1  2742 131 EXPOSURE TO THE PLASTICIZER, DI-(2-ETHYLHEXYL) PHTHALATE DURING JUVENILE PERIOD EXACERBATES AUTISM-LIKE BEHAVIOR IN ADULT BTBR T + TF/J MICE DUE TO DNA HYPOMETHYLATION AND ENHANCED INFLAMMATION IN BRAIN AND SYSTEMIC IMMUNE CELLS. EPIGENETIC MODIFICATIONS ARE KNOWN TO PLAY A CRUCIAL ROLE IN THE BEHAVIORAL MODIFICATIONS THROUGH REGULATION OF GENE EXPRESSION. ENVIRONMENTAL FACTORS ARE KNOWN TO REGULATE GENETIC TRANSCRIPTION THROUGH DNA METHYLATION WHICH IS ONE OF THE MECHANISMS OF EPIGENETIC MODIFICATION. DI-2-ETHYLHEXYL PHTHALATE (DEHP) IS ONE OF THE MOST ABUNDANT PHTHALATE PLASTICIZERS IN DAY-TO-DAY PRODUCTS. PRENATAL/POSTNATAL DEHP ADMINISTRATION HAS BEEN REPORTED TO CAUSE INFLAMMATION AS WELL AS BEHAVIORAL DYSREGULATION, HOWEVER IT IS NOT KNOWN IF EXPOSURE TO DEHP DURING JUVENILE STAGE AFFECTS PERIPHERAL/NEURONAL INFLAMMATION AND AUTISM-LIKE SYMPTOMS IN BTBR MICE AT ADULTHOOD. THIS STUDY INVESTIGATED EFFECT OF DEHP EXPOSURE DURING JUVENILE PERIOD ON DNA METHYLATION (GLOBAL DNA METHYLATION/DNMT1 EXPRESSION) AND INFLAMMATION (IL-17A, IL-6, MCP-1, TNF-ALPHA) IN CD4 + T CELLS/CD11C + DCS AND CORTEX, AND AUTISM-LIKE SYMPTOMS (THREE-CHAMBERED SOCIABILITY TEST, SELF-GROOMING AND MARBLE BURYING TEST) IN ASOCIAL BTBR AND SOCIAL C57 MICE AT ADULTHOOD. OUR DATA REVEAL THAT BTBR MICE EXPOSED TO DEHP DURING JUVENILE PERIOD HAVE HYPOMETHYLATED DNA/DNMT1 EXPRESSION IN CD11C + DCS AND CORTEX AS COMPARED TO VEHICLE-EXPOSED BTBR MICE. IT WAS ASSOCIATED WITH UPREGULATED INFLAMMATION IN PERIPHERY [PLASMA IL-6/IL-17A, CD11C + DCS (IL-6/MCP-1/TNF-ALPHA), AND CD4+ T CELLS (IL-17A)] AND CORTEX (IL-6, MCP-1, TNF-ALPHA), AND AGGRAVATION IN AUTISM-LIKE SYMPTOMS IN DEHP-TREATED BTBR MICE. THESE DATA PROPOSE THAT EXPOSURE OF DEHP DURING JUVENILE PERIOD MAY AFFECT AUTISM-LIKE BEHAVIOR AND INFLAMMATION IN BTBR MICE AT ADULTHOOD THROUGH EPIGENETIC REGULATION. THEREFORE, UNDERLYING GENETIC PREDISPOSITION MAY PLAY A CRUCIAL ROLE IN WORSENING OF AUTISTIC SYMPTOMS IN ASD SUBJECTS IN ADULTHOOD IF THEY ARE EXPOSED TO ENVIRONMENTAL POLLUTANTS SUCH AS DEHP DURING JUVENILE PERIOD.	2021	
                                  
2  5066  36 PHTHALATES SUPPRESS TYPE I INTERFERON IN HUMAN PLASMACYTOID DENDRITIC CELLS VIA EPIGENETIC REGULATION. BACKGROUND: EXPOSURE TO ENVIRONMENTAL ENDOCRINE-DISRUPTING CHEMICALS (EDCS) IS ASSOCIATED WITH ALLERGY, CHRONIC INFLAMMATION, AND IMMUNODEFICIENCY. PHTHALATES, THE COMMON EDCS USED IN PLASTIC INDUSTRY, MAY ACT AS ADJUVANTS TO DISRUPT IMMUNE SYSTEM AND ENHANCE ALLERGY. PLASMACYTOID DCS (PDCS) ARE PREDOMINANT CELLS SECRETING TYPE I INTERFERON (IFN) AGAINST INFECTION AND ARE PROFESSIONAL ANTIGEN-PRESENTING CELLS IN REGULATING ADAPTIVE IMMUNITY. HOWEVER, THE EFFECTS OF PHTHALATES ON THE FUNCTION OF PDCS ARE UNKNOWN. METHODS: CIRCULATING PDCS WERE ISOLATED FROM HEALTHY SUBJECTS, WERE PRETREATED WITH DIETHYLHEXYL PHTHALATE (DEHP) AND BUTYL BENZYL PHTHALATE (BBP), AND WERE STIMULATED WITH TOLL-LIKE RECEPTOR (TLR)-9 AGONIST CPG. IFN-ALPHA/IFN-BETA LEVELS, SURFACE MARKERS, AND T-CELL STIMULATORY FUNCTION WERE INVESTIGATED USING ELISA, FLOW CYTOMETRY, AND PDC/T-CELL COCULTURE ASSAY. MECHANISMS WERE INVESTIGATED USING RECEPTOR ANTAGONISTS, PATHWAY INHIBITORS, WESTERN BLOTTING, AND CHROMATIN IMMUNOPRECIPITATION. RESULTS: DIETHYLHEXYL PHTHALATE AND BUTYL BENZYL PHTHALATE SUPPRESSED CPG-INDUCED IFN-ALPHA/IFN-BETA EXPRESSION IN PDCS, AND THE EFFECT WAS REVERSED BY ARYL HYDROCARBON RECEPTOR (AHR) ANTAGONIST. DIETHYLHEXYL PHTHALATE SUPPRESSED CPG-ACTIVATED MITOGEN-ACTIVATED PROTEIN KINASE (MAPK)-MEK1/2-ERK-ELK1 AND NFKAPPAB SIGNALING PATHWAYS. DIETHYLHEXYL PHTHALATE SUPPRESSED CPG-INDUCED INTERFERON REGULATORY FACTOR (IRF)-7 EXPRESSION BY SUPPRESSING HISTONE H3K4 TRIMETHYLATION AT IRF7 GENE PROMOTER REGION THROUGH INHIBITING TRANSLOCATION OF H3K4-SPECIFIC TRIMETHYLTRANSFERASE WDR5 FROM CYTOPLASM INTO NUCLEUS. BUTYL BENZYL PHTHALATE OR DIETHYLHEXYL PHTHALATE-TREATED PDCS SUPPRESSED IFN-GAMMA BUT ENHANCED IL-13 PRODUCTION BY CD4+ T CELLS. CONCLUSION: PHTHALATES MAY INTERFERE WITH IMMUNITY AGAINST INFECTION AND PROMOTE THE DEVIATION OF TH2 RESPONSE TO INCREASE ALLERGY BY ACTING ON HUMAN PDCS VIA SUPPRESSING IFN-ALPHA/IFN-BETA EXPRESSION AND MODULATING THE ABILITY TO STIMULATE T-CELL RESPONSES.	2013	

