1 2468 148 EPIGENETIC TOXICOLOGY AS TOXICANT-INDUCED CHANGES IN INTRACELLULAR SIGNALLING LEADING TO ALTERED GAP JUNCTIONAL INTERCELLULAR COMMUNICATION. COMMUNICATION MECHANISMS [EXTRA-, INTRA-, AND GAP JUNCTIONAL INTER-CELLULAR COMMUNICATION (GJIC)] CONTROL, FROM THE FERTILIZED EGG, THROUGH EMBRYOGENESIS TO MATURITY AND AGING, WHETHER A CELL PROLIFERATES, DIFFERENTIATES, DIES BY APOPTOSIS, OR IF DIFFERENTIATED, ADAPTIVELY RESPONDS TO ENDOGENOUS AND EXOGENOUS SIGNALS. FROM THE EGG TO THE 100 TRILLION CELLS IN THE HUMAN BODY, HEALTH IS MAINTAINED WHEN THESE COMMUNICATION PROCESSES BETWEEN STEM, PROGENITOR AND TERMINALLY DIFFERENTIATED CELLS ARE INTEGRATED. EACH CELL CHOICE INVOLVES 'EPIGENETIC' MECHANISMS TO ALTER THE EXPRESSION OF GENES AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS. DISRUPTION OF THE COMMUNICATION MECHANISMS CAN BE EITHER ADAPTIVE OR MALADAPTIVE. MODULATION OF EXTRA-CELLULAR COMMUNICATION, EITHER BY GENETIC IMBALANCES OF GROWTH FACTORS, HORMONES OR NEUROTRANSMITTERS OR BY ENVIRONMENTAL, EXOGENOUS CHEMICALS CAN TRIGGER SIGNAL TRANSDUCING INTRA-CELLULAR MECHANISMS. THESE INTRA-CELLULAR SIGNALS CAN MODULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL, TRANSLATIONAL OR POST-TRANSLATIONAL LEVELS WHILE ALSO MODULATING GJIC. UNTIMELY OR CHRONIC DISRUPTION OF GJIC DURING EMBRYONIC OR FETAL DEVELOPMENT COULD LEAD TO EMBRYONIC LETHALITY OR TERATOGENESIS. BY MODULATION OF GJIC, HOMEOSTATIC CONTROL OF CELL GROWTH, DIFFERENTIATION OR APOPTOSIS COULD LEAD TO SPECIFIC DISEASES, SUCH AS NEUROLOGICAL, CARDIOVASCULAR, REPRODUCTIVE OR ENDOCRINOLOGICAL DYSFUNCTION. CHEMICAL MODULATION OR ONCOGENE DOWN-REGULATION OF GJIC IN INITIATED TISSUES HAS BEEN SHOWN TO LEAD TO TUMOR PROMOTION. GENETIC SYNDROMES CARRYING A MUTATED GAP JUNCTION GENE, TOGETHER WITH SOME TRANSGENIC AND KNOCK-OUT GAP JUNCTION GENE MICE, PROVIDE EVIDENCE FOR THE IMPORTANCE OF THIS ORGANELLE FOUND ONLY IN METAZOANS. IMPLICATIONS FOR 'THRESHOLDS' TO TOXICANTS AND FOR RISK ASSESSMENT ARE EVIDENT. 1998 2 2890 49 GAP JUNCTIONAL INTERCELLULAR COMMUNICATION AS A BIOLOGICAL "ROSETTA STONE" IN UNDERSTANDING, IN A SYSTEMS BIOLOGICAL MANNER, STEM CELL BEHAVIOR, MECHANISMS OF EPIGENETIC TOXICOLOGY, CHEMOPREVENTION AND CHEMOTHERAPY. IN SPITE OF THE EARLY SPECULATION BY LOEWENSTEIN THAT ONE OF THE CRITICAL DISTINGUISHING PHENOTYPES OF CANCERS FROM NORMAL CELLS WAS THE DYSFUNCTION OF GAP JUNCTIONAL INTERCELLULAR COMMUNICATION (GJIC), THIS HYPOTHESIS HAS NOT CAPTURED THE ATTENTION OF MOST BIRTH DEFECTS AND CANCER RESEARCHERS. MOREOVER, EVEN WITH LATER DEMONSTRATIONS THAT FACTORS THAT INFLUENCE NORMAL DEVELOPMENT AND CARCINOGENESIS BY MODULATING GJIC, SUCH AS CHEMICAL TERATOGENS AND TUMOR-PROMOTING CHEMICALS, INFLAMMATORY FACTORS, HORMONES AND GROWTH FACTORS, ANTISENSE CONNEXIN GENES, KNOCKOUT MOUSE MODELS, HUMAN INHERITED MUTATED CONNEXIN GENES, SI-CONNEXIN RNA, CHEMOPREVENTIVE AND CHEMOTHERAPEUTIC CHEMICALS, IT IS RARE THAT ONE SEES ANY REFERENCE TO THESE STUDIES BY THE MAINSTREAM