1 2758 118 EXPRESSION OF HORMONAL CARCINOGENESIS GENES AND RELATED REGULATORY MICRORNAS IN UTERUS AND OVARIES OF DDT-TREATED FEMALE RATS. THE INSECTICIDE DICHLORODIPHENYLTRICHLOROETHANE (DDT) IS A NONMUTAGENIC XENOBIOTIC COMPOUND ABLE TO EXERT ESTROGEN-LIKE EFFECTS RESULTING IN ACTIVATION OF ESTROGEN RECEPTOR-ALPHA (ERALPHA) FOLLOWED BY CHANGED EXPRESSION OF ITS DOWNSTREAM TARGET GENES. IN ADDITION, STUDIES PERFORMED OVER RECENT YEARS SUGGEST THAT DDT MAY ALSO INFLUENCE EXPRESSION OF MICRORNAS. HOWEVER, AN IMPACT OF DDT ON EXPRESSION OF ER, MICRORNAS, AND RELATED TARGET GENES HAS NOT BEEN FULLY ELUCIDATED. HERE, USING REAL-TIME PCR, WE ASSESSED CHANGES IN EXPRESSION OF KEY GENES INVOLVED IN HORMONAL CARCINOGENESIS AS WELL AS POTENTIALLY RELATED REGULATORY ONCOGENIC/TUMOR SUPPRESSOR MICRORNAS AND THEIR TARGET GENES IN THE UTERUS AND OVARIES OF FEMALE WISTAR RATS DURING SINGLE AND CHRONIC MULTIPLE-DOSE DDT EXPOSURE. WE FOUND THAT APPLYING DDT RESULTS IN ALTERED EXPRESSION OF MICRORNAS-221, -222, -205, -126A, AND -429, THEIR TARGET GENES (PTEN, DICER1), AS WELL AS GENES INVOLVED IN HORMONAL CARCINOGENESIS (ESR1, PGR, CCND1, CYP19A1). NOTABLY, CYP19A1 EXPRESSION SEEMS TO BE ALSO REGULATED BY MICRORNAS-221, -222, AND -205. THE DATA SUGGEST THAT EPIGENETIC EFFECTS INDUCED BY DDT AS A POTENTIAL CARCINOGEN MAY BE BASED ON AT LEAST TWO MECHANISMS: (I) ACTIVATION OF ERALPHA FOLLOWED BY ALTERED EXPRESSION OF THE TARGET GENES ENCODING RECEPTOR PGR AND CCND1 AS WELL AS IMPAIRED EXPRESSION OF CYP19A1, AFFECTING, THEREBY, CELL HORMONE BALANCE; AND (II) CHANGED EXPRESSION OF MICRORNAS RESULTING IN IMPAIRED EXPRESSION OF RELATED TARGET GENES INCLUDING REDUCED LEVEL OF CYP19A1 MRNA. 2017 2 1549 30 DNA METHYLATION IN THE HUMAN CEREBRAL CORTEX IS DYNAMICALLY REGULATED THROUGHOUT THE LIFE SPAN AND INVOLVES DIFFERENTIATED NEURONS. THE ROLE OF DNA CYTOSINE METHYLATION, AN EPIGENETIC REGULATOR OF CHROMATIN STRUCTURE AND FUNCTION, DURING NORMAL AND PATHOLOGICAL BRAIN DEVELOPMENT AND AGING REMAINS UNCLEAR. HERE, WE EXAMINED BY METHYLIGHT PCR THE DNA METHYLATION STATUS AT 50 LOCI, ENCOMPASSING PRIMARILY 5' CPG ISLANDS OF GENES RELATED TO CNS GROWTH AND DEVELOPMENT, IN TEMPORAL NEOCORTEX OF 125 SUBJECTS RANGING IN AGE FROM 17 WEEKS OF GESTATION TO 104 YEARS OLD. TWO PSYCHIATRIC DISEASE COHORTS--DEFINED BY CHRONIC NEURODEGENERATION (ALZHEIMER'S) OR LACK THEREOF (SCHIZOPHRENIA)--WERE INCLUDED. A ROBUST AND PROGRESSIVE RISE IN DNA METHYLATION LEVELS ACROSS THE LIFESPAN WAS OBSERVED FOR 8/50 LOCI (GABRA2, GAD1, HOXA1, NEUROD1, NEUROD2, PGR, STK11, SYK) TYPICALLY IN CONJUNCTION WITH DECLINING LEVELS OF THE CORRESPONDING MRNAS. ANOTHER 16 LOCI WERE DEFINED BY A SHARP RISE IN DNA METHYLATION LEVELS WITHIN THE FIRST FEW MONTHS OR YEARS AFTER BIRTH. DISEASE-ASSOCIATED CHANGES WERE LIMITED TO 2/50 LOCI IN THE ALZHEIMER'S COHORT, WHICH APPEARED TO REFLECT AN ACCELERATION OF THE AGE-RELATED CHANGE IN NORMAL BRAIN. ADDITIONALLY, METHYLATION STUDIES ON SORTED NUCLEI PROVIDED EVIDENCE FOR BIDIRECTIONAL METHYLATION EVENTS IN CORTICAL NEURONS DURING THE TRANSITION FROM CHILDHOOD TO ADVANCED AGE, AS REFLECTED BY SIGNIFICANT INCREASES AT 3, AND A DECREASE AT 1 OF 10 LOCI. FURTHERMORE, THE DNMT3A DE NOVO DNA METHYL-TRANSFERASE WAS EXPRESSED ACROSS ALL AGES, INCLUDING A SUBSET OF NEURONS RESIDING IN LAYERS III AND V OF THE MATURE CORTEX. THEREFORE, DNA METHYLATION IS DYNAMICALLY REGULATED IN THE HUMAN CEREBRAL CORTEX THROUGHOUT THE LIFESPAN, INVOLVES DIFFERENTIATED NEURONS, AND AFFECTS A SUBSTANTIAL PORTION OF GENES PREDOMINANTLY BY AN AGE-RELATED INCREASE. 2007 3 5241 25 PROGESTERONE RESISTANCE IN ENDOMETRIOSIS: CURRENT EVIDENCE AND PUTATIVE MECHANISMS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE CHARACTERIZED BY THE GROWTH OF ENDOMETRIAL-LIKE TISSUE OUTSIDE THE UTERUS. PROGESTINS ARE CURRENTLY THE MOST COMMONLY USED TREATMENT FOR ENDOMETRIOSIS BECAUSE OF THEIR EXCELLENT THERAPEUTIC EFFECTS AND LIMITED SIDE EFFECTS. HOWEVER, PROGESTINS HAVE BEEN UNSUCCESSFUL IN SOME SYMPTOMATIC PATIENTS. THE INABILITY OF THE ENDOMETRIUM TO RESPOND PROPERLY TO PROGESTERONE IS KNOWN AS PROGESTERONE RESISTANCE. AN INCREASING BODY OF EVIDENCE SUGGESTS THE LOSS OF PROGESTERONE SIGNALING AND THE EXISTENCE OF PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. THE MECHANISMS OF PROGESTERONE RESISTANCE HAVE RECEIVED CONSIDERABLE SCHOLARLY ATTENTION IN RECENT YEARS. ABNORMAL PGR SIGNALING, CHRONIC INFLAMMATION, ABERRANT GENE EXPRESSION, EPIGENETIC ALTERATIONS, AND ENVIRONMENTAL TOXINS ARE CONSIDERED POTENTIAL MOLECULAR CAUSES OF PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. THE GENERAL OBJECTIVE OF THIS REVIEW WAS TO SUMMARIZE THE EVIDENCE AND MECHANISMS OF PROGESTERONE RESISTANCE. A DEEPER UNDERSTANDING OF HOW THESE MECHANISMS CONTRIBUTE TO PROGESTERONE RESISTANCE MAY HELP DEVELOP A NOVEL THERAPEUTIC REGIMEN FOR WOMEN WITH ENDOMETRIOSIS BY REVERSING PROGESTERONE RESISTANCE. 