3  6338  28 THE ROLE OF ENDOCRINE-DISRUPTING CHEMICALS IN UTERINE FIBROID PATHOGENESIS. PURPOSE OF REVIEW: UTERINE LEIOMYOMA (FIBROIDS) IS A GYNECOLOGIC DISORDER IMPACTING THE MAJORITY OF WOMEN IN THE UNITED STATES. WHEN SYMPTOMATIC, THESE NONCANCEROUS TUMORS CAN CAUSE SEVERE MORBIDITY INCLUDING PELVIC PAIN, MENORRHAGIA, AND INFERTILITY. ENDOCRINE-DISRUPTING CHEMICALS (EDCS) MAY REPRESENT A MODIFIABLE RISK FACTOR. THE AIM OF THIS REVIEW IS TO SUMMARIZE RECENT HUMAN AND EXPERIMENTAL EVIDENCE ON EDCS EXPOSURES AND FIBROIDS. RECENT FINDINGS: MULTIPLE EDCS ARE ASSOCIATED WITH FIBROID OUTCOMES AND/OR PROCESSES INCLUDING PHTHALATES, PARABENS, ENVIRONMENTAL PHENOLS, ALTERNATE PLASTICIZERS, DIETHYLSTILBESTROL, ORGANOPHOSPHATE ESTERS, AND TRIBUTYLTIN. EPIDEMIOLOGIC STUDIES SUGGEST EXPOSURE TO CERTAIN EDCS, SUCH AS DI-(2-ETHYLHXYL)-PHTHALATE (DEHP), ARE ASSOCIATED WITH INCREASED FIBROID RISK AND SEVERITY. BOTH HUMAN AND EXPERIMENTAL STUDIES INDICATE THAT EPIGENETIC PROCESSES MAY PLAY AN IMPORTANT ROLE IN LINKING EDCS TO FIBROID PATHOGENESIS. IN-VITRO AND IN-VIVO STUDIES SHOW THAT DEHP, BISPHENOL A, AND DIETHYLSTILBESTROL CAN IMPACT BIOLOGICAL PATHWAYS CRITICAL TO FIBROID PATHOGENESIS. SUMMARY: WHILE RESEARCH ON EDCS AND FIBROIDS IS STILL EVOLVING, RECENT EVIDENCE SUGGESTS EDC EXPOSURES MAY CONTRIBUTE TO FIBROID RISK AND PROGRESSION. FURTHER RESEARCH IS NEEDED TO EXAMINE THE IMPACTS OF EDC MIXTURES AND TO IDENTIFY CRITICAL BIOLOGICAL PATHWAYS AND WINDOWS OF EXPOSURE. THESE RESULTS COULD OPEN THE DOOR TO NEW PREVENTION STRATEGIES FOR FIBROIDS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4  1381  35 DI-(2-ETHYLHEXYL) PHTHALATE TRIGGERS DNA METHYLTRANSFERASE 1 EXPRESSION RESULTING IN ELEVATED CPG-METHYLATION AND ENRICHMENT OF MECP2 IN THE P21 PROMOTER IN VITRO. LEACHING OF THE PLASTIC CONSTITUENTS LEADING TO THEIR CHRONIC EXPOSURE TO HUMANS IS A MAJOR CONCERN FOR OUR ENVIRONMENTAL AND OCCUPATIONAL HEALTH. OUR PREVIOUS AND OTHER NUMEROUS STUDIES HAVE DEMONSTRATED THAT ENVIRONMENTAL CHEMICALS LIKE DI (2-ETHYLHEXYL)-PHTHALATE (DEHP) COULD POSE A RISK TOWARDS THE EPIGENETIC MECHANISMS. YET, THE MECHANISMS UNDERLYING ITS POSSIBLE EPIGENOTOXICITY ARE POORLY UNDERSTOOD. WE AIMED TO ASSESS THE IMPACT OF DEHP EXPOSURE TO THE HUMAN BREAST CANCER CELLS (MCF-7) AND RESULTANT CHANGES IN DNA METHYLATION REGULATORS ULTIMATELY ALTERING THE EXPRESSION OF THE CELL CYCLE REGULATOR P21 AS A MODEL GENE. THE MCF-7 CELLS WERE EXPOSED TO ENVIRONMENTALLY RELEVANT CONCENTRATIONS (50-500 NM) FOR 24 H. THE RESULTS SHOWED THAT DEHP WAS PROLIFERATIVE TOWARDS THE MCF-7 CELLS WHILE IT INDUCED GLOBAL DNA HYPERMETHYLATION WITH SELECTIVE UPREGULATION OF DNMT1 AND MECP2. IN ADDITION, DEHP SIGNIFICANTLY REDUCED P53 PROTEIN AND ITS ENRICHMENT TO THE DNMT1 PROMOTER BINDING SITE, WHILE ELEVATING SP1 AND E2F1 TRANSCRIPTION FACTOR LEVELS, STIMULATING THEIR BINDING TO THE PROMOTER DNA. COINCIDENTLY, INCREASED DNMT1 LEVEL WAS HIGHLY ASSOCIATED WITH LOSS OF P21 EXPRESSION AND INCREASED CYCLIN D1 LEVELS. IMPORTANTLY, THE P21, BUT NOT CYCLIN D1 PROMOTER CPG-DINUCLEOTIDES WERE HYPERMETHYLATED AFTER EXPOSURE TO 500 NM DEHP FOR 24 H. FURTHERMORE, IT WAS OBSERVED THAT DEHP SIGNIFICANTLY ENRICHED DNMT1 AND MECP2 TO THE P21 PROMOTER TO INDUCE DNA METHYLATION-BASED EPIGENETIC SILENCING OF P21, RESULTING IN INCREASED CELL PROLIFERATION. OUR RESULTS SUGGEST DEHP COULD POTENTIALLY INDUCE THE EPIGENETIC ALTERATIONS THAT MIGHT INCREASE THE RISK OF BREAST CANCER, GIVEN THAT THE UNDERLYING MECHANISMS SHOULD BE FULLY ELUCIDATED.	2022	
                                                                                                                                                                                                               
