1 3741 128 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 2 2602 33 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 3 650 20 BISPHENOL A AND HUMAN CHRONIC DISEASES: CURRENT EVIDENCES, POSSIBLE MECHANISMS, AND FUTURE PERSPECTIVES. BISPHENOL-A (BPA) IS ONE OF THE HIGHEST VOLUME CHEMICALS PRODUCED WORLDWIDE, WITH OVER 6BILLION POUNDS PRODUCED AND OVER 100T RELEASED INTO THE ATMOSPHERE EACH YEAR. RECENT EXTENSIVE LITERATURE HAS RAISED CONCERNS ABOUT ITS POSSIBLE IMPLICATION IN THE ETIOLOGY OF SOME HUMAN CHRONIC DISEASES SUCH AS DIABETES, OBESITY, REPRODUCTIVE DISORDERS, CARDIOVASCULAR DISEASES, BIRTH DEFECTS, CHRONIC RESPIRATORY AND KIDNEY DISEASES AND BREAST CANCER. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCES ON THE RELATIONSHIP BETWEEN BPA EXPOSURE AND HUMAN CHRONIC DISEASES AND WE DISCUSS ITS EVENTUAL MECHANISMS OF ACTION, ESPECIALLY GENETIC, EPIGENETIC AND ENDOCRINE DISRUPTION MECHANISMS WITH THE POSSIBLE INVOLVEMENT OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION AND CELL SIGNALING. 2014 4 6649 17 UPDATE ON ENDOMETRIOSIS PATHOGENESIS. ENDOMETRIOSIS IS A CHRONIC, INFLAMMATORY, CONDITION OF HIGH INCIDENCE AND SERIOUS REPRODUCTIVE AND GENERAL HEALTH CONSEQUENCES. UNDERSTANDING THE PATHOGENESIS OF ENDOMETRIOSIS IS CRUCIAL FOR PROPER DIAGNOSTIC AND ORDERING THE MOST EFFECTIVE TREATMENT. EVEN THOUGH THERE IS A LARGE BODY OF DATA REGARDING THIS PATHOLOGY OUR UNDERSTANDING OF THE PATHOGENESIS OF THIS DISEASE REMAINS INCOMPLETE. THE AIM OF THIS REVIEW IS TO SUMMARIZE CONTEMPORARY DATA REGARDING PATHOGENESIS OF ENDOMETRIOSIS. CURRENT DATA REGARDING ENDOMETRIAL ORIGIN, METAPLASTIC AND MULLERIAN EMBRYONIC RESTS THEORY WILL BE REVIEWED HERE. ALSO GENETIC, EPIGENETIC, ENVIRONMENTAL FACTORS AND IMMUNOLOGICAL DYSFUNCTION ROLE IN ENDOMETRIOSIS WILL BE SUMMARIZED. TO CONCLUDE, A LOT OF EFFORT MUST BE PUT TO INTEGRATE THE ABUNDANT DATA FROM GENETIC, EPIGENETIC AND IMMUNOLOGICAL STUDIES TO PROPOSE ONE COHERENT THEORY FOR THE PATHOGENESIS OF ENDOMETRIOSIS. 2017 5 3870 26 JUNCTIONAL ZONE ENDOMETRIUM ALTERATIONS IN GYNECOLOGICAL AND OBSTETRICAL DISORDERS AND IMPACT ON DIAGNOSIS, PROGNOSIS AND TREATMENT. PURPOSE OF REVIEW: TO INVESTIGATE THE JZE ALTERATIONS IN GYNECOLOGICAL AND OBSTETRICAL DISORDERS AND IMPACT ON DIAGNOSIS, PROGNOSIS AND TREATMENT. RECENT FINDINGS: JZE WAS FOUND TO BE SIGNIFICANTLY EXTENDED IN PATIENTS WITH ENDOMETRIOSIS, LEADING TO THE CONCLUSION THAT ENDOMETRIOSIS IS A PRIMARY DISEASE OF THE UTERUS, MUCH LIKE ADENOMYOSIS. STATISTICAL CORRELATION WAS THEN DEMONSTRATED BETWEEN THE SEVERITY OF ENDOMETRIOSIS AND THE DEPTH OF THE ADENOMYOSIS INFILTRATES, HENCE THE THICKENING OF THE JZE. STEM CELLS, PREDOMINANTLY FOUND IN THE JZE WERE ALSO FOUND IN HISTOLOGICAL SECTIONS OF LEIOMYOMA, SUGGESTED TO BE THE ORIGIN OF LEIOMYOMA. THIS RESERVOIR OF