2023 4 5242 28 PROGESTERONE RESISTANCE IN ENDOMETRIOSIS: ORIGINS, CONSEQUENCES AND INTERVENTIONS. ENDOMETRIOSIS IS A COMMON CAUSE OF PELVIC PAIN AND AFFECTS UP TO 10% OF WOMEN OF REPRODUCTIVE AGE. ABERRANT PROGESTERONE SIGNALING IN THE ENDOMETRIUM PLAYS A SIGNIFICANT ROLE IN IMPAIRED DECIDUALIZATION AND ESTABLISHMENT OF ECTOPIC ENDOMETRIAL IMPLANTS. EUTOPIC ENDOMETRIAL CELLS FROM WOMEN WITH ENDOMETRIOSIS FAIL TO DOWNREGULATE GENES NEEDED FOR DECIDUALIZATION, SUCH AS THOSE INVOLVED IN CELL CYCLE REGULATION, LEADING TO UNBRIDLED PROLIFERATION. SEVERAL CAUSES OF PROGESTERONE RESISTANCE IN THE ENDOMETRIUM HAVE BEEN POSTULATED, INCLUDING CONGENITAL "PRECONDITIONING", WHEREBY THE IN UTERO ENVIRONMENT RENDERS INFANTS SUSCEPTIBLE TO NEONATAL UTERINE BLEEDING AND ENDOMETRIOSIS. PROGESTERONE ACTION IS CRUCIAL TO DECREASING INFLAMMATION IN THE ENDOMETRIUM, AND DEVIANT PROGESTERONE SIGNALING RESULTS IN A PROINFLAMMATORY PHENOTYPE. CONVERSELY, CHRONIC INFLAMMATION CAN INDUCE A PROGESTERONE-RESISTANT STATE. REPETITIVE RETROGRADE ENDOMETRIAL SHEDDING BEGETS CHRONIC PERITONEAL INFLAMMATION, WHICH FURTHER EXACERBATES PROGESTERONE RESISTANCE. GENETIC CAUSES OF PROGESTERONE RESISTANCE INCLUDE PROGESTERONE RECEPTOR GENE POLYMORPHISMS, ALTERED MICRORNA EXPRESSION, AND EPIGENETIC MODIFICATIONS TO PROGESTERONE RECEPTORS AND THEIR TARGETS. ENVIRONMENTAL TOXINS SUCH AS DIOXIN PLAY A POSSIBLE ROLE IN THE GENESIS OF ENDOMETRIOSIS BY PERMITTING AN INFLAMMATORY MILIEU. A CONSEQUENCE OF IMPAIRED PROGESTERONE ACTION IS THAT HORMONAL THERAPY IS RENDERED INEFFECTIVE FOR A SUBSET OF WOMEN WITH ENDOMETRIOSIS. SYNTHETIC PROGESTINS, SUCH AS DIENOGEST, MAY OVERCOME THIS PHENOMENON BY INCREASING PROGESTERONE RECEPTOR EXPRESSION AND DECREASING PROINFLAMMATORY CYTOKINES. OTHER MODALITIES INCLUDE HIGH DOSE DEPOT FORMULATIONS OF PROGESTINS, MEDICATED INTRAUTERINE DEVICES AND THE LIKELY ADVENT OF ORAL GNRH ANTAGONISTS. UNEARTHING ROOT CAUSES OF PROGESTERONE INACTION IN ENDOMETRIOSIS WILL AID IN THE DEVELOPMENT OF NOVEL THERAPEUTICS GEARED TOWARD PREVENTION AND TREATMENT. 2017 5 3999 28 LOSS OF HDAC3 RESULTS IN NONRECEPTIVE ENDOMETRIUM AND FEMALE INFERTILITY. ENDOMETRIOSIS IS A DISEASE IN WHICH TISSUE THAT NORMALLY GROWS INSIDE THE UTERUS GROWS OUTSIDE THE UTERUS AND CAUSES CHRONIC PELVIC PAIN AND INFERTILITY. HOWEVER, THE EXACT MECHANISMS OF THE PATHOGENESIS OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY ARE UNKNOWN. EPIGENETIC DYSREGULATION HAS RECENTLY BEEN IMPLICATED IN INFERTILITY. HERE, WE REPORT A REDUCTION OF HISTONE DEACETYLASE 3 (HDAC3) PROTEIN AMOUNTS IN EUTOPIC ENDOMETRIUM OF INFERTILE WOMEN WITH ENDOMETRIOSIS COMPARED TO A CONTROL GROUP. TO INVESTIGATE THE EFFECT OF HDAC3 LOSS IN THE UTERUS, WE GENERATED MICE WITH CONDITIONAL ABLATION OF HDAC3 IN PROGESTERONE RECEPTOR (PGR)-POSITIVE CELLS (PGR(CRE/+)HDAC3(F/F) ; HDAC3(D/D) ). LOSS OF HDAC3 IN THE UTERUS OF MICE RESULTS IN INFERTILITY DUE TO IMPLANTATION FAILURE AND DECIDUALIZATION DEFECT. EXPRESSION MICROARRAY AND CHIP-SEQ ANALYSES IDENTIFIED COL1A1 AND COL1A2 AS DIRECT TARGETS OF HDAC3 IN BOTH MICE AND HUMANS. REDUCTION OF HDAC3 ABROGATED DECIDUALIZATION IN A PRIMARY CULTURE OF HUMAN ENDOMETRIAL STROMAL CELLS (HESCS) SIMILAR TO THAT OBSERVED IN INFERTILE PATIENTS WITH ENDOMETRIOSIS. WHEREAS ATTENUATION OF HDAC3 RESULTED IN P300 RECRUITMENT TO COL1A1 AND COL1A2 GENES IN THE UTERUS OF MICE AS WELL AS HESCS, INHIBITION OF P300 PERMITTED HESCS TO UNDERGO DECIDUALIZATION. COLLECTIVELY, WE FOUND ATTENUATION OF HDAC3 AND OVEREXPRESSION OF COLLAGEN TYPE I IN THE EUTOPIC ENDOMETRIUM OF INFERTILE PATIENTS WITH ENDOMETRIOSIS. HDAC3 LOSS CAUSED A DEFECT OF DECIDUALIZATION THROUGH THE ABERRANT TRANSCRIPTIONAL ACTIVATION OF COL1A1 AND COL1A2 GENES IN MICE AND COL1A1 AND COL1A2 GENES IN HUMANS. OUR RESULTS SUGGEST THAT HDAC3 IS CRITICAL FOR ENDOMETRIAL RECEPTIVITY AND DECIDUALIZATION. 