5  3610  31 IN UTERO EXPOSURE TO ENDOCRINE-DISRUPTING CHEMICALS, MATERNAL FACTORS AND ALTERATIONS IN THE EPIGENETIC LANDSCAPE UNDERLYING LATER-LIFE HEALTH EFFECTS. WIDESPREAD PERSISTENCE OF ENDOCRINE-DISRUPTING CHEMICALS (EDCS) IN THE ENVIRONMENT HAS MANDATED THE NEED TO STUDY THEIR POTENTIAL EFFECTS ON AN INDIVIDUAL'S LONG-TERM HEALTH AFTER BOTH ACUTE AND CHRONIC EXPOSURE PERIODS. IN THIS REVIEW ARTICLE A PARTICULAR FOCUS IS GIVEN ON IN UTERO EXPOSURE TO EDCS IN RODENT MODELS WHICH RESULTED IN ALTERED EPIGENETIC PROGRAMMING AND TRANSGENERATIONAL EFFECTS IN THE OFFSPRING CAUSING DISRUPTED REPRODUCTIVE AND METABOLIC PHENOTYPES. THE LITERATURE TO DATE ESTABLISHES THE IMPACT OF TRANSGENERATIONAL EFFECTS OF EDCS POTENTIALLY ASSOCIATED WITH EPIGENETIC MEDIATED MECHANISMS. THEREFORE, THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF EPIGENETIC PROGRAMMING AND IT'S REGULATION IN MAMMALS, PRIMARILY FOCUSING ON THE EPIGENETIC PLASTICITY AND SUSCEPTIBILITY TO EXOGENOUS HORMONE ACTIVE CHEMICALS DURING THE EARLY DEVELOPMENTAL PERIOD. FURTHER, WE HAVE ALSO IN DEPTH DISCUSSED THE EPIGENETIC ALTERATIONS ASSOCIATED WITH THE EXPOSURE TO SELECTED EDCS SUCH AS BISPHENOL A (BPA), DI-2-ETHYLHEXYL PHTHALATE (DEHP) AND VINCLOZLIN UPON IN UTERO EXPOSURE ESPECIALLY IN RODENT MODELS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6   651  33 BISPHENOL A AND PHTHALATES MODULATE PERITONEAL MACROPHAGE FUNCTION IN FEMALE MICE INVOLVING SYMD2-H3K36 DIMETHYLATION. AMPLE EVIDENCE SUGGESTS THAT ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO BISPHENOL A (BPA) AND PHTHALATE, TWO CHEMICALS WIDELY USED IN THE PLASTICS INDUSTRY, DISTURBS HOMEOSTASIS OF INNATE IMMUNITY AND CAUSES INFLAMMATORY DISEASES. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS OF THESE TOXICANTS IN THE REGULATION OF MACROPHAGE INFLAMMATORY FUNCTIONS REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE ADDRESSED THE EFFECT OF CHRONIC EXPOSURE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE, EITHER IN VITRO OR IN VIVO, ON THE INFLAMMATORY REPROGRAMING OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT BPA AND PHTHALATES ADVERSELY AFFECTED EXPRESSION LEVELS OF THE PROINFLAMMATORY CYTOKINES AND MEDIATORS IN RESPONSE TO LIPOPOLYSACCHARIDE STIMULATION. EXPOSURE TO THESE TOXICANTS ALSO AFFECTED GENE EXPRESSION OF SCAVENGER RECEPTORS AND PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. OUR STUDIES REVEALED THAT THE EPIGENETIC INHIBITORS DIFFERENTIALLY MODULATED TARGET GENE EXPRESSION IN THESE CELLS. FURTHER ANALYSIS REVEALED THAT CERTAIN HISTONE MODIFICATION ENZYMES WERE ABERRANTLY EXPRESSED IN RESPONSE TO BPA OR PHTHALATE EXPOSURE, LEADING TO ALTERATION IN THE LEVELS OF H3K36 ACETYLATION AND DIMETHYLATION, TWO CHROMATIN MODIFICATIONS THAT ARE CRITICAL FOR TRANSCRIPTIONAL EFFICACY AND ACCURACY. OUR RESULTS FURTHER REVEALED THAT SILENCING OF H3K36-SPECIFIC METHYLTRANSFERASE SMYD2 EXPRESSION OR INHIBITION OF SMYD2 ENZYMATIC ACTIVITY ATTENUATED H3K36 DIMETHYLATION AND ENHANCED INTERLEUKIN-6 AND TUMOR NECROSIS FACTOR-ALPHA EXPRESSION BUT DAMPENED THE PHAGOCYTIC CAPACITY OF PERITONEAL MACROPHAGES. IN SUMMARY, OUR RESULTS INDICATE THAT PERITONEAL MACROPHAGES ARE VULNERABLE TO BPA OR PHTHALATE AT LEVELS RELEVANT TO HUMAN EXPOSURE. THESE ENVIRONMENTAL TOXICANTS AFFECT PHENOTYPIC PROGRAMMING OF MACROPHAGES VIA EPIGENETIC MECHANISMS INVOLVING SMYD2-MEDIATED H3K36 MODIFICATION.	2018	
                                                                                                       
7  4541  39 MULTISYSTEMIC ALTERATIONS IN HUMANS INDUCED BY BISPHENOL A AND PHTHALATES: EXPERIMENTAL, EPIDEMIOLOGICAL AND CLINICAL STUDIES REVEAL THE NEED TO CHANGE HEALTH POLICIES. A VAST AMOUNT OF EVIDENCE INDICATES THAT BISPHENOL A (BPA) AND PHTHALATES ARE WIDELY DISTRIBUTED IN THE ENVIRONMENT SINCE THESE COMPOUNDS ARE MASS-PRODUCED FOR THE MANUFACTURE OF PLASTICS AND PLASTICIZERS. THESE COMPOUNDS BELONG TO A LARGE GROUP OF SUBSTANCES TERMED ENDOCRINE-DISRUPTING CHEMICALS (EDC). IT IS WELL KNOWN THAT HUMANS AND LIVING ORGANISMS ARE UNAVOIDABLY AND UNINTENTIONALLY EXPOSED TO BPA AND PHTHALATES FROM FOOD PACKAGING MATERIALS AND MANY OTHER EVERYDAY PRODUCTS. BPA AND PHTHALATES EXERT THEIR EFFECT BY INTERFERING WITH HORMONE SYNTHESIS, BIOAVAILABILITY, AND ACTION, THEREBY ALTERING CELLULAR PROLIFERATION AND DIFFERENTIATION, TISSUE DEVELOPMENT, AND THE REGULATION OF SEVERAL PHYSIOLOGICAL PROCESSES. IN FACT, THESE