GENETIC AND EPIGENETIC EFFECTS OF THE HERBICIDE DIURON IN OYSTER GENITORS. DURING GAMETOGENESIS, WE EXPOSED CRASSOSTREA GIGAS TO ENVIRONMENTALLY REALISTIC HERBICIDE CONCENTRATIONS (0.2-0.3 MUG L(-1) DURING TWO 7-DAY PERIODS AT HALF-COURSE AND END OF GAMETOGENESIS). DIURON EXPOSURE WAS SHOWN TO DECREASE GLOBAL DNA METHYLATION AND TOTAL METHYLTRANSFERASE ACTIVITY IN WHOLE OYSTER TISSUE; THIS IS CONSISTENT WITH THE PREVIOUS OBSERVATION OF A SIGNIFICANT DECREASE IN DNMT1 GENE EXPRESSION. DIURON EFFECT SEEMED TO BE TISSUE-SPECIFIC; HYPERMETHYLATION WAS DETECTED IN THE DIGESTIVE GLAND, WHEREAS DIURON EXPOSURE HAD NO EFFECT ON GILL AND GONAD TISSUE. THE GENOTOXICITY OF DIURON WAS CONFIRMED BY THE DETECTION OF ONE ADDUCT IN GONAD DNA. BY USING IN VITRO APPROACHES AND HUMAN DNMT1 (DNMT1 HAS NOT BEEN PURIFIED YET IN BIVALVES), THE PRESENCE OF DNA LESIONS (ADDUCT, 8-OXODGUO) WAS SHOWN TO INTERFERE WITH DNMT1 ACTIVITY, INDICATING A COMPLEX INTERACTION BETWEEN DNA DAMAGE AND DNA METHYLATION. BASED ON OUR RESULTS, WE PROPOSE MECHANISMS TO EXPLAIN THE EFFECT OF DIURON EXPOSURE ON DNA METHYLATION, A WIDESPREAD EPIGENETIC MARK.	2021	
                                                                                                                                                                                                                     
15  2484  42 EPIGENETIC, TRANSCRIPTIONAL AND PHENOTYPIC RESPONSES IN TWO GENERATIONS OF DAPHNIA MAGNA EXPOSED TO THE DNA METHYLATION INHIBITOR 5-AZACYTIDINE. THE WATER FLEA DAPHNIA MAGNA IS A KEYSTONE SPECIES IN FRESHWATER ECOSYSTEMS AND HAS BEEN WIDELY USED AS A MODEL ORGANISM IN ENVIRONMENTAL ECOTOXICOLOGY. THIS AQUATIC CRUSTACEAN IS SENSITIVE TO ENVIRONMENTAL STRESSORS AND DISPLAYS CONSIDERABLE PLASTICITY IN ADAPTING TO CHANGING ENVIRONMENTAL CONDITIONS. PART OF THIS PLASTICITY MAY BE DUE TO EPIGENETIC REGULATION OF GENE EXPRESSION, INCLUDING CHANGES TO DNA METHYLATION AND HISTONE MODIFICATIONS. BECAUSE OF THE GENERALLY HYPOMETHYLATED GENOME OF THIS SPECIES, WE HYPOTHESIZED THAT THE HISTONE CODE MAY HAVE AN ESSENTIAL ROLE IN THE EPIGENETIC CONTROL AND THAT HISTONE MODIFICATIONS MIGHT BE AN EARLY MARKER FOR STRESS. THIS STUDY AIMS TO CHARACTERIZE THE EPIGENETIC, TRANSCRIPTIONAL AND PHENOTYPIC RESPONSES AND THEIR CAUSAL LINKAGES IN DIRECTLY EXPOSED ADULT (F0) DAPHNIA AND PERITONEAL EXPOSED NEONATES (F1) AFTER A CHRONIC (7-DAY) EXPOSURE TO A SUBLETHAL CONCENTRATION (10 MG/L) OF 5-AZACYTIDINE, A WELL-STUDIED