2019 6 1840 26 EFFECTS OF SELECTIVE INHIBITION OF PROSTAGLANDIN E2 RECEPTORS EP2 AND EP4 ON THE MIRNA PROFILE IN ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT, PROGESTERONE-RESISTANT, CHRONIC INFLAMMATORY GYNECOLOGICAL DISEASE OF REPRODUCTIVE-AGE WOMEN. TWO MAJOR CLINICAL SYMPTOMS OF ENDOMETRIOSIS ARE CHRONIC PELVIC PAIN AND INFERTILITY, WHICH PROFOUNDLY AFFECT THE QUALITY OF LIFE IN WOMEN. CURRENT HORMONAL THERAPIES TO INDUCE A HYPOESTROGENIC STATE ARE UNSUCCESSFUL BECAUSE OF UNDESIRABLE SIDE EFFECTS, REPRODUCTIVE HEALTH CONCERNS, AND FAILURE TO PREVENT DISEASE RECURRENCE. PROSTAGLANDIN E(2) (PGE(2)) PLAYS AN IMPORTANT ROLE IN THE SURVIVAL AND GROWTH OF ENDOMETRIOTIC LESIONS. MICRORNAS (MIRNAS) ARE SMALL, NONCODING RNAS THAT CONTROL GENE EXPRESSIONS THROUGH MULTIPLE MECHANISMS AND HAVE IMPORTANT ROLES IN THE PATHOGENESIS OF ENDOMETRIOSIS. THE OBJECTIVE OF THE PRESENT STUDY IS TO DETERMINE THE EFFECTS OF PHARMACOLOGICAL INHIBITION OF PGE(2) RECEPTORS, EP2 AND EP4, ON MIRNA PROFILE IN ENDOMETRIOSIS. THE NOVEL RESULTS COLLECTIVELY INDICATE THAT INHIBITION OF PGE(2)-EP2/EP4 SIGNALING REGULATED SEVERAL MIRNA CLUSTERS ASSOCIATED WITH CELL ADHESION, MIGRATION, INVASION, SURVIVAL AND GROWTH IN CELL-SPECIFIC AND THE CHROMOSOME-SPECIFIC MANNER AND REVERSES THE EPIGENETIC SILENCING OF PROAPOPTOTIC MIRNAS 15A AND 34C IN THE HUMAN ENDOMETRIOTIC EPITHELIAL AND STROMAL CELLS AND EXPERIMENTAL ENDOMETRIOTIC LESIONS. THUS, SELECTIVE INHIBITION OF EP2/EP4 RECEPTORS COULD EMERGE AS A POTENTIAL NONSTEROIDAL THERAPY FOR ENDOMETRIOSIS. 2022 7 5271 28 PROMOTER HYPERMETHYLATION OF PROGESTERONE RECEPTOR ISOFORM B (PR-B) IN ENDOMETRIOSIS. THE PHYSIOLOGICAL EFFECTS OF PROGESTERONE (P) ARE MEDIATED BY TWO ISOFORMS OF PROGESTERONE RECEPTORS (PRS): PR-A AND PR-B. PROGESTINS HAVE LONG BEEN USED IN THE TREATMENT OF ENDOMETRIOSIS BUT UNFORTUNATELY THE RELIEF OF PAIN IS RELATIVELY SHORT-TERM. IN ADDITION, ABOUT NINE PERCENT OF WOMEN WITH ENDOMETRIOSIS SIMPLY DO NOT RESPOND TO PROGESTIN THERAPY DUE TO UNKNOWN REASONS. IN FACT, A GENERAL TENDENCY FOR RELATIVE PROGESTERONE RESISTANCE WITHIN EUTOPIC AND ECTOPIC ENDOMETRIUM OF WOMEN WITH ENDOMETRIOSIS AND ALSO THE DOWNREGULATION OF PR-B, BUT NOT PR-A, IN ENDOMETRIOSIS HAVE BEEN NOTED. SINCE PROMOTER HYPERMETHYLATION IS WELL-DOCUMENTED TO BE ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WE SOUGHT TO DETERMINE THE METHYLATION STATUS OF THE PR-A AND PR-B PROMOTER REGIONS IN THE EPITHELIAL COMPONENT OF ENDOMETRIOTIC IMPLANTS USING A COMBINATION OF LASER CAPTURE MICRODISSECTION (LCM), METHYLATION SPECIFIC PCR, AND BISULFITE SEQUENCING. WE FOUND THAT THE PROMOTER REGION OF PR-B, BUT NOT PR-A, IS HYPERMETHYLATED IN ENDOMETRIOSIS AS COMPARED WITH CONTROLS. IN ADDITION, THE PR-B EXPRESSION WAS SIGNIFICANTLY REDUCED IN THE ECTOPIC ENDOMETRIUM. OUR FINDING SUGGESTS THAT PROGESTERONE RESISTANCE IN ENDOMETRIOSIS IN GENERAL AND THE DOWN REGULATION OF PR-B, BUT NOT PR-A, IN PARTICULAR, ARE A RESULT OF PROMOTER HYPERMETHYLATION OF PR-B, BUT NOT PR-A. THIS, IN CONJUNCTION WITH OUR REPORTED ABERRANT METHYLATION OF HOXA10 IN THE EUTOPIC ENDOMETRIUM OF WOMEN WITH ENDOMETRIOSIS, STRONGLY SUGGESTS THAT ENDOMETRIOSIS IS AN EPIGENETIC DISEASE. THIS PERSPECTIVE SHOULD POTENTIALLY OPEN UP NEW AVENUES FOR THE DELINEATION OF PATHOGENESIS OF ENDOMETRIOSIS, AND MIGHT ALSO LEAD TO NOVEL WAYS TO TREAT THE DISEASE THROUGH REVERSING ABERRANT METHYLATION VIA PHARMACOLOGICAL MEANS. 2006 8 4934 25 PATERNAL CHRONIC FOLATE SUPPLEMENTATION INDUCED THE TRANSGENERATIONAL INHERITANCE OF ACQUIRED DEVELOPMENTAL AND METABOLIC CHANGES IN CHICKENS. INCREASING EVIDENCE INDICATES THAT PATERNAL DIET CAN RESULT IN METABOLIC CHANGES IN OFFSPRING, BUT THE DEFINITE MECHANISM REMAINS UNCLEAR IN BIRDS. HERE, WE FED BREEDER COCKS FIVE DIFFERENT DIETS CONTAINING 0, 0.25, 1.25, 2.50 AND 5.00 MG KG(-1) FOLATE THROUGHOUT LIFE. PATERNAL FOLATE SUPPLEMENTATION (FS) WAS BENEFICIAL TO THE GROWTH AND ORGAN DEVELOPMENT OF BROILER OFFSPRING. MOST IMPORTANTLY, THE LIPID AND GLUCOSE METABOLISM OF BREEDER COCKS AND BROILER OFFSPRING WERE AFFECTED BY PATERNAL FS, ACCORDING TO BIOCHEMICAL AND METABOLOMIC ANALYSES. WE FURTHER EMPLOYED GLOBAL ANALYSES OF HEPATIC AND SPERMATOZOAL MESSENGER RNA (MRNA), LONG NON-CODING RNA (LNCRNA) AND