EDC CAN ALTER FETAL PROGRAMMING AT AN EPIGENETIC LEVEL, WHICH CAN BE TRANSGENERATIONAL TRANSMITTED AND MAY BE INVOLVED IN THE DEVELOPMENT OF VARIOUS CHRONIC PATHOLOGIES LATER IN THE ADULTHOOD, INCLUDING METABOLIC, REPRODUCTIVE AND DEGENERATIVE DISEASES, AND CERTAIN TYPES OF CANCER. IN THIS REVIEW, WE DESCRIBE THE MOST RECENT PROPOSED MECHANISMS OF ACTION OF THESE EDC AND OFFER A COMPELLING SELECTION OF EXPERIMENTAL, EPIDEMIOLOGICAL AND CLINICAL STUDIES, WHICH SHOW EVIDENCE OF HOW EXPOSURE TO THESE POLLUTANTS AFFECTS OUR HEALTH DURING DEVELOPMENT, AND THEIR ASSOCIATION WITH A WIDE RANGE OF REPRODUCTIVE, METABOLIC AND NEUROLOGICAL DISEASES, AS WELL AS HORMONE-RELATED CANCERS. WE STRESS THE IMPORTANCE OF CONCERN IN THE GENERAL POPULATION AND THE URGENT NEED FOR THE MEDICAL HEALTH CARE SYSTEM TO CLOSELY MONITOR EDC LEVELS IN THE POPULATION DUE TO UNAVOIDABLE AND INVOLUNTARY EXPOSURE TO THESE POLLUTANTS AND THEIR IMPACT ON HUMAN HEALTH.	2021	
                                                                                                                                                                                                                                                               
8  1644  35 DOES THE ENVIRONMENT AFFECT MENOPAUSE? A REVIEW OF THE EFFECTS OF ENDOCRINE DISRUPTING CHEMICALS ON MENOPAUSE. ENDOCRINE DISRUPTING CHEMICALS ARE WIDELY DISTRIBUTED IN OUR ENVIRONMENT. HUMANS ARE EXPOSED TO THESE COMPOUNDS NOT ONLY THROUGH THEIR OCCUPATIONS, BUT ALSO THROUGH DIETARY CONSUMPTION AND EXPOSURE TO CONTAMINATED WATER, PERSONAL CARE PRODUCTS AND TEXTILES. CHEMICALS THAT ARE PERSISTENT IN THE BODY AND IN OUR ENVIRONMENT INCLUDE DIOXINS AND POLYCHLORINATED BIPHENYLS. NON-PERSISTENT CHEMICALS INCLUDING BISPHENOL A, PHTHALATES AND PARABENS ARE EQUALLY AS IMPORTANT BECAUSE THEY ARE UBIQUITOUS IN OUR ENVIRONMENT. HEAVY METALS, INCLUDING LEAD AND CADMIUM, CAN ALSO HAVE ENDOCRINE DISRUPTING PROPERTIES. ALTHOUGH DIFFICULT TO STUDY DUE TO THEIR VARIETY OF SOURCES OF EXPOSURES AND MECHANISMS OF ACTION, THESE CHEMICALS HAVE BEEN ASSOCIATED WITH EARLY MENOPAUSE, INCREASED FREQUENCY OF VASOMOTOR SYMPTOMS, ALTERED STEROID HORMONE LEVELS AND MARKERS OF DIMINISHED OVARIAN RESERVE. UNDERSTANDING THE IMPACTS OF THESE EXPOSURES IS IMPORTANT GIVEN THE POTENTIAL FOR EPIGENETIC MODIFICATION, WHICH CAN ALTER GENE FUNCTION AND RESULT IN MULTI-GENERATIONAL EFFECTS. THIS REVIEW SUMMARIZES FINDINGS IN HUMANS AND ANIMALS OR CELL-BASED MODELS FROM THE PAST DECADE OF RESEARCH. CONTINUED RESEARCH IS NEEDED TO ASSESS THE EFFECTS OF MIXTURES OF CHEMICALS, CHRONIC EXPOSURES AND NEW COMPOUNDS THAT ARE CONTINUOUSLY BEING DEVELOPED AS REPLACEMENTS FOR TOXIC CHEMICALS THAT ARE BEING PHASED OUT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  1767  31 EARLY-LIFE EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS AND LATER-LIFE HEALTH OUTCOMES: AN EPIGENETIC BRIDGE? A GROWING BODY OF EVIDENCE DEMONSTRATES THAT ADVERSE EVENTS EARLY IN DEVELOPMENT, AND PARTICULARLY DURING INTRAUTERINE LIFE, MAY PROGRAM RISKS FOR DISEASES IN ADULT LIFE. INCREASING EVIDENCE HAS BEEN ACCUMULATED INDICATING THE IMPORTANT ROLE OF EPIGENETIC REGULATION INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNAS IN DEVELOPMENTAL PROGRAMMING. AMONG THE ENVIRONMENTAL FACTORS WHICH PLAY AN IMPORTANT ROLE IN PROGRAMMING OF CHRONIC PATHOLOGIES, THE ENDOCRINE-DISRUPTING CHEMICALS (EDCS) THAT HAVE ESTROGENIC, ANTI-ESTROGENIC, AND ANTI-ANDROGENIC ACTIVITY ARE OF SPECIFIC CONCERN BECAUSE THE DEVELOPING ORGANISM IS EXTREMELY SENSITIVE TO PERTURBATION BY SUBSTANCES WITH HORMONE-LIKE ACTIVITY. AMONG EDCS, THERE ARE MANY SUBSTANCES THAT ARE CONSTANTLY PRESENT IN THE MODERN HUMAN ENVIRONMENT OR ARE IN WIDESPREAD USE, INCLUDING DIOXIN AND DIOXIN-LIKE COMPOUNDS, PHTHALATES, AGRICULTURAL PESTICIDES, POLYCHLORINATED BIPHENYLS, INDUSTRIAL SOLVENTS, PHARMACEUTICALS, AND HEAVY METALS. APART FROM THEIR COMMON ENDOCRINE ACTIVE PROPERTIES, SEVERAL EDCS HAVE BEEN SHOWN TO DISRUPT DEVELOPMENTAL EPIGENOMIC PROGRAMMING. THE PURPOSE OF THIS REVIEW IS TO PROVIDE A SUMMARY OF RECENT RESEARCH FINDINGS WHICH INDICATE THAT EXPOSURE TO EDCS DURING