VERTEBRATE DNA METHYLATION INHIBITOR. EXPOSURE OF THE F0 GENERATION SIGNIFICANTLY REDUCED THE CUMULATIVE FECUNDITY, ACCOMPANIED WITH DIFFERENTIAL EXPRESSION OF GENES IN THE ONE-CARBON-CYCLE METABOLIC PATHWAY. IN THE EPIGENOME OF THE F0 GENERATION, A DECREASE IN GLOBAL DNA METHYLATION, BUT NO SIGNIFICANT CHANGES ON H3K4ME3 OR H3K27ME3, WERE OBSERVED. IN THE F1 OFFSPRING GENERATION, CHANGES IN GENE EXPRESSION, A SIGNIFICANT REDUCTION IN GLOBAL DNA METHYLATION AND CHANGES IN HISTONE MODIFICATIONS WERE IDENTIFIED. THE RESULTS INDICATE THAT EXPOSURE DURING ADULTHOOD MAY RESULT IN MORE PRONOUNCED EFFECTS ON EARLY DEVELOPMENT IN THE OFFSPRING GENERATION, THOUGH INTERPRETATION OF THE DATA SHOULD BE CAREFULLY DONE SINCE BOTH THE EXPOSURE REGIME AND DEVELOPMENTAL PERIOD IS DIFFERENT IN THE TWO GENERATIONS EXAMINED. THE OBTAINED RESULTS IMPROVE OUR UNDERSTANDING OF CRUSTACEAN EPIGENETICS AND THE TOOLS DEVELOPED MAY PROMOTE USE OF EPIGENETIC MARKERS IN HAZARD ASSESSMENT OF ENVIRONMENTAL STRESSORS.	2019	
                                                         
16  2698  35 EXAMINING MULTI- AND TRANSGENERATIONAL BEHAVIORAL AND MOLECULAR ALTERATIONS RESULTING FROM PARENTAL EXPOSURE TO AN ENVIRONMENTAL PCB AND PBDE MIXTURE. POLYCHLORINATED BIPHENYLS (PCBS) AND POLYBROMINATED DIPHENYL ETHERS (PBDES) ARE PERSISTENT ORGANIC POLLUTANTS EXTENSIVELY USED DURING THE 20(TH) CENTURY AND STILL PRESENT IN AQUATIC ENVIRONMENTS DESPITE THEIR BAN. EFFECTS OF EXPOSURE TO THESE COMPOUNDS OVER GENERATIONS ARE POORLY DOCUMENTED. THEREFORE, OUR AIMS WERE TO CHARACTERIZE BEHAVIORAL RESPONSES AND UNDERLYING MOLECULAR MECHANISMS IN ZEBRAFISH EXPOSED TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PCBS AND PBDES AS WELL AS IN FOUR UNEXPOSED OFFSPRING GENERATIONS. ZEBRAFISH (F0) WERE CHRONICALLY EXPOSED FROM THE FIRST MEAL ONWARD TO A DIET SPIKED WITH A MIXTURE CONTAINING 22 PCB AND 7 PBDE CONGENERS IN PROPORTIONS AND CONCENTRATIONS REFLECTING ENVIRONMENTAL SITUATIONS (SIGMAPCBS = 1991 AND SIGMAPBDES = 411 NG/G). FOUR OFFSPRING GENERATIONS (F1 TO F4) WERE OBTAINED FROM THIS F0 AND WERE NOT FURTHER EXPOSED. BEHAVIOR WAS ASSESSED AT BOTH LARVAL AND ADULT STAGES. MECHANISMS RELATED TO BEHAVIORAL DEFECTS (HABENULA MATURATION AND C-FOS TRANSCRIPTION) AND METHYLATION (DNMTS TRANSCRIPTION) WERE MONITORED IN LARVAE. EXPOSED ADULT F0 AS WELL AS F1 AND F3 ADULTS DISPLAYED NO BEHAVIORAL CHANGE WHILE F2 EXPRESSED ANXIETY-LIKE BEHAVIOR. LARVAL BEHAVIOR WAS ALSO DISRUPTED, I.E. HYPERACTIVE