INVESTIGATORS IN THESE FIELDS. BASED ON THE ASSUMPTION THAT THE EVOLUTIONARILY CONSERVED CONNEXIN GENES FOUND IN METAZOANS ARE NEEDED FOR NORMAL DEVELOPMENT AND THE MAINTENANCE OF HEALTH AND T. DOBZHANSKY'S STATEMENT "NOTHING IN BIOLOGY MAKES SENSE EXCEPT IN THE LIGHT OF EVOLUTION," A SHORT REVIEW OF THE ROLES OF ENDOGENOUS AND EXOGENOUS MODULATORS OF GJIC WILL BE MADE IN THE CONTEXT OF THE MULTISTAGE, MULTIMECHANISM PROCESS OF CARCINOGENESIS, THE STEM CELL THEORY OF CARCINOGENESIS, THE DISCOVERY AND CHARACTERIZATION OF NORMAL ADULT STEM "CANCER STEM" CELLS AND THE OBSERVATION THAT TWO DISTINCT CLASSES OF GJIC-DEFICIENT CANCER CELLS ARE KNOWN. THE IMPLICATIONS OF THESE OBSERVATIONS TO A "SYSTEMS BIOLOGICAL" VIEW OF THE ROLE OF GAP JUNCTIONS AND THE NUTRITIONAL PREVENTION AND TREATMENT OF SEVERAL CHRONIC DISEASES AND CANCER WILL BE DISCUSSED. 2007 3 1270 33 CYTOSINE METHYLATION IS A CONSERVED EPIGENETIC FEATURE FOUND THROUGHOUT THE PHYLUM PLATYHELMINTHES. BACKGROUND: THE PHYLUM PLATYHELMINTHES (FLATWORMS) CONTAINS AN IMPORTANT GROUP OF BILATERIAN ORGANISMS RESPONSIBLE FOR MANY DEBILITATING AND CHRONIC INFECTIOUS DISEASES OF HUMAN AND ANIMAL POPULATIONS INHABITING THE PLANET TODAY. IN ADDITION TO THEIR BIOMEDICAL AND VETERINARY RELEVANCE, SOME PLATYHELMINTHS ARE ALSO FREQUENTLY USED MODELS FOR UNDERSTANDING TISSUE REGENERATION AND STEM CELL BIOLOGY. THEREFORE, THE MOLECULAR (GENETIC AND EPIGENETIC) CHARACTERISTICS THAT UNDERLIE TROPHIC SPECIALISM, PATHOGENICITY OR DEVELOPMENTAL MATURATION ARE LIKELY TO BE PIVOTAL IN OUR CONTINUED STUDIES OF THIS IMPORTANT METAZOAN GROUP. INDEED, IN CONTRAST TO EARLIER STUDIES THAT FAILED TO DETECT EVIDENCE OF CYTOSINE OR ADENINE METHYLATION IN PARASITIC FLATWORM TAXA, OUR LABORATORY HAS RECENTLY DEFINED A CRITICAL ROLE FOR CYTOSINE METHYLATION IN SCHISTOSOMA MANSONI OVIPOSITION, EGG MATURATION AND OVARIAN DEVELOPMENT. THUS, IN ORDER TO IDENTIFY WHETHER THIS EPIGENETIC MODIFICATION FEATURES IN OTHER PLATYHELMINTH SPECIES OR IS A NOVELTY OF S. MANSONI, WE CONDUCTED A STUDY SIMULTANEOUSLY SURVEYING FOR DNA METHYLATION MACHINERY COMPONENTS AND DNA METHYLATION MARKS THROUGHOUT THE PHYLUM USING BOTH PARASITIC AND NON-PARASITIC REPRESENTATIVES. RESULTS: FIRSTLY, USING BOTH S. MANSONI DNA METHYLTRANSFERASE 2 (SMDNMT2) AND METHYL-CPG BINDING DOMAIN PROTEIN (SMMBD) AS QUERY SEQUENCES, WE ILLUSTRATE THAT ESSENTIAL DNA METHYLATION MACHINERY COMPONENTS ARE WELL CONSERVED THROUGHOUT THE PHYLUM. SECONDLY, USING BOTH MOLECULAR (METHYLATION SPECIFIC AMPLIFICATION POLYMORPHISM, MSAP) AND IMMUNOLOGICAL (ENZYME-LINKED IMMUNOABSORBENT ASSAY, ELISA) METHODOLOGIES, WE DEMONSTRATE THAT REPRESENTATIVE SPECIES (ECHINOCOCCUS MULTILOCULARIS, PROTOPOLYSTOMA XENOPODIS, SCHISTOSOMA HAEMATOBIUM, SCHISTOSOMA JAPONICUM, FASCIOLA HEPATICA AND POLYCELIS NIGRA) WITHIN ALL FOUR PLATYHELMINTH CLASSES (CESTODA, MONOGENEA, TREMATODA AND 'TURBELLARIA') CONTAIN METHYLATED CYTOSINES WITHIN THEIR GENOME COMPARTMENTS. CONCLUSIONS: COLLECTIVELY, THESE FINDINGS PROVIDE THE FIRST DIRECT EVIDENCE FOR A FUNCTIONALLY CONSERVED AND ENZYMATICALLY ACTIVE DNA METHYLATION SYSTEM THROUGHOUT THE PLATYHELMINTHES. DEFINING HOW THIS EPIGENETIC FEATURE SHAPES PHENOTYPIC DIVERSITY AND DEVELOPMENT WITHIN THE PHYLUM REPRESENTS AN EXCITING NEW AREA OF METAZOAN BIOLOGY. 