MICRO RNA (MIRNA). SOME KEY GENES INVOLVED IN THE GLYCOLYSIS OR GLUCONEOGENESIS PATHWAY AND THE PPAR SIGNALLING PATHWAY, INCLUDING PEPCK, ANGPTL4 AND THRSP, WERE REGULATED BY DIFFERENTIALLY EXPRESSED HEPATIC AND SPERMATOZOAL MIRNAS AND LNCRNAS IN BREEDER COCKS AND BROILER OFFSPRING. MOREOVER, THE EXPRESSION OF ANGPTL4 COULD ALSO BE REGULATED BY DIFFERENTIALLY EXPRESSED MIRNAS AND LNCRNAS IN SPERMATOZOA VIA COMPETITIVE ENDOGENOUS RNA (CERNA) MECHANISMS. OVERALL, THIS MODEL SUGGESTS THAT PATERNAL FOLATE COULD TRANSGENERATIONALLY REGULATE LIPID AND GLUCOSE METABOLISM IN BROILER OFFSPRING AND THE EPIGENETIC TRANSMISSION MAY INVOLVE ALTERED SPERMATOZOAL MIRNAS AND LNCRNAS. 2019 9 3570 31 IMPACT OF JUVENILE HORMONE ANALOGUE INSECTICIDES ON THE WATER FLEA MOINA MACROCOPA: GROWTH, REPRODUCTION AND TRANSGENERATIONAL EFFECT. THE INCREASING QUANTITIES OF INSECTICIDES THAT LEACH INTO WATER BODIES SEVERELY AFFECT THE HEALTH OF THE AQUATIC ENVIRONMENT. JUVENILE HORMONE ANALOGUE (JHA) INSECTICIDES ARE ENDOCRINE DISRUPTERS THAT INTERFERE WITH HORMONAL ACTIVITY IN INSECTS BY MIMICKING JUVENILE HORMONES (JHS). BECAUSE THE STRUCTURE AND FUNCTIONS OF METHYL FARNESOATE IN CRUSTACEANS ARE SIMILAR TO THE INSECT JHS, EXOGENOUS JHA INSECTICIDES MAY CAUSE ADVERSE EFFECTS ON THE GROWTH AND REPRODUCTION IN CRUSTACEANS SIMILAR TO THOSE OBSERVED IN INSECTS. THIS STUDY EXAMINED THE TOXIC EFFECTS OF TWO JHA INSECTICIDES, METHOPRENE AND FENOXYCARB, ON THE WATER FLEA MOINA MACROCOPA. THE 24-H AND 48-H LC(50) VALUES FOR FENOXYCARB AND METHOPRENE WERE 0.53 AND 0.32 MG/L AND 0.70 AND 0.54 MG/L, RESPECTIVELY. CHRONIC EXPOSURE TO THE TWO JHAS CAUSED A SERIES OF TOXIC EFFECTS IN M. MACROCOPA, INCLUDING SHORTENING OF LIFE EXPECTANCY, REPRESSION OF BODY GROWTH, REDUCTION IN FECUNDITY, AND DISTURBED THE EXPRESSION OF GENES INVOLVED IN THE JH SIGNALING PATHWAY, IN CUTICLE DEVELOPMENT, AND IN THE CARBOHYDRATE, AMINO ACID, AND ATP METABOLIC PROCESSES. MOREOVER, JHA EXPOSURE IMPAIRED THE GROWTH AND REPRODUCTION OF THE OFFSPRING OF M. MACROCOPA EXPOSED TO JHAS, EVEN WHEN THE NEONATES WERE NOT EXPOSED TO THE CHEMICALS. IN ADDITION, CHANGES IN THE EXPRESSION OF GENES RELATED TO HISTONE METHYLATION INDICATE THAT EPIGENETIC CHANGES MAY PROMOTE TRANSGENERATIONAL IMPAIRMENT IN M. MACROCOPA. THESE RESULTS DEMONSTRATE THE TOXIC EFFECTS OF FENOXYCARB AND METHOPRENE ON NON-TARGET AQUATIC ORGANISMS. THE DAMAGES DONE BY THESE JHA INSECTICIDES TO THE AQUATIC ENVIRONMENT IS WORTHY OF OUR ATTENTION AND FURTHER STUDIES. 2020 10 3667 30 INFILTRATING MACROPHAGES INDUCE ERALPHA EXPRESSION THROUGH AN IL17A-MEDIATED EPIGENETIC MECHANISM TO SENSITIZE ENDOMETRIAL CANCER CELLS TO ESTROGEN. PERSISTENT UNOPPOSED ESTROGEN STIMULATION IS A CENTRAL ONCOGENIC MECHANISM DRIVING THE FORMATION OF TYPE I ENDOMETRIAL CANCER. RECENT EPIDEMIOLOGIC AND CLINICAL STUDIES OF ENDOMETRIAL CANCER HAVE ALSO REVEALED A ROLE FOR INSULIN RESISTANCE, CLINICALLY MANIFESTED BY CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF INFLAMMATION IN ESTROGEN-DRIVEN ENDOMETRIAL CANCER IS NOT WELL CHARACTERIZED. IN THIS STUDY, WE INVESTIGATED THE ASSOCIATION BETWEEN INFILTRATING MACROPHAGES AND ESTROGEN SENSITIVITY IN ENDOMETRIAL CANCER. EVALUATING TISSUE SAMPLES AND SERUM FROM PATIENTS WITH PRECANCEROUS LESIONS OR ENDOMETRIAL CANCER, WE FOUND THAT TISSUE MACROPHAGE INFILTRATION, BUT NOT SERUM ESTRADIOL LEVELS, CORRELATED POSITIVELY WITH ENDOMETRIAL CANCER DEVELOPMENT. FURTHERMORE, IL4/IL13-INDUCED CD68(+)CD163(+) MACROPHAGES ENHANCED THE PROLIFERATIVE EFFECTS OF ESTRADIOL IN ENDOMETRIAL CANCER CELLS BY UPREGULATING ESTROGEN RECEPTOR ALPHA (ERALPHA), BUT NOT ERBETA. MECHANISTIC INVESTIGATIONS REVEALED THAT CD68(+)CD163(+) MACROPHAGES SECRETED CYTOKINES, SUCH AS IL17A, THAT UPREGULATED ERALPHA EXPRESSION THROUGH TET1-MEDIATED EPIGENETIC MODULATION OF THE ERALPHA GENE. OVERALL, OUR FINDINGS SHOW HOW CYTOKINES PRODUCED BY INFILTRATING MACROPHAGES IN THE ENDOMETRIAL MICROENVIRONMENT CAN INDUCE EPIGENETIC UPREGULATION OF ERALPHA EXPRESSION, WHICH IN TURN SENSITIZES ENDOMETRIAL CELLS TO ESTROGEN STIMULATION. THE CONCEPT THAT INFLAMMATION-INDUCED ESTROGEN SENSITIVITY IN THE ENDOMETRIUM ACTS AS A DRIVER OF TYPE I ENDOMETRIAL CANCER HAS IMPLICATIONS FOR INFILTRATING MACROPHAGES AS A PROGNOSTIC BIOMARKER OF PROGRESSION IN THIS DISEASE SETTING. 