JZE STEM CELLS IS INFLUENCED BY DIFFERENT STRESSORS LEADING TO THEIR DIFFERENTIATION INTO LEIOMYOMA, ENDOMETRIOSIS, ADENOMYOSIS OR ENDOMETRIAL CANCER, ACCORDING TO THE STRESSOR. THE VARIABILITY IN PRESENTATION WAS HYPOTHESIZED TO BE CONNECTED TO GENETIC AND EPIGENETIC FACTORS. JZE WAS ALSO SUGGESTED TO ACT AS A BARRIER, STOPPING ENDOMETRIAL CARCINOMA CELLS INVASION AND METASTASIS. IN ADDITION, JZE PLAYS A MAJOR ROLE IN CONCEPTION, PREGNANCY AND POSTPARTUM. SUMMARY: JZE IS AN IMPORTANT ANATOMICAL LANDMARK OF THE UTERUS CONTRIBUTING TO NORMAL UTERINE FUNCTION UNDER THE INFLUENCE OF OVARIAN HORMONES. ALTERATIONS OF THE JZE THICKNESS AND CONTRACTILITY CAN BE USED AS PATHOGNOMONIC CLINICAL MARKERS IN INFERTILITY AND CHRONIC PELVIC PAIN, FOR SUBENDOMETRIAL AND MYOMETRIAL DISORDERS, FOR EXAMPLE, ADENOMYOSIS AND FIBROIDS. PROSPECTIVE RANDOMIZED CONTROL TRIALS WILL CLARIFY THE DIAGNOSTIC STEPS, IMAGING MODALITIES TO FOLLOW AND PROBABLY TRIAGE THE PATIENTS BETWEEN MEDICAL AND SURGICAL TREATMENTS. 2019 6 4399 22 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 7 752 31 CARDIOMETABOLIC RISK FACTORS AND BENIGN GYNECOLOGIC DISORDERS. IMPORTANCE: WHILE IT HAS LONG BEEN KNOWN THAT POLYCYSTIC OVARIAN SYNDROME IS ASSOCIATED WITH CARDIOMETABOLIC RISK FACTORS (CMRFS), THERE IS EMERGING EVIDENCE THAT OTHER BENIGN GYNECOLOGIC CONDITIONS, SUCH AS UTERINE LEIOMYOMAS, ENDOMETRIOSIS, AND EVEN HYSTERECTOMY WITHOUT OOPHORECTOMY, CAN BE ASSOCIATED WITH CMRFS. UNDERSTANDING THE EVIDENCE AND MECHANISMS OF THESE ASSOCIATIONS CAN LEAD TO NOVEL PREVENTIVE AND THERAPEUTIC INTERVENTIONS. OBJECTIVE: THIS ARTICLE DISCUSSES THE EVIDENCE AND THE POTENTIAL MECHANISMS MEDIATING THE ASSOCIATION BETWEEN CMRFS AND BENIGN GYNECOLOGIC DISORDERS. EVIDENCE ACQUISITION: WE REVIEWED PUBMED, EMBASE, SCOPUS, AND GOOGLE SCHOLAR DATABASES TO OBTAIN PLAUSIBLE CLINICAL AND BIOLOGICAL EVIDENCE, INCLUDING HORMONAL, IMMUNOLOGIC, INFLAMMATORY, GROWTH FACTOR-RELATED, GENETIC, EPIGENETIC, ATHEROGENIC, VITAMIN D-RELATED, AND DIETARY FACTORS. RESULTS: CARDIOMETABOLIC RISK FACTORS APPEAR TO CONTRIBUTE TO UTERINE LEIOMYOMA PATHOGENESIS. FOR EXAMPLE, OBESITY CAN MODULATE LEIOMYOMATOUS CELLULAR PROLIFERATION AND EXTRACELLULAR MATRIX DEPOSITION THROUGH HYPERESTROGENIC STATES, CHRONIC INFLAMMATION, INSULIN RESISTANCE, AND ADIPOKINES. ON THE OTHER HAND, ENDOMETRIOSIS HAS BEEN SHOWN TO INDUCE SYSTEMIC INFLAMMATION, THEREBY INCREASING CARDIOMETABOLIC RISKS, FOR EXAMPLE, THROUGH INDUCING ATHEROSCLEROTIC CHANGES. CONCLUSION AND RELEVANCE: CLINICAL IMPLICATIONS OF THESE ASSOCIATIONS ARE 2-FOLD. FIRST, SCREENING AND EARLY MODIFICATION OF CMRFS CAN BE PART OF A PREVENTIVE STRATEGY FOR UTERINE LEIOMYOMAS AND HYSTERECTOMY. SECOND, PATIENTS DIAGNOSED WITH UTERINE LEIOMYOMAS OR ENDOMETRIOSIS CAN BE SCREENED AND CLOSELY FOLLOWED FOR CMRFS AND CARDIOVASCULAR DISEASE. 