2013 4 6644 36 UNRAVELLING THE MOLECULAR MECHANISMS OF NICKEL IN WOODLICE. DURING THE LAST FEW YEARS, THERE HAS BEEN AN ALARMING INCREASE IN THE AMOUNT OF NICKEL (NI) BEING RELEASED INTO THE ENVIRONMENT, PRIMARILY DUE TO ITS USE IN THE PRODUCTION OF STAINLESS STEEL BUT ALSO FROM OTHER SOURCES SUCH AS BATTERIES MANUFACTURING AND CONSEQUENT DISPOSAL. THE ESTABLISHED BIOTIC LIGAND MODELS PROVIDE PRECISE ESTIMATES FOR NI BIOAVAILABILITY, IN CONTRAST, STUDIES DESCRIBING THE MECHANISMS UNDERPINNING TOXICOLOGICAL EFFECT OF NI ARE SCARCE. THIS STUDY EXPLOITS RNA-SEQ TO DETERMINE THE TRANSCRIPTOMIC RESPONSES OF ISOPODS USING PORCELLIONIDES PRUINOSUS AS AN EXAMPLE OF A TERRESTRIAL METAL-RESISTANT WOODLOUSE. FURTHERMORE, THE RECENTLY PROPOSED MODEL FOR NI ADVERSE OUTCOME PATHWAYS (NI-AOP) PRESENTS AN UNPRECEDENTED OPPORTUNITY TO FIT ISOPOD RESPONSES TO NI TOXICITY AND DEFINE PORCELLIONIDES PRUINOSUS AS A METALOMIC MODEL. PRIOR TO THIS STUDY, P. PRUINOSUS REPRESENTED AN IMPORTANT ENVIRONMENTAL SENTINEL, THOUGH LACKING GENETIC/OMIC DATA. THE REFERENCE TRANSCRIPTOME GENERATED HERE THUS REPRESENTS A MAJOR ADVANCE AND A NOVEL RESOURCE. A DETAILED ANNOTATION OF THE TRANSCRIPTS OBTAINED IS PRESENTED TOGETHER WITH THE HOMOLOGY TO GENES/GENE PRODUCTS FROM METAZOAN AND ARTHROPODA PHYLUM, GENE ONTOLOGY (GO) CLASSIFICATION, CLUSTERS OF ORTHOLOGOUS GROUPS (COG) AND ASSIGNMENT TO KEGG METABOLIC PATHWAYS. THE DIFFERENTIAL GENE EXPRESSION COMPARISON WAS DETERMINED IN RESPONSE TO NICKEL (NI) EXPOSURE AND USED TO DERIVE THE ENRICHED PATHWAYS AND PROCESSES. IT REVEALED A SIGNIFICANT IMPACT ON ION TRAFFICKING AND STORAGE, OXIDATIVE STRESS, NEUROTOXICITY, REPRODUCTION IMPAIRMENT, GENETICS AND EPIGENETICS. MANY OF THE PROCESSES OBSERVED SUPPORT THE CURRENT NI-AOP ALTHOUGH THE DATA HIGHLIGHTS THAT THE CURRENT MODEL CAN BE IMPROVED BY INCLUDING EPIGENETIC ENDPOINTS, WHICH REPRESENTS KEY CHRONIC RISKS UNDER A SCENARIO OF NI TOXICITY. 2019 5 1501 21 DNA METHYLATION ANALYSIS OF HUMAN TISSUE-SPECIFIC CONNEXIN GENES. CONNEXINS ARE THE STRUCTURAL PROTEINS OF GAP JUNCTIONS AND THEIR FUNCTIONING AS TUMOR SUPPRESSORS IS WELL KNOWN. EPIGENETIC MODIFICATIONS, SUCH AS METHYLATION OF CONNEXIN GENES, PLAY IMPORTANT ROLES IN REGULATING GENE EXPRESSION. OVER THE PAST DECADE, SEVERAL METHODS HAVE BEEN APPLIED TO CHARACTERIZE DNA METHYLATION-SPECIFIC LOCI OF CONNEXIN GENES. THIS CHAPTER DESCRIBES ANALYSIS OF SELECTIVE CONNEXIN32 AND CONNEXIN43 GENE DNA METHYLATION IN HUMAN GASTRIC TISSUES USING METHYLATION-SPECIFIC PCR, BISULFITE-SPECIFIC PCR SEQUENCING AS WELL AS MASSARRAY TECHNIQUES. 