AFTER LIGHT TO DARK TRANSITION IN F1 OR HYPOACTIVE IN F2, F3 AND F4. BEHAVIORAL DISRUPTIONS MAY BE RELATED TO DEFECT IN HABENULA MATURATION (OBSERVED IN F1) AND CHANGE IN C-FOS TRANSCRIPTION (OBSERVED IN F1 AND F2). TRANSCRIPTION OF THE GENE ENCODING DNA METHYLTRANSFERASE (DNMT3BA) WAS ALSO MODIFIED IN ALL GENERATIONS. OUR RESULTS LEAD US TO HYPOTHESIZE THAT CHRONIC DIETARY EXPOSURE TO AN ENVIRONMENTALLY RELEVANT MIXTURE OF PCB AND PBDE TRIGGERS MULTIGENERATIONAL AND TRANSGENERATIONAL MOLECULAR AND BEHAVIORAL DISRUPTIONS IN A VERTEBRATE MODEL.	2019	
                                                                                                                                                                                                                              
17   985  19 CHRONIC RADIATION EXPOSURE AS AN ECOLOGICAL FACTOR: HYPERMETHYLATION AND GENETIC DIFFERENTIATION IN IRRADIATED SCOTS PINE POPULATIONS. GENETIC AND EPIGENETIC CHANGES WERE INVESTIGATED IN CHRONICALLY IRRADIATED SCOTS PINE (PINUS SYLVESTRIS L.) POPULATIONS FROM TERRITORIES THAT WERE HEAVILY CONTAMINATED BY RADIONUCLIDES AS RESULT OF THE CHERNOBYL NUCLEAR POWER PLANT ACCIDENT. IN COMPARISON TO THE REFERENCE SITE, THE GENETIC DIVERSITY REVEALED BY ELECTROPHORETIC MOBILITY OF AFLPS WAS FOUND TO BE SIGNIFICANTLY HIGHER AT THE RADIOACTIVELY CONTAMINATED AREAS. IN ADDITION, THE GENOME OF PINE TREES WAS SIGNIFICANTLY HYPERMETHYLATED AT 4 OF THE 7 AFFECTED SITES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18   903  33 CHRONIC EXPOSURE TO BISPHENOL A RESULTED IN ALTERATIONS OF REPRODUCTIVE FUNCTIONS VIA IMMUNE DEFENSE, OXIDATIVE DAMAGE AND DISRUPTION DNA/HISTONE METHYLATION IN MALE RARE MINNOW GOBIOCYPRIS RARUS. BISPHENOL A (BPA) IS A WIDELY USED CHEMICAL THAT REPRESENTS A REPRODUCTIVE HAZARD IN FISH. HOWEVER, THE MOLECULAR PATHWAYS MEDIATING REPRODUCTIVE TOXICITY UNDER CHRONIC BPA EXPOSURE REMAIN UNCLEAR. TO STUDY THE REPRODUCTIVE HAZARDS ASSOCIATED WITH CHRONIC BPA EXPOSURE, ADULT MALE RARE MINNOWS (GOBIOCYPRIS RARUS) WERE TREATED WITH 15 MUG L (-) (1) AND 225 MUG L (-) (1) BPA FOR 90 DAYS. RESULTS SHOWED THAT CHRONIC BPA TREATMENT INDUCED REPRODUCTIVE IMPAIRMENTS WITH DECREASED FERTILIZATION CAPACITY AND MOVEMENT TIME OF SPERM. TRANSCRIPTOME ANALYSIS INDICATED 1421 TRANSCRIPTS THAT WERE DIFFERENTIALLY EXPRESSED IN RESPONSE TO BPA EXPOSURE, WHICH ARE INVOLVED IN THE BIOLOGICAL PROCESS OF OXIDATIVE STRESS, IMMUNE RESPONSES AND DNA/HISTONE METHYLATION. BPA