2019 8 3667 35 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 9 2669 35 ESTROGEN- AND PROGESTERONE (P4)-MEDIATED EPIGENETIC MODIFICATIONS OF ENDOMETRIAL STROMAL CELLS (ENSCS) AND/OR MESENCHYMAL STEM/STROMAL CELLS (MSCS) IN THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS IS A COMMON CHRONIC INFLAMMATORY CONDITION IN WHICH ENDOMETRIAL TISSUE APPEARS OUTSIDE THE UTERINE CAVITY. BECAUSE ECTOPIC ENDOMETRIOSIS CELLS EXPRESS BOTH ESTROGEN AND PROGESTERONE (P4) RECEPTORS, THEY GROW AND UNDERGO CYCLIC PROLIFERATION AND BREAKDOWN SIMILAR TO THE ENDOMETRIUM. THIS DEBILITATING GYNECOLOGICAL DISEASE AFFECTS UP TO 15% OF REPRODUCTIVE AGED WOMEN. DESPITE MANY YEARS OF RESEARCH, THE ETIOPATHOGENESIS OF ENDOMETRIAL LESIONS REMAINS UNCLEAR. RETROGRADE TRANSPORT OF THE VIABLE MENSTRUAL ENDOMETRIAL CELLS WITH RETAINED ABILITY FOR ATTACHMENT WITHIN THE PELVIC CAVITY, PROLIFERATION, DIFFERENTIATION AND SUBSEQUENT INVASION INTO THE SURROUNDING TISSUE CONSTITUTES THE RATIONALE FOR WIDELY ACCEPTED IMPLANTATION THEORY. ACCORDINGLY, THE MOST ABUNDANT CELLS IN THE ENDOMETRIUM ARE ENDOMETRIAL STROMAL CELLS (ENSCS). THESE CELLS CONSTITUTE A PARTICULAR POPULATION WITH CLONOGENIC ACTIVITY THAT RESEMBLES PROPERTIES OF MESENCHYMAL STEM/STROMAL CELLS (MSCS). THUS, A SIGNIFICANT ROLE OF STEM CELL-BASED DYSFUNCTION IN FORMATION OF THE INITIAL ENDOMETRIAL LESIONS IS SUSPECTED. THERE IS INCREASING EVIDENCE THAT THE ROLE OF EPIGENETIC MECHANISMS AND PROCESSES IN ENDOMETRIOSIS HAVE BEEN UNDERESTIMATED. THE IMPORTANCE OF EXCESS ESTROGEN EXPOSURE AND P4 RESISTANCE IN EPIGENETIC HOMEOSTASIS FAILURE IN THE ENDOMETRIAL/ENDOMETRIOTIC TISSUE ARE CRUCIAL. EPIGENETIC ALTERATIONS REGARDING TRANSCRIPTION FACTORS OF ESTROGEN AND P4 SIGNALING PATHWAYS IN MSCS ARE ROBUST IN ENDOMETRIOTIC TISSUE. THUS, PERSPECTIVES FOR THE FUTURE MAY INCLUDE MSCS AND ENSCS AS THE TARGETS OF EPIGENETIC THERAPIES IN THE PREVENTION AND TREATMENT OF ENDOMETRIOSIS. HERE, WE REVIEWED THE CURRENT KNOWN CHANGES IN THE EPIGENETIC BACKGROUND OF ENSCS AND MSCS DUE TO ESTROGEN/P4 IMBALANCES IN THE CONTEXT OF ETIOPATHOGENESIS OF ENDOMETRIOSIS. GRAPHICAL ABSTRACT. 2021 10 1840 34 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 11 2616 24 EPIGENOME MODULATION INDUCED BY KETOGENIC DIETS. KETOGENIC DIETS (KD) ARE DIETARY STRATEGIES LOW IN CARBOHYDRATES, NORMAL IN PROTEIN, AND HIGH, NORMAL, OR REDUCED IN FAT WITH OR WITHOUT (VERY LOW-CALORIES KETOGENIC DIET, VLCKD) A REDUCED CALORIC INTAKE. KDS HAVE BEEN SHOWN TO BE USEFUL IN THE TREATMENT OF OBESITY, METABOLIC DISEASES AND RELATED DISORDERS, NEUROLOGICAL DISEASES, AND VARIOUS PATHOLOGICAL CONDITIONS SUCH AS CANCER, NONALCOHOLIC LIVER DISEASE, AND CHRONIC PAIN. SEVERAL STUDIES HAVE INVESTIGATED THE INTRACELLULAR METABOLIC PATHWAYS THAT CONTRIBUTE TO THE BENEFICIAL