2016 6 5450 38 REPRODUCTIVE TOXICITY OF COMBINED EFFECTS OF ENDOCRINE DISRUPTORS ON HUMAN REPRODUCTION. CONFLUENCE OF ENVIRONMENTAL, GENETIC, AND LIFESTYLE VARIABLES IS RESPONSIBLE FOR DETERIORATION OF HUMAN FECUNDITY. ENDOCRINE DISRUPTORS OR ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY BE FOUND IN A VARIETY OF FOODS, WATER, AIR, BEVERAGES, AND TOBACCO SMOKE. IT HAS BEEN DEMONSTRATED IN EXPERIMENTAL INVESTIGATIONS THAT A WIDE RANGE OF ENDOCRINE DISRUPTING CHEMICALS HAVE NEGATIVE EFFECTS ON HUMAN REPRODUCTIVE FUNCTION. HOWEVER, EVIDENCE ON THE REPRODUCTIVE CONSEQUENCES OF HUMAN EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS IS SPARSE AND/OR CONFLICTING IN THE SCIENTIFIC LITERATURE. THE COMBINED TOXICOLOGICAL ASSESSMENT IS A PRACTICAL METHOD FOR ASSESSING THE HAZARDS OF COCKTAILS OF CHEMICALS, CO-EXISTING IN THE ENVIRONMENT. THE CURRENT REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF STUDIES EMPHASIZING THE COMBINED TOXICITY OF ENDOCRINE DISRUPTING CHEMICALS ON HUMAN REPRODUCTION. ENDOCRINE DISRUPTING CHEMICALS INTERACT WITH EACH OTHER TO DISRUPT THE DIFFERENT ENDOCRINE AXES, RESULTING IN SEVERE GONADAL DYSFUNCTIONS. TRANSGENERATIONAL EPIGENETIC EFFECTS HAVE ALSO BEEN INDUCED IN GERM CELLS, MOSTLY THROUGH DNA METHYLATION AND EPIMUTATIONS. SIMILARLY, AFTER ACUTE OR CHRONIC EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS COMBINATIONS, INCREASED OXIDATIVE STRESS (OS), ELEVATED ANTIOXIDANT ENZYMATIC ACTIVITY, DISRUPTED REPRODUCTIVE CYCLE, AND REDUCED STEROIDOGENESIS ARE OFTEN REPORTED CONSEQUENCES. THE ARTICLE ALSO DISCUSSES THE CONCENTRATION ADDITION (CA) AND INDEPENDENT ACTION (IA) PREDICTION MODELS, WHICH REVEAL THE IMPORTANCE OF VARIOUS SYNERGISTIC ACTIONS OF ENDOCRINE DISRUPTING CHEMICALS MIXTURES. MORE CRUCIALLY, THIS EVIDENCE-BASED STUDY ADDRESSES THE RESEARCH LIMITATIONS AND INFORMATION GAPS, AS WELL AS PARTICULARLY PRESENTS THE FUTURE RESEARCH VIEWS ON COMBINED ENDOCRINE DISRUPTING CHEMICALS TOXICITY ON HUMAN REPRODUCTION. 2023 7 356 34 ALTERING A HISTONE H3K4 METHYLATION PATHWAY IN GLOMERULAR PODOCYTES PROMOTES A CHRONIC DISEASE PHENOTYPE. METHYLATION OF SPECIFIC LYSINE RESIDUES IN CORE HISTONE PROTEINS IS ESSENTIAL FOR EMBRYONIC DEVELOPMENT AND CAN IMPART ACTIVE AND INACTIVE EPIGENETIC MARKS ON CHROMATIN DOMAINS. THE UBIQUITOUS NUCLEAR PROTEIN PTIP IS ENCODED BY THE PAXIP1 GENE AND IS AN ESSENTIAL COMPONENT OF A HISTONE H3 LYSINE 4 (H3K4) METHYLTRANSFERASE COMPLEX CONSERVED IN METAZOANS. IN ORDER TO DETERMINE IF PTIP AND ITS ASSOCIATED COMPLEXES ARE NECESSARY FOR MAINTAINING STABLE GENE EXPRESSION PATTERNS IN A TERMINALLY DIFFERENTIATED, NON-DIVIDING CELL, WE CONDITIONALLY DELETED PTIP IN GLOMERULAR PODOCYTES IN MICE. RENAL DEVELOPMENT AND FUNCTION WERE NOT IMPAIRED IN YOUNG MICE. HOWEVER, OLDER ANIMALS PROGRESSIVELY EXHIBITED PROTEINURIA AND PODOCYTE ULTRA STRUCTURAL DEFECTS SIMILAR TO CHRONIC GLOMERULAR DISEASE. LOSS OF PTIP RESULTED IN SUBTLE CHANGES IN GENE EXPRESSION PATTERNS PRIOR TO THE ONSET OF A RENAL DISEASE PHENOTYPE. CHROMATIN IMMUNOPRECIPITATION SHOWED A LOSS OF PTIP BINDING AND LOWER H3K4 METHYLATION AT THE NTRK3 (NEUROTROPHIC TYROSINE KINASE RECEPTOR, TYPE 3) LOCUS, WHOSE EXPRESSION WAS SIGNIFICANTLY REDUCED AND WHOSE FUNCTION MAY BE ESSENTIAL FOR PODOCYTE FOOT PROCESS PATTERNING. THESE DATA DEMONSTRATE THAT ALTERATIONS OR MUTATIONS IN AN EPIGENETIC REGULATORY PATHWAY CAN ALTER THE PHENOTYPES OF DIFFERENTIATED CELLS AND LEAD TO A CHRONIC DISEASE STATE. 