2016 11 4360 40 MIR-6769B-5P TARGETS CCND-1 TO REGULATE PROLIFERATION IN CADMIUM-TREATED PLACENTAL TROPHOBLASTS: ASSOCIATION WITH THE IMPAIRMENT OF FETAL GROWTH. ENVIRONMENTAL CADMIUM (CD) IS POSITIVELY ASSOCIATED WITH PLACENTAL IMPAIRMENT AND FETAL GROWTH RETARDATION. NEVERTHELESS, ITS POTENTIAL MECHANISMS REMAIN UNCLEAR. MICRORNAS (MIRNAS) ARE KNOWN TO INFLUENCE PLACENTAL DEVELOPMENT AND FETAL GROWTH. THIS WORK WAS AIMED TO DETERMINE WHICH MIRNAS ARE INVOLVED IN CD-IMPAIRED PLACENTAL AND FETAL DEVELOPMENT BASED ON THE MRNA AND MIRNA EXPRESSION PROFILES ANALYSIS. AS A RESULT, GESTATIONAL CD EXPOSURE DECEASED FETAL AND PLACENTAL WEIGHT, AND REDUCED THE PROTEIN LEVEL OF PCNA IN HUMAN AND MOUSE PLACENTAE. FURTHERMORE, THE RESULTS OF MRNA MICROARRAY SHOWED THAT CD-DOWNREGULATED MRNAS WERE PREDICTIVELY CORRELATED WITH SEVERAL BIOLOGICAL PROCESSES, INCLUDING CELL PROLIFERATION, DIFFERENTIATION AND MOTILITY. IN ADDITION, THE RESULTS OF MIRNA MICROARRAY AND QPCR ASSAY DEMONSTRATED THAT CD SIGNIFICANTLY INCREASED THE LEVEL OF MIR-6769B-5P, MIR-146B-5P AND MIR-452-5P. INTEGRATED ANALYSIS OF CD-UPREGULATED MIRNAS PREDICTED TARGET GENES AND CD-DOWNREGULATED MRNAS FOUND THAT OVERLAPPING MRNAS, SUCH AS CCND1, CDK13, RINT1 AND CDC26 WERE ALSO SIGNIFICANTLY ASSOCIATED WITH CELL PROLIFERATION. FURTHER EXPERIMENTS SHOWED THAT MIR-6769B-5P INHIBITOR, BUT NOT MIR-146B-5P AND MIR-452-5P, MARKEDLY REVERSED CD-DOWNREGULATED THE EXPRESSION OF PROLIFERATION-RELATED MRNAS, AND THEREBY RESTORED CD-DECREASED THE PROTEINS LEVEL OF CCND1 AND PCNA IN HUMAN PLACENTAL TROPHOBLASTS. DUAL LUCIFERASE REPORTER ASSAY FURTHER REVEALED THAT MIR-6769B-5P DIRECTLY TARGETS CCND1. FINALLY, THE CASE-CONTROL STUDY DEMONSTRATED THAT INCREASED MIR-6769B-5P LEVEL AND IMPAIRED CELL PROLIFERATION WERE OBSERVED IN SMALL-FOR-GESTATIONAL-AGE HUMAN PLACENTAE. IN CONCLUSION, MIR-6769B-5P TARGETS CCND-1 TO REGULATE PROLIFERATION IN CD-TREATED PLACENTAL TROPHOBLASTS, WHICH IS ASSOCIATED WITH THE IMPAIRMENT OF FETAL GROWTH. OUR FINDINGS IMPLY THAT PLACENTAL MIR-6769B-5P MAY BE USED AS AN EPIGENETIC MARKER FOR ENVIRONMENTAL POLLUTANTS-CAUSED FETAL GROWTH RESTRICTION AND ITS LATE-ONSET CHRONIC DISEASES. 2021 12 5239 33 PROGESTERONE ALLEVIATES ENDOMETRIOSIS VIA INHIBITION OF UTERINE CELL PROLIFERATION, INFLAMMATION AND ANGIOGENESIS IN AN IMMUNOCOMPETENT MOUSE MODEL. ENDOMETRIOSIS, DEFINED AS GROWTH OF THE ENDOMETRIAL CELLS OUTSIDE THE UTERUS, IS AN INFLAMMATORY DISORDER THAT IS ASSOCIATED WITH CHRONIC PELVIC PAIN AND INFERTILITY IN WOMEN OF CHILDBEARING AGE. ALTHOUGH THE ESTROGEN-DEPENDENCE OF ENDOMETRIOSIS IS WELL KNOWN, THE ROLE OF PROGESTERONE IN DEVELOPMENT OF THIS DISEASE REMAINS POORLY UNDERSTOOD. IN THIS STUDY, WE DEVELOPED A DISEASE MODEL IN WHICH ENDOMETRIOSIS WAS INDUCED IN THE PERITONEAL CAVITIES OF IMMUNOCOMPETENT FEMALE MICE, AND MAINTAINED WITH EXOGENOUS ESTROGEN. THE ENDOMETRIOSIS-LIKE LESIONS THAT WERE IDENTIFIED AT A VARIETY OF ECTOPIC LOCATIONS EXHIBITED ABUNDANT BLOOD SUPPLY AND EXTENSIVE ADHESIONS. HISTOLOGICAL EXAMINATION REVEALED THAT THESE LESIONS HAD A WELL-ORGANIZED ENDOMETRIAL ARCHITECTURE AND FIBROTIC RESPONSE, RESEMBLING THOSE RECOVERED FROM CLINICAL PATIENTS. IN ADDITION, AN EXTENSIVE PROLIFERATION, INFLAMMATORY RESPONSE, AND LOSS OF ESTROGEN RECEPTOR ALPHA (ERALPHA) AND PROGESTERONE RECEPTOR (PR) EXPRESSION WERE ALSO OBSERVED IN THESE LESIONS. INTERESTINGLY, ADMINISTRATION OF PROGESTERONE BEFORE, BUT NOT AFTER, LESION INDUCTION SUPPRESSED LESION EXPANSION AND MAINTAINED ERALPHA AND PR EXPRESSIONS. THESE PROGESTERONE-PRETREATED LESIONS EXHIBITED ATTENUATION IN KI67, CD31, AND PRO-INFLAMMATORY CYTOKINE EXPRESSION AS WELL AS MACROPHAGE INFILTRATION, INDICATING THAT PROGESTERONE AMELIORATES ENDOMETRIOSIS PROGRESSION BY INHIBITING CELL PROLIFERATION, INFLAMMATION AND NEOVASCULARIZATION. OUR STUDIES FURTHER SHOWED THAT SUPPRESSION OF GLOBAL DNA METHYLATION BY APPLICATION OF DNA METHYLTRANSFERASE INHIBITOR TO FEMALE MICE BEARING ECTOPIC LESIONS RESTRAINED LESION EXPANSION AND RESTORED ERALPHA AND PR EXPRESSION IN EUTOPIC ENDOMETRIUM AND ECTOPIC LESIONS. THESE RESULTS INDICATE THAT EPIGENETIC REGULATION OF TARGET GENE EXPRESSION VIA DNA METHYLATION CONTRIBUTES, AT LEAST IN PART, TO PROGESTERONE RESISTANCE IN ENDOMETRIOSIS. 