EFFECTS OF THESE DIETS. ALTHOUGH EPIGENETIC CHANGES ARE AMONG THE MOST IMPORTANT DETERMINANTS OF AN ORGANISM'S ABILITY TO ADAPT TO ENVIRONMENTAL CHANGES, DATA ON THE EPIGENETIC CHANGES ASSOCIATED WITH THESE DIETARY PATHWAYS ARE STILL LIMITED. THIS REVIEW PROVIDES AN OVERVIEW OF THE MAJOR EPIGENETIC CHANGES ASSOCIATED WITH KDS. 2022 12 4187 38 METABOLIC AND VASCULAR EFFECT OF THE MEDITERRANEAN DIET. SEVERAL STUDIES INDICATED HOW DIETARY PATTERNS THAT WERE OBTAINED FROM NUTRITIONAL CLUSTER ANALYSIS CAN PREDICT DISEASE RISK OR MORTALITY. LOW-GRADE CHRONIC INFLAMMATION REPRESENTS A BACKGROUND PATHOGENETIC MECHANISM LINKING METABOLIC RISK FACTORS TO INCREASED RISK OF CHRONIC DEGENERATIVE DISEASES. A MEDITERRANEAN DIET (MEDI) STYLE HAS BEEN REPORTED AS ASSOCIATED WITH A LOWER DEGREE OF INFLAMMATION BIOMARKERS AND WITH A PROTECTIVE ROLE ON CARDIOVASCULAR AND CEREBROVASCULAR EVENTS. THERE IS HETEROGENEITY IN DEFINING THE MEDDIET, AND IT CAN, OWING TO ITS COMPLEXITY, BE CONSIDERED AS AN EXPOSOME WITH THOUSANDS OF NUTRIENTS AND PHYTOCHEMICALS. RECENTLY, IT HAS BEEN REPORTED A NOVEL POSITIVE ASSOCIATION BETWEEN BASELINE PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR EVENTS AND HOW ADHERENCE TO A MEDITERRANEAN DIET-STYLE MAY INFLUENCE THE POTENTIAL NEGATIVE RELATIONSHIP BETWEEN ELEVATED PLASMA CERAMIDE CONCENTRATIONS AND CARDIOVASCULAR DISEASES (CVD). SEVERAL RANDOMIZED CONTROLLED TRIALS (RCTS) SHOWED THE POSITIVE EFFECTS OF THE MEDI DIET STYLE ON SEVERAL CARDIOVASCULAR RISK FACTORS, SUCH AS BODY MASS INDEX, WAIST CIRCUMFERENCE, BLOOD LIPIDS, BLOOD PRESSURE, INFLAMMATORY MARKERS AND ADHESION MOLECULES, AND DIABETES AND HOW THESE ADVANTAGES OF THE MEDI ARE MAINTAINED IN COMPARISON OF A LOW-FAT DIET. SOME STUDIES REPORTED A POSITIVE EFFECT OF ADHERENCE TO A MEDITERRANEAN DIET AND HEART FAILURE INCIDENCE, WHEREAS SOME RECENT STUDIES, SUCH AS THE PREDIMED STUDY, SHOWED THAT THE INCIDENCE OF MAJOR CARDIOVASCULAR EVENTS WAS LOWER AMONG THOSE ASSIGNED TO MEDI SUPPLEMENTED WITH EXTRA-VIRGIN OLIVE OIL OR NUTS THAN AMONG THOSE ASSIGNED TO A REDUCED-FAT DIET. NEW STUDIES ARE NEEDED TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS, WHEREBY THE MEDDIET MAY EXERCISE ITS EFFECTS. HERE, WE PRESENT RECENT ADVANCES IN UNDERSTANDING THE MOLECULAR BASIS OF MEDDIET EFFECTS, MAINLY FOCUSING ON CARDIOVASCULAR DISEASES, BUT ALSO DISCUSSING OTHER RELATED DISEASES. WE REVIEW MEDDIET COMPOSITION AND ASSESSMENT AS WELL AS THE LATEST ADVANCES IN THE GENOMIC, EPIGENOMIC (DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS, AND OTHER EMERGING REGULATORS), TRANSCRIPTOMIC (SELECTED GENES AND WHOLE TRANSCRIPTOME), AND METABOLOMIC AND METAGENOMIC ASPECTS OF THE MEDDIET EFFECTS (AS A WHOLE AND FOR ITS MOST TYPICAL FOOD COMPONENTS). WE ALSO PRESENT A REVIEW OF THE CLINICAL EFFECTS OF THIS DIETARY STYLE UNDERLYING THE BIOCHEMICAL AND MOLECULAR EFFECTS OF THE MEDITERRANEAN DIET. OUR PURPOSE IS TO REVIEW THE MAIN FEATURES OF THE MEDITERRANEAN DIET IN PARTICULAR ITS BENEFITS ON HUMAN HEALTH, UNDERLING THE ANTI-INFLAMMATORY, ANTI-OXIDANT AND ANTI-ATHEROSCLEROTIC EFFECTS TO WHICH NEW KNOWLEDGE ABOUT EPIGENETIC AND GUT-MICROBIOTA RELATIONSHIP IS RECENTLY ADDED. 