2010 8 4663 41 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 9 2772 44 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 10 1066 39 CLINICAL USE OF AMINO ACIDS AS DIETARY SUPPLEMENT: PROS AND CONS. NITROGEN SUPPLY IS PIVOTAL FOR THE MAINTENANCE OF LIFE. AMINO ACIDS CAN BE UTILIZED TO SYNTHESIZE BOTH GLUCOSE AND LIPIDS. THE OPPOSITE, I.E., PRODUCTION OF AMINO ACIDS FROM EITHER ONE OF THEM, IS NOT POSSIBLE IN THE ABSENCE OF OTHER AMINO ACIDS AS DONORS OF NITROGEN. THE QUALITY OF AMINO ACID CONTENT IN PROTEIN HAS BEEN RE-EVALUATED RECENTLY, AND THE RELEVANCE OF ESSENTIAL AMINO ACIDS HAS BEEN REPEATEDLY UNDERLINED. ESSENTIAL AMINO ACID REQUIREMENTS IN DIFFERENT MAMMALS ARE NOT IDENTICAL, AND RATIOS AMONG THEM SHOULD BE TAKEN INTO ACCOUNT WHEN PROJECTING AN EFFICIENT FORMULATION. RECENT RESEARCH HAS DEMONSTRATED THAT GENES RESPOND TO DIFFERENT QUALITIES AND QUANTITIES OF NUTRITIONAL SUPPLY, AND INCREASED PROVISION OF ESSENTIAL AMINO ACIDS INCREASES LIFESPAN IN ANIMAL EXPERIMENTS THROUGH MITOCHONDRIOGENESIS AND MAINTENANCE OF ELEVATED RATES OF SYNTHESIS OF ANTI-OXIDANT MOLECULES. MOREOVER, GENETIC EXPRESSION OF KEY CONTROLLERS OF SYNTHESIS, LIKE MTOR, MAY BE PARTICULARLY IMPORTANT FOR UNDERSTANDING SKELETAL MUSCLE MAINTENANCE. LOSSES OF MUSCLE MASS AND IMPAIRED IMMUNE FUNCTION ARE RELATED TO REDUCED PROTEIN SUPPLY, AND THERE IS INCREASING EVIDENCE THAT REGULAR ESSENTIAL AMINO ACID INTAKE AS PART OF AN ORAL DIET IS EFFECTIVE IN REVERSING MUSCLE CATABOLISM, PROMOTING MUSCLE ANABOLISM, AND RESTORING IMMUNOLOGICAL FUNCTION. THEREFORE, THE USE OF AMINO ACIDS AS SUPPLEMENTS TO DIET WOULD BE EXPANDING IN THE NEAR FUTURE. IS THIS SAFE? FEW DATA ARE AVAILABLE ON AMINO ACID TOXICITY, AND ONLY ONE ESSENTIAL AMINO ACID MAY BE CONSIDERED TO HAVE CLINICALLY RELEVANT TOXICITY: METHIONINE, BECAUSE IT IS TRANSFORMED INTO A TOXIC INTERMEDIATE, HOMOCYSTEINE, WHEN CYSTEINE SYNTHESIS IS REQUIRED BY METABOLIC NEEDS. MATCHING OF STOICHIOMETRIC RATIOS BETWEEN METHIONINE AND CYSTEINE MAY SOLVE THE PROBLEM OF SUPPLYING SUFFICIENT AMOUNTS OF SULFUR TO THE BODY. ARGININE AND GLUTAMINE ARE TWO NON-ESSENTIAL AMINO ACIDS THAN CAN BECOME "CONDITIONALLY ESSENTIAL" BECAUSE OF ELEVATED NEEDS DURING PATHOLOGICAL CONDITIONS, AND METABOLISM MAY NOT BE ABLE TO MAINTAIN THEIR CONCENTRATIONS AT SUFFICIENT LEVELS TO MATCH METABOLIC REQUIREMENTS. CHRONIC EXOGENOUS ARGININE SUPPLEMENTATION HAS NOT PROVEN TO EXERT POSITIVE CLINICAL EFFECTS IN DIFFERENT TRIALS, AND SEQUENTIAL ARTICULATION OF THE KNOWLEDGE OF INTRODUCTION OF ARGININE-DRIVEN TRANSCRIPTIONAL, TRANSLATIONAL, AND EPIGENETIC ADAPTATIONS MAY GIVE US A KEY FOR INTERPRETING THOSE PUZZLING RESULTS. 