IN-UTERO AND/OR NEONATAL DEVELOPMENT CAN CAUSE LONG-TERM HEALTH OUTCOMES VIA MECHANISMS OF EPIGENETIC MEMORY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10  1919  26 ENVIRONMENTAL ENDOCRINE DISRUPTORS: NEW DIABETOGENS? THE PREVALENCE OF TYPE-2 DIABETES HAS DRAMATICALLY INCREASED WORLDWIDE DURING THE LAST FEW DECADES. WHILE LIFESTYLE FACTORS (SEDENTARINESS, NOXIOUS FOOD), TOGETHER WITH GENETIC SUSCEPTIBILITY, ARE WELL-KNOWN ACTORS, THERE IS ACCUMULATING EVIDENCE SUGGESTING THAT ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY ALSO PLAY A PATHOPHYSIOLOGICAL ROLE IN THE OCCURRENCE OF METABOLIC DISEASES. BOTH EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A ROLE FOR EARLY AND CHRONIC EXPOSURE TO LOW DOSES OF CHEMICAL POLLUTANTS WITH ENDOCRINE AND METABOLIC DISRUPTING EFFECTS. MOST ARE PRESENT IN THE FOOD CHAIN AND ACCUMULATE IN THE FAT MASS AFTER ABSORPTION. IN RODENTS, BISPHENOL A STIMULATES SYNTHESIS AND SECRETION OF PANCREATIC BETA CELLS AND DISTURBS INSULIN SIGNALING IN LIVER, MUSCLE AND ADIPOSE TISSUE THROUGH EPIGENETIC CHANGES LEADING TO INSULIN RESISTANCE AND BETA CELL IMPAIRMENT. IN HUMANS, EPIDEMIOLOGICAL REPORTS SHOW STATISTICAL LINK BETWEEN EXPOSURE TO PESTICIDES, POLYCHLORINATED BISPHENYLS, BISPHENOL A, PHTHALATES, DIOXINS OR AROMATIC POLYCYCLIC HYDROCARBIDES OR HEAVY METALS AND DT2 AFTER ACUTE ACCIDENTAL RELEASES OR EARLY IN LIFE AND/OR CHRONIC, LOW DOSES EXPOSURE. MORE PROSPECTIVE, LONGITUDINAL STUDIES ARE NEEDED TO DETERMINE THE IMPORTANCE OF SUCH ENVIRONMENTAL RISK FACTORS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11   910  31 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS.	2014	
                                                                                                                                                                                                                                                           
12   936  34 CHRONIC LOW-LEVEL PERFLUOROOCTANE SULFONATE (PFOS) EXPOSURE PROMOTES TESTICULAR STEROIDOGENESIS THROUGH ENHANCED HISTONE ACETYLATION. PERFLUOROOCTANE SULFONATE (PFOS), AN ARTIFICIAL PERFLUORINATED COMPOUND, HAS BEEN ASSOCIATED WITH MALE REPRODUCTIVE DISORDERS. HISTONE MODIFICATIONS ARE IMPORTANT EPIGENETIC MEDIATORS; HOWEVER, THE IMPACT OF PFOS EXPOSURE ON TESTICULAR STEROIDOGENESIS THROUGH HISTONE MODIFICATION REGULATIONS REMAINS TO BE ELUCIDATED. IN THIS STUDY, WE EXAMINED THE ROLES OF HISTONE MODIFICATIONS IN REGULATING STEROID HORMONE PRODUCTION IN MALE RATS CHRONICALLY EXPOSED TO LOW-LEVEL PFOS. THE RESULTS INDICATE THAT PFOS EXPOSURE SIGNIFICANTLY UP-REGULATED THE EXPRESSIONS OF STAR, CYP11A1 AND 3BETA-HSD, WHILE CYP17A1 AND 17BETA-HSD WERE DOWN-REGULATED, THUS CONTRIBUTING TO THE ELEVATED PROGESTERONE AND TESTOSTERONE LEVELS. FURTHERMORE, PFOS SIGNIFICANTLY INCREASED THE HISTONES H3K9ME2, H3K9AC AND H3K18AC WHILE REDUCED H3K9ME3 IN RAT TESTIS. IT IS KNOWN THAT HISTONE MODIFICATIONS ARE CLOSELY INVOLVED IN GENE TRANSCRIPTION. THEREFORE, TO INVESTIGATE THE ASSOCIATION BETWEEN HISTONE MODIFICATIONS AND STEROIDOGENIC GENE REGULATION, THE LEVELS OF THESE HISTONE MARKS WERE FURTHER MEASURED IN STEROIDOGENIC GENE PROMOTER REGIONS BY CHIP. IT WAS FOUND THAT H3K18AC WAS AUGMENTED IN CYP11A1 PROMOTER, AND H3K9AC WAS INCREASED IN HSD3B AFTER PFOS EXPOSURE, WHICH IS PROPOSED TO RESULT IN THE ACTIVATION OF CYP11A1 AND 3BETA-HSD, RESPECTIVELY. TO SUM UP, CHRONIC LOW-LEVEL PFOS EXPOSURE ACTIVATED KEY STEROIDOGENIC GENE EXPRESSION THROUGH ENHANCING HISTONE ACETYLATION (H3K9AC AND H3K18AC), ULTIMATELY STIMULATING STEROID HORMONE BIOSYNTHESIS IN RAT TESTIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13   903  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14  5191  26 PRENATAL DEXAMETHASONE EXPOSURE PROGRAMS THE DECREASED TESTOSTERONE SYNTHESIS IN OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS. PRENATAL DEXAMETHASONE EXPOSURE (PDE) CAN DECREASE MATERNAL ENDOGENOUS GLUCOCORTICOID LEVEL AND INDUCE TESTICULAR DYSPLASIA IN MALE OFFSPRING RATS. IN THIS STUDY WE INVESTIGATED LOW LEVEL ENDOGENOUS GLUCOCORTICOID-MEDIATED TESTICULAR DYSPLASIA IN PDE OFFSPRING AND ELUCIDATED THE