CAUSED THE OXIDATIVE STRESS VIA SIGNIFICANTLY INCREASING HYDROGEN PEROXIDE (H(2)O(2)) LEVELS AND INHIBITING THE ACTIVITIES OF ANTIOXIDANT-RELATED ENZYMES (CATALASE, CAT). BPA CAUSED AN INFLAMMATORY RESPONSE IN THE TESTES BY SIGNIFICANTLY INCREASING IL-1BETA LEVELS AND INDUCING INFILTRATION OF INFLAMMATORY CELLS. MOREOVER, EXPOSURE TO 15 MUG L (-) (1) BPA SIGNIFICANTLY DECREASED THE GENOMIC DNA METHYLATION LEVEL. THESE DATA REVEALED THAT CHRONIC BPA EXPOSURE HAD ADVERSE EFFECTS ON MALE REPRODUCTION. OXIDATIVE STRESS, INFLAMMATORY RESPONSE AND DNA/HISTONE METHYLATION MIGHT ACCOUNT FOR THE DECREASED SPERM QUALITY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  4077  25 MATERNAL INFLAMMATION INDUCES SPATIAL LEARNING AND MEMORY IMPAIRMENT IN THE F1 AND F2 GENERATIONS OF MICE VIA SEX-SPECIFIC EPIGENETIC MECHANISMS. MOUNTING EVIDENCE INDICATES THAT HISTONE MODIFICATIONS ARE INVOLVED IN AGING-ASSOCIATED COGNITIVE DECLINE (AACD) AND CAN BE TRANSMITTED TO OFFSPRING OVER MULTIPLE GENERATIONS UNDER CONDITIONS OF STRESS. HERE, WE INVESTIGATED THE EFFECTS OF MATERNAL SUB-CHRONIC INFLAMMATION CAUSED BY LIPOPOLYSACCHARIDE (LPS) ON AACD AND HISTONE MODIFICATIONS IN THE F1 AND F2 GENERATIONS OF EXPERIMENTAL MICE AS WELL AS THE POTENTIAL SEX SPECIFICITY OF INTERGENERATIONAL EFFECTS. IN BRIEF, F0-GENERATION CD-1 DAMS WERE EXPOSED TO LPS (50 MICROG/KG) OR SALINE (CON) DURING LATE PREGNANCY. SUBSEQUENTLY, F1 MALES AND FEMALES (AT 2 MONTHS-OF-AGE) FROM THE LPS TREATMENT GROUP WERE MATED WITH NON-LITTERMATES FROM THE LPS GROUP OR WILD-TYPE MICE TO PRODUCE F2 GENERATIONS OF PARENTAL- (F2-LPS(2)), PATERNAL- (F2M-LPS(1)) AND MATERNAL-ORIGIN (F2F-LPS(1)) MICE. THEN, CON-F1 MALES AND FEMALES WERE MATED WITH WILD-TYPE MICE TO GENERATE F2 GENERATIONS OF PATERNAL- (F2M-CON(1)) AND MATERNAL-ORIGIN (F2F-CON(1)). NEXT, WE EVALUATED THE COGNITIVE ABILITY AND LEVELS OF HIPPOCAMPAL H4K12AC AND H3K9ME3 IN THE F1 AND F2 OFFSPRING AT 3- AND 13 MONTHS-OF-AGE. OVERALL, F1 MALE AND FEMALE LPS GROUPS PRESENTED WITH ELEVATED CORTICOSTERONE (P < 0.001, P = 0.036, P = 0.025, 0.012, RESPECTIVELY) AND CYTOKINE RESPONSES, POORER COGNITIVE PERFORMANCE (ALL P < 0.05) AND H3K9 HYPERMETHYLATION AND H4K12 HYPOACETYLATION IN THE DORSAL HIPPOCAMPUS (ALL P < 0.05); THESE ISSUES WERE CARRIED OVER TO THE F2 GENERATION VIA THE PARENTS, PREDOMINANTLY IN THE PATERNAL LINEAGE. MOREOVER, THE LEVELS OF H3K9ME3 AND H4K12AC WERE SIGNIFICANT CORRELATED WITH COGNITIVE PERFORMANCE (ALL P < 