2019 13 6398 32 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 14 2597 28 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 15 49 23 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 16 461 25 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 17 5595 22 ROLES OF GENETIC PREDISPOSITION IN THE SEX BIAS OF PULMONARY PATHOPHYSIOLOGY, AS A FUNCTION OF ESTROGENS : SEX MATTERS IN THE PREVALENCE OF LUNG DISEASES. IN ADDITION TO STUDIES FOCUSED ON ESTROGEN MEDIATION OF SEX-DIFFERENT REGULATION OF SYSTEMIC CIRCULATIONS, THERE IS NOW INCREASING CLINICAL RELEVANCE AND RESEARCH INTERESTS IN THE PULMONARY CIRCULATION, IN TERMS OF SEX DIFFERENCES IN THE MORBIDITY AND MORTALITY OF LUNG DISEASES SUCH AS INHERENT-, ALLERGIC- AND INFLAMMATORY-BASED EVENTS. THUS, FEMALE PREDISPOSITION TO PULMONARY ARTERY HYPERTENSION (PAH) IS AN INEVITABLE TOPIC. TO BETTER UNDERSTAND THE NATURE OF SEXUAL DIFFERENTIATION IN THE PULMONARY CIRCULATION, AND HOW HERITABLE FACTORS, IN VIVO- AND/OR IN VITRO-ALTERED ESTROGEN CIRCUMSTANCES AND CHANGES IN THE LIVE ENVIRONMENT WORK IN CONCERT TO DISCERN THE SEX BIAS, THIS CHAPTER REVIEWS PULMONARY EVENTS CHARACTERIZED BY SEX-DIFFERENT FEATURES, CONCOMITANT WITH EXPLORATION OF HOW ALTERATIONS OF GENETIC EXPRESSION AND ESTROGEN METABOLISMS TRIGGER THE FEMALE-PREDOMINANT PATHOLOGICAL SIGNALING. WE ADDRESS THE FOLLOWING: PAH (SECT.7.2) IS CHARACTERIZED AS AN ESTROGENIC PROMOTION OF ITS INCIDENCE (SECT. 7.2.2), AS A FUNCTION OF SPECIFIC GERMLINE MUTATIONS, AND AS AN ESTROGEN-ELICITED PROTECTION OF ITS PROGNOSIS (SECT.7.2.1). MORE DETAIL IS PROVIDED TO INTRODUCE A LESS RECOGNIZED GENE OF EPHX2 THAT ENCODES SOLUBLE EPOXIDE HYDROLASE (SEH) TO DEGRADE EPOXYEICOSATRIENIC ACIDS (EETS). AS A SUSCEPTIBLE TARGET OF ESTROGEN, EPHX2/SEH EXPRESSION IS DOWNREGULATED BY AN ESTROGEN-DEPENDENT EPIGENETIC MECHANISM. INCREASES IN PULMONARY EETS THEN EVOKE A POTENTIATION OF PAH GENERATION, BUT MITIGATION OF ITS PROGRESSION, A PHENOMENON SIMILAR TO THE ESTROGEN-PARADOX REGULATION OF PAH. ADDITIONALLY, THE FEMALE SUSCEPTIBILITY TO CHRONIC OBSTRUCTIVE PULMONARY DISEASES (SECT. 7.3) AND ASTHMA (SECT.7.4), BUT LESS PREFERENCE TO COVID-19 (SECT. 7.5), AND ROLES OF ESTROGEN IN THEIR PATHOGENESES ARE BRIEFLY DISCUSSED. 2021 18 3418 23 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 19 705 25 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 20 6334 24 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019