INTRAUTERINE EPIGENETIC PROGRAMMING MECHANISMS. PREGNANT RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG.KG(-1).D(-1), SC) ON GESTATIONAL DAY (GD) 9-20. THE OFFSPRING RAT BLOOD AND TESTIS WERE COLLECTED AFTER EUTHANASIA ON GD20, POSTNATAL WEEK (PW) 12 OR PW28. WE SHOWED THAT PDE INDUCED ABNORMAL MORPHOLOGY OF TESTIS AND SIGNIFICANTLY DECREASED THE EXPRESSION OF TESTOSTERONE SYNTHESIS-RELATED GENES AS WELL AS TESTOSTERONE PRODUCTION BEFORE AND AFTER BIRTH. MEANWHILE, SERUM CORTICOSTERONE, THE EXPRESSION AND HISTONE 3 LYSINE 14 ACETYLATION (H3K14AC) OF TESTICULAR INSULIN-LIKE GROWTH FACTOR 1 (IGF1) WERE SIGNIFICANTLY DECREASED. AFTER THE PREGNANT RATS WERE SUBJECTED TO CHRONIC STRESS FOR 2 WEEKS (PW10-12), SERUM CORTICOSTERONE LEVEL WAS INCREASED IN THE ADULT PDE OFFSPRING, AND THE ABOVE-MENTIONED OTHER INDICATORS WERE ALSO IMPROVED. CULTURED LEYDIG CELLS (TM3) WERE TREATED WITH CORTICOSTERONE (62.5-500 NM) IN VITRO. WE SHOWED THAT CORTICOSTERONE CONCENTRATION-DEPENDENTLY INHIBITED GLUCOCORTICOID RECEPTOR ALPHA (GRALPHA) AND MIR-124-3P EXPRESSION, INCREASED HISTONE DEACETYLASE 5 (HDAC5) EXPRESSION, AND DECREASED IGF1 H3K14AC LEVEL AND THE EXPRESSION OF IGF1/STEROIDOGENIC ACUTE REGULATORY PROTEIN (STAR), SUGGESTING THAT CORTICOSTERONE AT LOWER THAN PHYSIOLOGICAL LEVEL (<500 NM) INHIBITED TESTOSTERONE SYNTHESIS BY REDUCING H3K14AC AND THE EXPRESSION LEVEL OF IGF1 THROUGH GRALPHA/MIR-124-3P/HDAC5 PATHWAY. IN CONCLUSION, PDE CAN CAUSE PERSISTENT INHIBITION OF TESTOSTERONE SYNTHESIS BEFORE AND AFTER BIRTH IN THE OFFSPRING RATS BY LOW LEVEL OF ENDOGENOUS GLUCOCORTICOIDS.	2022	
                                                                                                       
15  4383  34 MITOCHONDRIAL EPIGENETICS AND ENVIRONMENTAL HEALTH: MAKING A CASE FOR ENDOCRINE DISRUPTING CHEMICALS. RECENT STUDIES IMPLICATE MITOCHONDRIAL DYSFUNCTION IN THE DEVELOPMENT AND PROGRESSION OF NUMEROUS CHRONIC DISEASES, WHICH MAY BE PARTIALLY DUE TO MODIFICATIONS IN MITOCHONDRIAL DNA (MTDNA). THERE IS ALSO MOUNTING EVIDENCE THAT EPIGENETIC MODIFICATIONS TO MTDNA MAY BE AN ADDITIONAL LAYER OF REGULATION THAT CONTROLS MITOCHONDRIAL BIOGENESIS AND FUNCTION. SEVERAL ENVIRONMENTAL FACTORS (EG, SMOKING, AIR POLLUTION) HAVE BEEN ASSOCIATED WITH ALTERED MTDNA METHYLATION IN A HANDFUL OF MECHANISTIC STUDIES AND IN OBSERVATIONAL HUMAN STUDIES. HOWEVER, LITTLE IS UNDERSTOOD ABOUT OTHER ENVIRONMENTAL CONTAMINANTS THAT INDUCE MTDNA EPIGENETIC CHANGES. NUMEROUS ENVIRONMENTAL TOXICANTS ARE CLASSIFIED AS ENDOCRINE DISRUPTING CHEMICALS (EDCS). BEYOND THEIR ACTIONS ON HORMONAL PATHWAYS, EDC EXPOSURE IS ASSOCIATED WITH ELEVATED OXIDATIVE STRESS, WHICH MAY OCCUR THROUGH OR RESULT IN MITOCHONDRIAL DYSFUNCTION. ALTHOUGH ONLY A FEW STUDIES HAVE ASSESSED THE IMPACTS OF EDCS ON MTDNA METHYLATION, THE CURRENT REVIEW PROVIDES REASONS TO CONSIDER MTDNA EPIGENETIC DISRUPTION AS A MECHANISM OF ACTION OF EDCS AND REVIEWS POTENTIAL LIMITATIONS RELATED TO CURRENTLY AVAILABLE EVIDENCE. FIRST, THERE IS SUFFICIENT EVIDENCE THAT EDCS (INCLUDING BISPHENOLS AND PHTHALATES) DIRECTLY TARGET MITOCHONDRIAL FUNCTION, AND MORE DIRECT EVIDENCE IS NEEDED TO CONNECT THIS TO MTDNA METHYLATION. SECOND, THESE AND OTHER EDCS ARE POTENT MODULATORS OF NUCLEAR DNA EPIGENETICS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. FINALLY, EDCS HAVE BEEN SHOWN TO DISRUPT SEVERAL MODULATORS OF MTDNA METHYLATION, INCLUDING DNA METHYLTRANSFERASES AND THE MITOCHONDRIAL TRANSCRIPTION FACTOR A/NUCLEAR RESPIRATORY FACTOR 1 PATHWAY. TAKEN TOGETHER, THESE STUDIES HIGHLIGHT THE NEED FOR FUTURE RESEARCH EVALUATING MTDNA EPIGENETIC DISRUPTION BY EDCS AND TO DETAIL SPECIFIC MECHANISMS RESPONSIBLE FOR SUCH DISRUPTIONS.	2020	
                                                                                                                                 