2011 11 3934 46 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982 12 835 35 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES. 1996 13 375 21 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 14 4015 41 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS. 2017 15 5113 25 POPULATION-LEVEL IMPACTS OF PESTICIDE-INDUCED CHRONIC EFFECTS ON INDIVIDUALS DEPEND MORE ON ECOLOGY THAN TOXICOLOGY. THE CURRENT METHOD FOR ASSESSING LONG-TERM RISK OF PESTICIDES TO MAMMALS IN THE EU IS BASED ON THE INDIVIDUAL RATHER THAN THE POPULATION-LEVEL AND LACKS ECOLOGICAL REALISM. HENCE THERE IS LITTLE POSSIBILITY FOR REGULATORY AUTHORITIES TO INCREASE ECOLOGICAL REALISM AND UNDERSTANDING OF RISKS AT THE POPULATION-LEVEL. HERE WE DEMONSTRATE HOW, USING ABM MODELLING, ASSESSMENTS AT THE POPULATION-LEVEL CAN BE OBTAINED EVEN FOR A PESTICIDE WITH COMPLEX LONG-TERM EFFECTS SUCH AS EPIGENETIC TRANSMISSION OF REPRODUCTIVE DEPRESSION. BY OBJECTIVELY FITTING NONLINEAR MODELS TO THE SIMULATION OUTPUTS IT WAS POSSIBLE TO COMPARE POPULATION DEPRESSION AND RECOVERY RATES FOR A RANGE OF SCENARIOS IN WHICH TOXICITY AND EXPOSURE FACTORS WERE VARIED. THE SYSTEM WAS DIFFERENTIALLY SENSITIVE TO THE VARIOUS FACTORS, BUT VOLE ECOLOGY AND BEHAVIOUR WERE AT LEAST AS IMPORTANT PREDICTORS OF POPULATION-LEVEL EFFECTS AS TOXICOLOGY. THIS EMPHASISES THE NEED FOR GREATER FOCUS ON ANIMAL ECOLOGY IN RISK ASSESSMENTS. 2009 16 4805 36 OBESITY AND METABOLIC COMORBIDITIES: ENVIRONMENTAL DISEASES? OBESITY AND METABOLIC COMORBIDITIES REPRESENT INCREASING HEALTH PROBLEMS. ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ARE EXOGENOUS AGENTS THAT CHANGE ENDOCRINE FUNCTION AND CAUSE ADVERSE HEALTH EFFECTS. MOST EDCS ARE SYNTHETIC CHEMICALS; SOME ARE NATURAL FOOD COMPONENTS AS PHYTOESTROGENS. PEOPLE ARE EXPOSED TO COMPLEX MIXTURES OF CHEMICALS THROUGHOUT THEIR LIVES. EDCS IMPACT HORMONE-DEPENDENT METABOLIC SYSTEMS AND BRAIN FUNCTION. LABORATORY AND HUMAN STUDIES PROVIDE COMPELLING EVIDENCE THAT HUMAN CHEMICAL CONTAMINATION CAN PLAY A ROLE IN OBESITY EPIDEMIC. CHEMICAL EXPOSURES MAY INCREASE THE RISK OF OBESITY BY ALTERING THE DIFFERENTIATION OF ADIPOCYTES. EDCS CAN ALTER METHYLATION PATTERNS AND NORMAL EPIGENETIC PROGRAMMING IN CELLS. OXIDATIVE STRESS MAY BE INDUCED BY MANY OF THESE CHEMICALS, AND ACCUMULATING EVIDENCE INDICATES THAT IT PLAYS IMPORTANT ROLES IN THE ETIOLOGY OF CHRONIC DISEASES. THE INDIVIDUAL SENSITIVITY TO CHEMICALS IS VARIABLE, DEPENDING ON ENVIRONMENT AND ABILITY TO METABOLIZE HAZARDOUS CHEMICALS. A NUMBER OF GENES, ESPECIALLY THOSE REPRESENTING ANTIOXIDANT AND DETOXIFICATION PATHWAYS, HAVE POTENTIAL APPLICATION AS BIOMARKERS OF RISK ASSESSMENT. THE POTENTIAL HEALTH EFFECTS OF COMBINED EXPOSURES MAKE THE RISK ASSESSMENT PROCESS MORE COMPLEX COMPARED TO THE ASSESSMENT OF SINGLE CHEMICALS. TECHNIQUES AND METHODS NEED TO BE FURTHER DEVELOPED TO FILL DATA GAPS AND INCREASE THE KNOWLEDGE ON HARMFUL EXPOSURE COMBINATIONS. 