2016 13 3741 28 INSIGHT INTO THE POTENTIAL MECHANISMS OF ENDOCRINE DISRUPTION BY DIETARY PHYTOESTROGENS IN THE CONTEXT OF THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. PHYTOESTROGENS (PES) ARE ESTROGEN-LIKE NONSTEROIDAL COMPOUNDS DERIVED FROM PLANTS (E.G., NUTS, SEEDS, FRUITS, AND VEGETABLES) AND FUNGI THAT ARE STRUCTURALLY SIMILAR TO 17BETA-ESTRADIOL. PES BIND TO ALL TYPES OF ESTROGEN RECEPTORS, INCLUDING ERALPHA AND ERBETA RECEPTORS, NUCLEAR RECEPTORS, AND A MEMBRANE-BOUND ESTROGEN RECEPTOR KNOWN AS THE G PROTEIN-COUPLED ESTROGEN RECEPTOR (GPER). AS ENDOCRINE-DISRUPTING CHEMICALS (EDCS) WITH PRO- OR ANTIESTROGENIC PROPERTIES, PES CAN POTENTIALLY DISRUPT THE HORMONAL REGULATION OF HOMEOSTASIS, RESULTING IN DEVELOPMENTAL AND REPRODUCTIVE ABNORMALITIES. HOWEVER, A LACK OF PES IN THE DIET DOES NOT RESULT IN THE DEVELOPMENT OF DEFICIENCY SYMPTOMS. TO PROPERLY ASSESS THE BENEFITS AND RISKS ASSOCIATED WITH THE USE OF A PE-RICH DIET, IT IS NECESSARY TO DISTINGUISH BETWEEN ENDOCRINE DISRUPTION (ENDOCRINE-MEDIATED ADVERSE EFFECTS) AND NONSPECIFIC EFFECTS ON THE ENDOCRINE SYSTEM. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE OF UNKNOWN ETIOPATHOGENESIS, IN WHICH TISSUE SIMILAR TO THE LINING OF THE UTERUS (THE ENDOMETRIUM) GROWS OUTSIDE OF THE UTERUS WITH SUBSEQUENT COMPLICATIONS BEING MANIFESTED AS A RESULT OF LOCAL INFLAMMATORY REACTIONS. ENDOMETRIOSIS AFFECTS 10-15% OF WOMEN OF REPRODUCTIVE AGE AND IS ASSOCIATED WITH CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, AND INFERTILITY. IN THIS REVIEW, THE ENDOCRINE-DISRUPTIVE ACTIONS OF PES ARE REVIEWED IN THE CONTEXT OF ENDOMETRIOSIS TO DETERMINE WHETHER A PE-RICH DIET HAS A POSITIVE OR NEGATIVE EFFECT ON THE RISK AND COURSE OF ENDOMETRIOSIS. 2023 14 4310 28 MICRORNAS AND PROGESTERONE RECEPTOR SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY. ENDOMETRIOSIS IS A SIGNIFICANT DISEASE CHARACTERIZED BY INFERTILITY AND PELVIC PAIN IN WHICH ENDOMETRIAL STROMAL AND GLANDULAR TISSUE GROW IN ECTOPIC LOCATIONS. ALTERED RESPONSIVENESS TO PROGESTERONE IS A CONTRIBUTING FACTOR TO ENDOMETRIOSIS PATHOPHYSIOLOGY, BUT THE PRECISE MECHANISMS ARE POORLY UNDERSTOOD. PROGESTERONE RESISTANCE INFLUENCES BOTH THE EUTOPIC AND ECTOPIC (ENDOMETRIOTIC LESION) ENDOMETRIUM. AN INABILITY OF THE EUTOPIC ENDOMETRIUM TO PROPERLY RESPOND TO PROGESTERONE IS BELIEVED TO CONTRIBUTE TO THE INFERTILITY ASSOCIATED WITH THE DISEASE, WHILE AN ALTERED RESPONSIVENESS OF ENDOMETRIOTIC LESION TISSUE MAY CONTRIBUTE TO THE SURVIVAL OF THE ECTOPIC TISSUE AND ASSOCIATED SYMPTOMS. WOMEN WITH ENDOMETRIOSIS EXPRESS ALTERED LEVELS OF SEVERAL ENDOMETRIAL PROGESTERONE TARGET GENES WHICH MAY BE DUE TO THE ABNORMAL EXPRESSION AND/OR FUNCTION OF PROGESTERONE RECEPTORS AND/OR CHAPERONE PROTEINS, AS WELL AS INFLAMMATION, GENETICS, AND EPIGENETICS. MIRNAS ARE A CLASS OF EPIGENETIC MODULATORS PROPOSED TO PLAY A ROLE IN ENDOMETRIOSIS PATHOPHYSIOLOGY, INCLUDING THE MODULATION OF PROGESTERONE SIGNALING. IN THIS PAPER, WE SUMMARIZE THE ROLE OF PROGESTERONE RECEPTORS AND PROGESTERONE SIGNALING IN ENDOMETRIOSIS PATHOPHYSIOLOGY, REVIEW MIRNAS, WHICH ARE OVER-EXPRESSED IN ENDOMETRIOSIS TISSUES AND FLUIDS, AND FOLLOW THIS WITH A DISCUSSION ON THE POTENTIAL REGULATION OF KEY PROGESTERONE SIGNALING COMPONENTS BY THESE MIRNAS, CONCLUDING WITH SUGGESTIONS FOR FUTURE RESEARCH ENDEAVORS IN THIS AREA. 2022 15 5235 24 PROFILE OF EPIGENETIC MECHANISMS IN LUNG TUMORS OF PATIENTS WITH UNDERLYING CHRONIC RESPIRATORY CONDITIONS. BACKGROUND: CHRONIC LUNG DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND EPIGENETIC EVENTS UNDERLIE LUNG CANCER (LC) DEVELOPMENT. THE STUDY OBJECTIVE WAS THAT LUNG TUMOR EXPRESSION LEVELS OF SPECIFIC MICRORNAS AND THEIR DOWNSTREAM BIOMARKERS MAY BE DIFFERENTIALLY REGULATED IN PATIENTS WITH AND WITHOUT COPD. METHODS: IN LUNG SPECIMENS (TUMOR AND NON-TUMOR), MICRORNAS KNOWN TO BE INVOLVED IN LUNG TUMORIGENESIS (MIR-21, MIR-200B, MIR-126, MIR-451, MIR-210, MIR-LET7C, MIR-30A-30P, MIR-155 AND MIR-LET7A, QRT-PCR), DNA METHYLATION, AND DOWNSTREAM BIOMARKERS WERE DETERMINED (QRT-PCR AND IMMUNOBLOTTING) IN 40 PATIENTS WITH LC (PROSPECTIVE STUDY, SUBDIVIDED INTO LC-COPD AND LC, N = 20/GROUP). RESULTS: EXPRESSION OF MIR-21, MIR-200B, MIR-210, AND MIR-LET7C AND DNA METHYLATION WERE GREATER IN LUNG TUMOR SPECIMENS OF LC-COPD THAN OF LC PATIENTS. EXPRESSION OF DOWNSTREAM MARKERS PTEN, MARCKS, TPM-1, PDCD4, SPRY-2, ETS-1, ZEB-2, FGFRL-1, EFNA-3, AND K-RAS TOGETHER WITH P53 WERE