0.05), REGARDLESS OF WHETHER INFLAMMATORY INSULTS HAD BEEN INCURRED DIRECTLY OR INDIRECTLY. THESE FINDINGS INDICATED THAT GESTATIONAL INFLAMMATORY INSULTS IN THE F0 GENERATION ACCELERATED AACD IN THE F2 GENERATION, ALONG WITH H3K9 HYPERMETHYLATION AND H4K12 HYPOACETYLATION IN THE HIPPOCAMPUS, AND THAT THESE ISSUES WERE DERIVED FROM THE F1 PARENTS, ESPECIALLY FROM THE F1 FATHERS.	2022	

20  1440  34 DIFFERENTIAL REGULATION OF HUMAN 3BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 FOR STEROID HORMONE BIOSYNTHESIS BY STARVATION AND CYCLIC AMP STIMULATION: STUDIES IN THE HUMAN ADRENAL NCI-H295R CELL MODEL. HUMAN STEROID BIOSYNTHESIS DEPENDS ON A SPECIFICALLY REGULATED CASCADE OF ENZYMES INCLUDING 3BETA-HYDROXYSTEROID DEHYDROGENASES (HSD3BS). TYPE 2 HSD3B CATALYZES THE CONVERSION OF PREGNENOLONE, 17ALPHA-HYDROXYPREGNENOLONE AND DEHYDROEPIANDROSTERONE TO PROGESTERONE, 17ALPHA-HYDROXYPROGESTERONE AND ANDROSTENEDIONE IN THE HUMAN ADRENAL CORTEX AND THE GONADS BUT THE EXACT REGULATION OF THIS ENZYME IS UNKNOWN. THEREFORE, SPECIFIC DOWNREGULATION OF HSD3B2 AT ADRENARCHE AROUND AGE 6-8 YEARS AND CHARACTERISTIC UPREGULATION OF HSD3B2 IN THE OVARIES OF WOMEN SUFFERING FROM THE POLYCYSTIC OVARY SYNDROME REMAIN UNEXPLAINED PROMPTING US TO STUDY THE REGULATION OF HSD3B2 IN ADRENAL NCI-H295R CELLS. OUR STUDIES CONFIRM THAT THE HSD3B2 PROMOTER IS REGULATED BY TRANSCRIPTION FACTORS GATA, NUR77 AND SF1/LRH1 IN CONCERT AND THAT THE NBRE/NUR77 SITE IS CRUCIAL FOR HORMONAL STIMULATION WITH CAMP. IN FACT, THESE THREE TRANSCRIPTION FACTORS TOGETHER WERE ABLE TO TRANSACTIVATE THE HSD3B2 PROMOTER IN PLACENTAL JEG3 CELLS WHICH NORMALLY DO NOT EXPRESS HSD3B2. BY CONTRAST, EPIGENETIC MECHANISMS SUCH AS METHYLATION AND ACETYLATION SEEM NOT INVOLVED IN CONTROLLING HSD3B2 EXPRESSION. CYCLIC AMP WAS FOUND TO EXERT DIFFERENTIAL EFFECTS ON HSD3B2 WHEN COMPARING SHORT (ACUTE) VERSUS LONG-TERM (CHRONIC) STIMULATION. SHORT CAMP STIMULATION INHIBITED HSD3B2 ACTIVITY DIRECTLY POSSIBLY DUE TO REGULATION AT CO-FACTOR OR SUBSTRATE LEVEL OR POSTTRANSLATIONAL MODIFICATION OF THE PROTEIN. LONG CAMP STIMULATION ATTENUATED HSD3B2 INHIBITION AND INCREASED HSD3B2 EXPRESSION THROUGH TRANSCRIPTIONAL REGULATION. ALTHOUGH PKA AND MAPK PATHWAYS ARE OBVIOUS CANDIDATES FOR POSSIBLY TRANSMITTING THE CAMP SIGNAL TO HSD3B2, OUR STUDIES USING PKA AND MEK1/2 INHIBITORS REVEALED NO SUCH DOWNSTREAM SIGNALING OF CAMP. HOWEVER, BOTH SIGNALING PATHWAYS WERE CLEARLY REGULATING HSD3B2 EXPRESSION.	2013