2013 17 6076 35 THE DYNAMICS OF NUCLEAR RECEPTORS AND NUCLEAR RECEPTOR COREGULATORS IN THE PATHOGENESIS OF ENDOMETRIOSIS. BACKGROUND: ENDOMETRIOSIS IS DEFINED AS THE COLONIZATION AND GROWTH OF ENDOMETRIAL TISSUE AT ANATOMIC SITES OUTSIDE THE UTERINE CAVITY. UP TO 15% OF REPRODUCTIVE-AGED WOMEN IN THE USA SUFFER FROM PAINFUL SYMPTOMS OF ENDOMETRIOSIS, SUCH AS INFERTILITY, PELVIC PAIN, MENSTRUAL CYCLE ABNORMALITIES AND INCREASED RISK OF CERTAIN CANCERS. HOWEVER, MANY OF THE CURRENT CLINICAL TREATMENTS FOR ENDOMETRIOSIS ARE NOT SUFFICIENTLY EFFECTIVE AND YIELD UNACCEPTABLE SIDE EFFECTS. THERE IS CLEARLY AN URGENT NEED TO IDENTIFY NEW MOLECULAR MECHANISMS THAT CRITICALLY UNDERPIN THE INITIATION AND PROGRESSION OF ENDOMETRIOSIS IN ORDER TO DEVELOP MORE SPECIFIC AND EFFECTIVE THERAPEUTICS WHICH LACK THE SIDE EFFECTS OF CURRENT THERAPIES. THE AIM OF THIS REVIEW IS TO DISCUSS HOW NUCLEAR RECEPTORS (NRS) AND THEIR COREGULATORS PROMOTE THE PROGRESSION OF ENDOMETRIOSIS. UNDERSTANDING THE PATHOGENIC MOLECULAR MECHANISMS FOR THE GENESIS AND MAINTENANCE OF ENDOMETRIOSIS AS MODULATED BY NRS AND COREGULATORS CAN REVEAL NEW THERAPEUTIC TARGETS FOR ALTERNATIVE ENDOMETRIOSIS TREATMENTS. METHODS: THIS REVIEW WAS PREPARED USING PUBLISHED GENE EXPRESSION MICROARRAY DATA SETS OBTAINED FROM PATIENTS WITH ENDOMETRIOSIS AND PUBLISHED LITERATURE ON NRS AND THEIR COREGULATORS THAT DEAL WITH ENDOMETRIOSIS PROGRESSION. USING THE ABOVE OBSERVATIONS, OUR CURRENT UNDERSTANDING OF HOW NRS AND NR COREGULATORS ARE INVOLVED IN THE PROGRESSION OF ENDOMETRIOSIS IS SUMMARIZED. RESULTS: ABERRANT LEVELS OF NRS AND NR COREGULATORS IN ECTOPIC ENDOMETRIOSIS LESIONS ARE ASSOCIATED WITH THE PROGRESSION OF ENDOMETRIOSIS. AS AN EXAMPLE, ENDOMETRIOTIC CELL-SPECIFIC ALTERATIONS IN GENE EXPRESSION ARE CORRELATED WITH A DIFFERENTIAL METHYLATION STATUS OF THE GENOME COMPARED WITH THE NORMAL ENDOMETRIUM. THESE DIFFERENTIAL EPIGENETIC REGULATIONS CAN GENERATE FAVORABLE CELL-SPECIFIC NR AND COREGULATOR MILIEUS FOR ENDOMETRIOSIS PROGRESSION. GENETIC ALTERATIONS, SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS AND INSERTION/DELETION POLYMORPHISMS OF NR AND COREGULATOR GENES, ARE FREQUENTLY DETECTED IN ECTOPIC LESIONS COMPARED WITH THE NORMAL ENDOMETRIUM. THESE GENETIC VARIATIONS IMPART NEW MOLECULAR PROPERTIES TO NRS AND COREGULATORS TO INCREASE THEIR CAPACITY TO STIMULATE PROGRESSION OF ENDOMETRIOSIS. FINALLY, POST-TRANSLATIONAL MODIFICATIONS OF NR COREGULATORS, SUCH AS PROTEOLYTIC PROCESSING, GENERATE ENDOMETRIOSIS-SPECIFIC ISOFORMS. COMPARED WITH THE UNMODIFIED COREGULATORS, THESE COREGULATOR ISOFORMS HAVE UNIQUE FUNCTIONS THAT ENHANCE THE PATHOGENESIS OF ENDOMETRIOSIS. CONCLUSIONS: EPIGENETIC/GENETIC VARIATIONS AND POSTTRANSLATIONAL MODIFICATIONS OF NRS AND COREGULATORS ALTER THEIR ORIGINAL FUNCTION SO THAT THEY BECOME POTENT 'DRIVERS' OF ENDOMETRIOSIS PROGRESSION. 