SELECTIVELY DOWNREGULATED IN TUMOR SAMPLES OF LC-COPD PATIENTS. IN THESE PATIENTS, TUMOR EXPRESSION OF MIR-126 AND MIR-451 AND THAT OF THE BIOMARKERS PTEN, MARCKS, FGFRL-1, SNAIL-1, P63, AND K-RAS WERE REDUCED. CONCLUSIONS: BIOMARKERS OF MECHANISMS INVOLVED IN TUMOR GROWTH, ANGIOGENESIS, MIGRATION, AND APOPTOSIS WERE DIFFERENTIALLY EXPRESSED IN TUMORS OF PATIENTS WITH UNDERLYING RESPIRATORY DISEASE. THESE FINDINGS SHED LIGHT INTO THE UNDERLYING BIOLOGY OF THE REPORTED GREATER RISK TO DEVELOP LC SEEN IN PATIENTS WITH CHRONIC RESPIRATORY CONDITIONS. THE PRESENCE OF AN UNDERLYING RESPIRATORY DISEASE SHOULD BE IDENTIFIED IN ALL PATIENTS WITH LC AS THE DIFFERENTIAL BIOLOGICAL PROFILE MAY HELP DETERMINE TUMOR PROGRESSION AND THE THERAPEUTIC RESPONSE. ADDITIONALLY, EPIGENETIC EVENTS OFFER A NICHE FOR PHARMACOLOGICAL THERAPEUTIC TARGETS. 2018 16 2668 25 ESTROGEN RECEPTORS AND ENDOMETRIOSIS. ENDOMETRIOSIS IS A FREQUENT AND CHRONIC INFLAMMATORY DISEASE WITH IMPACTS ON REPRODUCTION, HEALTH AND QUALITY OF LIFE. THIS DISORDER IS HIGHLY ESTROGEN-DEPENDENT AND THE PURPOSE OF HORMONAL TREATMENTS IS TO DECREASE THE ENDOGENOUS OVARIAN PRODUCTION OF ESTROGENS. HIGH ESTROGEN PRODUCTION IS A CONSISTENTLY OBSERVED ENDOCRINE FEATURE OF ENDOMETRIOSIS. MRNA AND PROTEIN LEVELS OF ESTROGEN RECEPTORS (ER) ARE DIFFERENT BETWEEN A NORMAL HEALTHY ENDOMETRIUM AND ECTOPIC/EUTOPIC ENDOMETRIAL LESIONS: ENDOMETRIOTIC STROMAL CELLS EXPRESS EXTRAORDINARILY HIGHER ERBETA AND SIGNIFICANTLY LOWER ERALPHA LEVELS COMPARED WITH ENDOMETRIAL STROMAL CELLS. ABERRANT EPIGENETIC REGULATION SUCH AS DNA METHYLATION IN ENDOMETRIOTIC CELLS IS ASSOCIATED WITH THE PATHOGENESIS AND DEVELOPMENT OF ENDOMETRIOSIS. ALTHOUGH THERE IS A LARGE BODY OF DATA REGARDING ERS IN ENDOMETRIOSIS, OUR UNDERSTANDING OF THE ROLES OF ERALPHA AND ERBETA IN THE PATHOGENESIS OF ENDOMETRIOSIS REMAINS INCOMPLETE. THE GOAL OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE LINKS BETWEEN ENDOMETRIOSIS, ERS AND THE RECENT ADVANCES OF TREATMENT STRATEGIES BASED ON ERS MODULATION. WE WILL ALSO ATTEMPT TO SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR MECHANISMS OF ACTION OF ERS AND HOW THIS COULD PAVE THE WAY TO NEW THERAPEUTIC STRATEGIES. 2020 17 146 23 ABERRANT ENDOMETRIAL DNA METHYLOME AND ASSOCIATED GENE EXPRESSION IN WOMEN WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT, PROGESTERONE-RESISTANT DISORDER LARGELY DERIVED FROM RETROGRADE TRANSPLANTATION OF MENSTRUAL TISSUE/CELLS INTO THE PELVIS, ELICITING AN INFLAMMATORY RESPONSE, PELVIC PAIN, AND INFERTILITY. EUTOPIC ENDOMETRIUM (WITHIN THE UTERUS), GIVING RISE TO PELVIC DISEASE, DISPLAYS CYCLE-DEPENDENT TRANSCRIPTOMIC, PROTEOMIC, AND SIGNALING ABNORMALITIES, AND ALTHOUGH ITS DNA METHYLATION PROFILES DYNAMICALLY CHANGE ACROSS THE CYCLE IN HEALTHY WOMEN, STUDIES IN ENDOMETRIOSIS ARE LIMITED. HEREIN, WE INVESTIGATED THE DNA METHYLOME AND ASSOCIATED GENE EXPRESSION IN THREE PHASES OF THE CYCLE IN EUTOPIC ENDOMETRIUM OF WOMEN WITH SEVERE ENDOMETRIOSIS VERSUS CONTROLS, MATCHED FOR ETHNICITY, MEDICATIONS, SMOKING, AND NO RECENT CONTRACEPTIVE STEROID USE. GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION WERE COASSESSED IN EACH SAMPLE. CYCLE PHASE WAS DETERMINED BY HISTOLOGY, SERUM HORMONE LEVELS, AND UNSUPERVISED PRINCIPAL COMPONENT AND HIERARCHICAL CLUSTER ANALYSES OF MICROARRAY DATA. ALTERED ENDOMETRIAL DNA METHYLATION IN ENDOMETRIOSIS WAS MOST PROMINENT IN THE MIDSECRETORY PHASE (PEAK PROGESTERONE), WITH DISRUPTION OF THE NORMAL PATTERN OF CYCLE-DEPENDENT DNA METHYLATION CHANGES, INCLUDING A BIAS TOWARD METHYLATION OF CPG ISLANDS, SUGGESTING WIDE-RANGE ABNORMALITIES OF THE CHROMATIN REMODELING MACHINERY IN ENDOMETRIOSIS. DNA METHYLATION CHANGES WERE ASSOCIATED WITH ALTERED GENE EXPRESSION RELEVANT TO ENDOMETRIAL FUNCTION/DYSFUNCTION, INCLUDING CELL PROLIFERATION, INFLAMMATION/IMMUNE RESPONSE, ANGIOGENESIS, AND STEROID HORMONE RESPONSE. THE DATA PROVIDE INSIGHT INTO EPIGENETIC REPROGRAMMING AND STEROID HORMONE ACTIONS IN ENDOMETRIUM CONTRIBUTING TO THE PATHOGENESIS AND PATHOPHYSIOLOGY OF ENDOMETRIOSIS. 