16  5020  35 PERSISTENT OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 ATTENUATING GABAERGIC INHIBITION IN BASOLATERAL AMYGDALA ACCOUNTS FOR ANXIETY IN RAT OFFSPRING EXPOSED PERINATALLY TO LOW-DOSE BISPHENOL A. SUBSTANTIAL EVIDENCE INDICATES THAT PREDISPOSITION TO DISEASES CAN BE ACQUIRED DURING EARLY STAGES OF DEVELOPMENT AND INTERACTIONS BETWEEN ENVIRONMENTAL AND GENETIC FACTORS MAY BE IMPLICATED IN THE ONSET OF MANY PATHOLOGICAL CONDITIONS. WE HAVE SHOWN THAT PERINATAL EXPOSURE TO BISPHENOL A (BPA) AT ENVIRONMENTAL DOSE LEVEL CAUSES LONG-TERM ANXIETY-LIKE BEHAVIORS IN RATS. THE AIM OF THIS STUDY WAS TO EXAMINE EPIGENETIC REPROGRAMMING EFFECT OF BPA ON ANXIETY-RELATED NEUROBEHAVIOR IN THE RAT OFFSPRING. THE RESULTS OF REAL-TIME RT-PCR DISPLAYED THAT THE OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 (DNMT1) MRNA WAS ACCOMPANIED BY THE REDUCTION OF GLUTAMIC ACID DECARBOXYLASE 67 (GAD67) MRNA LEVEL IN THE BASOLATERAL AMYGDALA (BLA) OF POSTNATAL DAY 45 BPA-EXPOSED FEMALE RATS. CHRONIC INTRO-BLA INJECTION WITH 5-ADA-CDR COULD RECTIFY THE GAD67 MRNA EXPRESSION. BEHAVIORAL DATA SHOWED THAT THE ANXIETY-LIKE BEHAVIORS IN BPA-EXPOSED RATS WERE REVERSED BY INTRO-BLA TREATMENT WITH 5-ADA-CDR WHICH COULD BE FURTHER BLOCKED BY PTX. ELECTROPHYSIOLOGICAL STUDY REVEALED BEHAVIORAL ALTERATIONS WERE ASSOCIATED WITH THE INCREASE OF POSTSYNAPTIC NEURONAL EXCITABILITY IN THE CORTICAL-BLA PATHWAY WHICH APPEARED AS MULTISPIKE RESPONSES, PAIRED-PULSE FACILITATION INSTEAD OF PAIRED-PULSE INHIBITION AND LONG-TERM POTENTIATION AND 5-AZA-CDR TREATMENT RESTORED THE INCREASED SYNAPTIC TRANSMISSION IN THE BLA VIA IMPROVING GABAERGIC SYSTEM. THE ABOVE RESULTS SUGGEST THAT THE OVEREXPRESSION OF DNMT1 IN THE BLA IS RESPONSIBLE FOR THE ETIOLOGY OF ANXIETY ASSOCIATED WITH BPA EXPOSURE VIA GABAERGIC DISINHIBITION. IN ADDITION, WE ALSO FIND THESE LONG-TERM NEUROBEHAVIORAL EFFECTS OF DEVELOPMENTAL BPA EXPOSURE ARE REVERSIBLE IN ADOLESCENT PERIOD.	2013	
                                                                                                                                                                                              
17  5187  30 PRENATAL AIRBORNE POLYCYCLIC AROMATIC HYDROCARBON EXPOSURE, ALTERED REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR)GAMMA, AND LINKS WITH MAMMARY CANCER. ENVIRONMENTAL EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAH) HAS BEEN SHOWN TO BE ASSOCIATED WITH CHRONIC DISEASE OUTCOMES THROUGH MULTIPLE MECHANISMS INCLUDING ALTERED REGULATION OF THE TRANSCRIPTION FACTOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR) GAMMA. BECAUSE PAH EXPOSURE AND PPARGAMMA EACH HAVE BEEN ASSOCIATED WITH MAMMARY CANCER, WE ASKED WHETHER PAH WOULD INDUCE ALTERED REGULATION OF PPARGAMMA IN MAMMARY TISSUE, AND WHETHER THIS ASSOCIATION MAY UNDERLIE THE ASSOCIATION BETWEEN PAH AND MAMMARY CANCER. PREGNANT MICE WERE EXPOSED TO AEROSOLIZED PAH AT PROPORTIONS THAT MIMIC EQUIVALENT HUMAN EXPOSURES IN NEW YORK CITY AIR. WE HYPOTHESIZED THAT PRENATAL PAH EXPOSURE WOULD ALTER PPARGAMMA DNA METHYLATION AND GENE EXPRESSION AND INDUCE THE EPITHELIAL TO MESENCHYMAL TRANSITION (EMT) IN MAMMARY TISSUE OF OFFSPRING (F1) AND GRANDOFFSPRING (F2) MICE. WE ALSO HYPOTHESIZED THAT ALTERED REGULATION OF PPARGAMMA IN MAMMARY TISSUE WOULD ASSOCIATE WITH BIOMARKERS OF EMT, AND EXAMINED ASSOCIATIONS WITH WHOLE BODY WEIGHT. WE FOUND THAT PRENATAL PAH EXPOSURE LOWERED PPARGAMMA MAMMARY TISSUE METHYLATION AMONG GRANDOFFSPRING MICE AT POSTNATAL DAY (PND) 28. HOWEVER, PAH EXPOSURE DID NOT ASSOCIATE WITH ALTERED PPARGAMMA GENE EXPRESSION OR CONSISTENTLY WITH BIOMARKERS OF EMT. FINALLY, LOWER PPARGAMMA METHYLATION, BUT NOT GENE EXPRESSION, WAS ASSOCIATED WITH HIGHER BODY WEIGHT AMONG OFFSPRING AND GRANDOFFSPRING MICE AT PND28 AND PND60. FINDINGS SUGGEST ADDITIONAL EVIDENCE OF MULTI-GENERATIONAL ADVERSE EPIGENETIC EFFECTS OF PRENATAL PAH EXPOSURE AMONG GRANDOFFSPRING MICE.	2023	
                                                                                                                                                                                                                                                                                                                                                   
18  5097  36 PLASTICS DERIVED ENDOCRINE-DISRUPTING COMPOUNDS AND THEIR EFFECTS ON EARLY DEVELOPMENT. DESPITE THE FACT THAT THE ESTROGENIC EFFECTS OF BISPHENOLS WERE FIRST DESCRIBED 80 YEARS AGO, RECENT DATA ABOUT ITS POTENTIAL NEGATIVE IMPACT ON BIRTH OUTCOME PARAMETERS RAISES A STRONG RATIONALE TO INVESTIGATE FURTHER. THE ADVERSE HEALTH EFFECTS OF PLASTICS RECOMMEND TO MEASURE THE IMPACTS OF ENDOCRINE-DISRUPTING COMPOUNDS (EDCS) SUCH AS BISPHENOLS (BPA, BPS, BPF), BIS(2-ETHYLHEXYL) PHTHALATE, AND DIBUTYL PHTHALATE (DBP) IN HUMAN HEALTH. EXPOSURE TO THESE COMPOUNDS IN UTERO MAY PROGRAM THE DISEASES OF THE TESTIS, PROSTATE, KIDNEY AND ABNORMALITIES IN THE IMMUNE SYSTEM, AND CAUSE TUMORS, UTERINE HEMORRHAGE DURING PREGNANCY AND POLYCYSTIC OVARY. THESE COMPOUNDS ALSO CONTROL THE PROCESSES OF EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ADULT-ONSET DISEASES BY MODULATING DNA METHYLATION AND EPIMUTATIONS IN REPRODUCTIVE CELLS. THE EARLY DEVELOPMENTAL STAGE IS THE MOST SUSCEPTIBLE WINDOW FOR DEVELOPMENTAL AND GENOMIC PROGRAMMING. THE CRITICAL STAGES OF THE EVENTS FOR A NORMAL HUMAN BIRTH LIE BETWEEN THE MANY TRANSITIONS OCCURRING BETWEEN SPERMATOGENESIS, EGG FERTILIZATION AND THE FULLY FORMED FETUS. AS THE CELLS BEGIN TO GROW AND DIFFERENTIATE, THERE ARE CRITICAL BALANCES OF HORMONES, AND PROTEIN SYNTHESIS. DATA ARE EMERGING ON HOW THESE PLASTIC-DERIVED COMPOUNDS AFFECT EMBRYOGENESIS, PLACENTATION AND FETO-PLACENTAL DEVELOPMENT SINCE PREGNANT WOMEN AND UNBORN FETUSES ARE OFTEN EXPOSED TO THESE FACTORS DURING PRECONCEPTION AND THROUGHOUT GESTATION. IMPAIRED EARLY DEVELOPMENT THAT ULTIMATELY INFLUENCES FETAL OUTCOMES IS AT THE CENTER OF MANY DEVELOPMENTAL DISORDERS AND CONTRIBUTES AN INDEPENDENT RISK FACTOR FOR ADULT CHRONIC DISEASES. THIS REVIEW WILL SUMMARIZE THE CURRENT STATUS ON THE IMPACT OF EXPOSURE TO PLASTIC DERIVED EDCS ON THE GROWTH, GENE EXPRESSION, EPIGENETIC AND ANGIOGENIC ACTIVITIES OF THE EARLY FETAL DEVELOPMENT PROCESS AND THEIR POSSIBLE EFFECTS ON BIRTH OUTCOMES.	2020	
                                                                                                                      
19    73  30 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	
                                                                                                                                                  
20  3373  30 HISTONE MODULATION BLOCKS TREG-INDUCED FOXP3 BINDING TO THE IL-2 PROMOTER OF VIRUS-SPECIFIC CD8(+) T CELLS FROM FELINE IMMUNODEFICIENCY VIRUS-INFECTED CATS. CD8(+) T CELLS ARE CRITICAL FOR CONTROLLING HIV INFECTION. DURING THE CHRONIC PHASE OF LENTIVIRAL INFECTION, CD8(+) T CELLS LOSE THEIR PROLIFERATIVE CAPACITY AND EXHIBIT IMPAIRED ANTIVIRAL FUNCTION. THIS LOSS OF CD8(+) T CELL FUNCTION IS DUE, IN PART, TO CD4(+)CD25(+) T REGULATORY (TREG) CELL-MEDIATED SUPPRESSION. OUR RESEARCH GROUP HAS DEMONSTRATED THAT LENTIVIRUS-ACTIVATED CD4(+)CD25(+) TREG CELLS INDUCE THE REPRESSIVE TRANSCRIPTION FACTOR FORKHEAD BOX P3 (FOXP3) IN AUTOLOGOUS CD8(+) T CELLS FOLLOWING CO-CULTURE. WE HAVE RECENTLY REPORTED THAT TREG-INDUCED FOXP3 BINDS THE INTERLEUKIN-2 (IL-2), INTERFERON-GAMMA (IFN- GAMMA), AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PROMOTERS IN VIRUS-SPECIFIC CD8(+) T CELLS. THESE DATA SUGGEST AN IMPORTANT ROLE OF FOXP3-MEDIATED CD8(+) T CELL DYSFUNCTION IN LENTIVIRAL INFECTION. TO ELUCIDATE THE MECHANISM OF THIS SUPPRESSION, WE PREVIOUSLY REPORTED THAT DECREASED METHYLATION FACILITATES FOXP3 BINDING IN MITOGEN-ACTIVATED CD8(+) T CELLS FROM FELINE IMMUNODEFICIENCY VIRUS (FIV)-INFECTED CATS. WE DEMONSTRATED THE REDUCED BINDING OF FOXP3 TO THE IL-2 PROMOTER BY INCREASING METHYLATION OF CD8(+) T CELLS. IN THE STUDIES PRESENTED HERE, WE ASK IF ANOTHER FORM OF EPIGENETIC MODULATION MIGHT ALLEVIATE FOXP3-MEDIATED SUPPRESSION IN CD8(+) T CELLS. WE HYPOTHESIZED THAT DECREASING HISTONE ACETYLATION IN VIRUS-SPECIFIC CD8(+) T CELLS WOULD DECREASE TREG-INDUCED FOXP3 BINDING TO THE IL-2 PROMOTER. INDEED, USING ANACARDIC ACID (AA), A KNOWN HISTONE ACETYL TRANSFERASE (HAT) INHIBITOR, WE DEMONSTRATE A REDUCTION IN FOXP3 BINDING TO THE IL-2 PROMOTER IN VIRUS-SPECIFIC CD8(+) T CELLS CO-CULTURED WITH AUTOLOGOUS TREG CELLS. THESE DATA IDENTIFY A NOVEL MECHANISM OF FOXP3-MEDIATED CD8(+) T CELL DYSFUNCTION DURING LENTIVIRAL INFECTION.	2018