2016 18 2575 23 EPIGENETICS OF ESTROGEN AND PROGESTERONE RECEPTORS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT INFLAMMATORY GYNECOLOGICAL DISEASE. INCREASED ESTROGEN ACTIVITY AND PROGESTERONE RESISTANCE ARE THE MAIN HORMONAL SUBSTRATE OF THIS DISEASE AND ARE ASSOCIATED WITH INFLAMMATORY RESPONSE AND DEBILITATING SYMPTOMS, INCLUDING PAIN AND INFERTILITY. ESTROGENS AND PROGESTERONE ACT VIA THEIR SPECIFIC NUCLEAR RECEPTORS. THE REGULATION OF RECEPTOR EXPRESSION BY EPIGENETICS MAYBE A CRITICAL FACTOR FOR ENDOMETRIOSIS. THE PRESENT REVIEW AIMS TO DISCUSS THE EPIGENETIC MECHANISMS RELATED TO THE EXPRESSION OF ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS, INCLUDING TWO CLASSIC EPIGENETIC MECHANISMS: DNA METHYLATION AND HISTONE MODIFICATION, AND, OTHER NON-CLASSIC MECHANISMS: MIRNAS AND LNCRNA. SEVERAL IN VITRO AND IN VIVO STUDIES SUPPORT THE KEY ROLE OF EPIGENETICS IN THE REGULATION OF THE EXPRESSION OF ERS AND PRS, WHICH MAY PROVIDE NEW MOLECULES AND TARGETS FOR THE DIAGNOSIS AND TREATMENT OF ENDOMETRIOSIS. 2020 19 2602 27 EPIGENETICS, ENDOMETRIOSIS AND SEX STEROID RECEPTORS: AN UPDATE ON THE EPIGENETIC REGULATORY MECHANISMS OF ESTROGEN AND PROGESTERONE RECEPTORS IN PATIENTS WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS A BENIGN GYNECOLOGICAL DISEASE AFFECTING APPROXIMATELY 10% OF REPRODUCTIVE-AGED WOMEN AND IS DEFINED AS THE PRESENCE OF ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. ENDOMETRIOSIS CAN CAUSE A VARIETY OF HEALTH PROBLEMS, FROM PELVIC DISCOMFORT TO CATAMENIAL PNEUMOTHORAX, BUT IT'S MAINLY LINKED WITH SEVERE AND CHRONIC PELVIC PAIN, DYSMENORRHEA, AND DEEP DYSPAREUNIA, AS WELL AS REPRODUCTIVE ISSUES. THE PATHOGENESIS OF ENDOMETRIOSIS INVOLVES AN ENDOCRINE DYSFUNCTION, WITH ESTROGEN DEPENDENCY AND PROGESTERONE RESISTANCE, AND INFLAMMATORY MECHANISM ACTIVATION, TOGETHER WITH IMPAIRED CELL PROLIFERATION AND NEUROANGIOGENESIS. THE PRESENT CHAPTER AIMS TO DISCUSS THE MAIN EPIGENETIC MECHANISMS RELATED TO ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS. THERE ARE NUMEROUS EPIGENETIC MECHANISMS PARTICIPATING IN ENDOMETRIOSIS, REGULATING THE EXPRESSION OF THE GENES ENCODING THESE RECEPTORS BOTH INDIRECTLY, THROUGH THE REGULATION OF TRANSCRIPTION FACTORS, AND DIRECTLY, THROUGH DNA METHYLATION, HISTONE MODIFICATIONS, MICRO RNAS AND LONG NONCODING RNAS. THIS REPRESENTS AN OPEN FIELD OF INVESTIGATION, WHICH MAY LEAD TO IMPORTANT CLINICAL IMPLICATIONS SUCH AS THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF ENDOMETRIOSIS AND THE IDENTIFICATION OF SPECIFIC AND EARLY BIOMARKERS FOR THE DISEASE. 2023 20 1899 33 ENERGY BALANCE MODULATION IMPACTS EPIGENETIC REPROGRAMMING, ERALPHA AND ERBETA EXPRESSION, AND MAMMARY TUMOR DEVELOPMENT IN MMTV-NEU TRANSGENIC MICE. THE ASSOCIATION BETWEEN OBESITY AND BREAST CANCER RISK AND PROGNOSIS IS WELL ESTABLISHED IN ESTROGEN RECEPTOR (ER)-POSITIVE DISEASE BUT LESS CLEAR IN HER2-POSITIVE DISEASE. HERE, WE REPORT PRECLINICAL EVIDENCE SUGGESTING WEIGHT MAINTENANCE THROUGH CALORIE RESTRICTION (CR) MAY LIMIT RISK OF HER2-POSITIVE BREAST CANCER. IN FEMALE MMTV-HER2/NEU TRANSGENIC MICE, WE FOUND THAT ERALPHA AND ERBETA EXPRESSION, MAMMARY TUMORIGENESIS, AND SURVIVAL ARE ENERGY BALANCE DEPENDENT IN ASSOCIATION WITH EPIGENETIC REPROGRAMMING. MICE WERE RANDOMIZED TO RECEIVE A CR, OVERWEIGHT-INDUCING, OR DIET-INDUCED OBESITY REGIMEN (N = 27/GROUP). SUBSETS OF MICE (N = 4/GROUP/TIME POINT) WERE EUTHANIZED AFTER 1, 3, AND 5 MONTHS TO CHARACTERIZE DIET-DEPENDENT METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC PERTURBATIONS. REMAINING MICE WERE FOLLOWED UP TO 22 MONTHS. RELATIVE TO THE OVERWEIGHT AND DIET-INDUCED OBESITY REGIMENS, CR DECREASED BODY WEIGHT, ADIPOSITY, AND SERUM METABOLIC HORMONES AS EXPECTED AND ALSO ELICITED AN INCREASE IN MAMMARY ERALPHA AND ERBETA EXPRESSION. INCREASED DNA METHYLATION ACCOMPANIED THIS PATTERN, PARTICULARLY AT CPG DINUCLEOTIDES LOCATED WITHIN BINDING OR FLANKING REGIONS FOR THE TRANSCRIPTIONAL REGULATOR CCCTC-BINDING FACTOR OF ESR1 AND ESR2, CONSISTENT WITH SUSTAINED TRANSCRIPTIONAL ACTIVATION OF ERALPHA AND ERBETA. MAMMARY EXPRESSION OF THE DNA METHYLATION ENZYME DNMT1 WAS STABLE IN CR MICE BUT INCREASED OVER TIME IN OVERWEIGHT AND DIET-INDUCED OBESITY MICE, SUGGESTING CR OBVIATES EPIGENETIC ALTERATIONS CONCURRENT WITH CHRONIC EXCESS ENERGY INTAKE. IN THE SURVIVAL STUDY, CR ELICITED A SIGNIFICANT SUPPRESSION IN SPONTANEOUS MAMMARY TUMORIGENESIS. OVERALL, OUR FINDINGS SUGGEST A MECHANISTIC RATIONALE TO PREVENT OR REVERSE EXCESS BODY WEIGHT AS A STRATEGY TO REDUCE HER2-POSITIVE BREAST CANCER RISK. CANCER RES; 77(9); 2500-11. (C)2017 AACR. 2017