2014 18 3817 33 INTRAUTERINE PROGRAMMING OF THE ENDOCRINE PANCREAS. EPIDEMIOLOGICAL STUDIES HAVE REVEALED STRONG RELATIONSHIPS BETWEEN POOR FOETAL GROWTH AND SUBSEQUENT DEVELOPMENT OF THE METABOLIC SYNDROME. PERSISTING EFFECTS OF EARLY MALNUTRITION BECOME TRANSLATED INTO PATHOLOGY, THEREBY DETERMINE CHRONIC RISK FOR DEVELOPING GLUCOSE INTOLERANCE AND DIABETES. THESE EPIDEMIOLOGICAL OBSERVATIONS IDENTIFY THE PHENOMENA OF FOETAL PROGRAMMING WITHOUT EXPLAINING THE UNDERLYING MECHANISMS THAT ESTABLISH THE CAUSAL LINK. ANIMAL MODELS HAVE BEEN ESTABLISHED AND STUDIES HAVE DEMONSTRATED THAT REDUCTION IN THE AVAILABILITY OF NUTRIENTS DURING FOETAL DEVELOPMENT PROGRAMS THE ENDOCRINE PANCREAS AND INSULIN-SENSITIVE TISSUES. WHATEVER THE TYPE OF FOETAL MALNUTRITION, WHETHER THERE ARE NOT ENOUGH CALORIES OR PROTEIN IN FOOD OR AFTER PLACENTAL DEFICIENCY, MALNOURISHED PUPS ARE BORN WITH A DEFECT IN THEIR BETA-CELL POPULATION THAT WILL NEVER COMPLETELY RECOVER, AND INSULIN-SENSITIVE TISSUES WILL BE DEFINITIVELY ALTERED. DESPITE THE SIMILAR ENDPOINT, DIFFERENT CELLULAR AND PHYSIOLOGICAL MECHANISMS ARE PROPOSED. HORMONES OPERATIVE DURING FOETAL LIFE LIKE INSULIN ITSELF, INSULIN-LIKE GROWTH FACTORS AND GLUCOCORTICOIDS, AS WELL AS SPECIFIC MOLECULES LIKE TAURINE, OR ISLET VASCULARIZATION WERE IMPLICATED AS POSSIBLE FACTORS AMPLIFYING THE DEFECT. THE MOLECULAR MECHANISMS RESPONSIBLE FOR INTRAUTERINE PROGRAMMING OF THE BETA CELLS ARE STILL ELUSIVE, BUT TWO HYPOTHESES RECENTLY EMERGED: THE FIRST ONE IMPLIES PROGRAMMING OF MITOCHONDRIA AND THE SECOND, EPIGENETIC REGULATION. 2007 19 229 35 ADAPTATION OR PATHOLOGY? THE ROLE OF PRENATAL STRESSOR TYPE AND INTENSITY IN THE DEVELOPMENTAL PROGRAMING OF ADULT PHENOTYPE. THE MOTHER IS THE MAJOR INTERFACE BETWEEN THE OFFSPRING AND ITS PRENATAL ENVIRONMENT. PRENATAL TOXINS AND STRESS-INDUCING PHYSICAL AGENTS ARE IMPORTANT FACTORS PROGRAMMING THE DEVELOPMENTAL TRAJECTORY OF MAMMALS THAT LIKELY INVOLVE EPIGENETIC MODIFICATIONS. HOWEVER, PRENATAL STRESSORS COMMONLY-USED IN THE LABORATORY (E.G. PRENATAL RESTRAINT STRESS AND PRENATAL CHRONIC VARIABLE STRESS) ARE TYPICALLY ADMINISTERED AT HIGH INTENSITIES. THESE EXPOSURES TYPICALLY LEAD TO PATHOLOGICAL PHENOTYPES SUPPORTING THE DEVELOPMENT ORIGIN OF HEALTH AND DISEASE HYPOTHESIS. IN THIS REVIEW, WE COMPARE THE PHENOTYPIC OUTCOMES OF THESE COMMONLY-USED PRENATAL STRESSORS TO AN ECOLOGICALLY-RELEVANT, PSYCHOGENIC STRESSOR THAT HAS BEEN PRESENT OVER EVOLUTIONARY TIMES, PREDATOR OR PREDATOR CUES PRESENCE. PRENATAL STRESS BY PREDATOR THREAT RESULTS IN BEHAVIORAL, PHYSIOLOGICAL, ENDOCRINE, TRANSCRIPT ABUNDANCE AND EPIGENETIC (DNA METHYLATION) MODIFICATIONS. THESE PHENOTYPIC MODIFICATIONS ARE CONSISTENT WITH DEVELOPMENTAL FORECASTING ACCORDING TO THE PREDICTIVE ADAPTIVE RESPONSE HYPOTHESIS, YIELDING ADAPTIVE RESPONSES IN ENVIRONMENTS WHERE SUCH PREDATION STRESS IS PRESENT. THE EVIDENCE DESCRIBED IN THIS REVIEW SUGGESTS THAT THE TYPE OF PRENATAL STRESS AGENT AND ITS INTENSITY MODIFIES THE PHENOTYPE EXPRESSED, WHICH CAN RANGE FROM ADAPTIVE TO PATHOLOGICAL. PRENATAL BISPHENOL A EXPOSURE STUDIES ARE PRESENTED AS AN EXAMPLE WHERE GRADED INTENSITIES (CONCENTRATIONS) OF PRENATAL TOXIN EXPOSURE CAN BE COMPARED DIRECTLY. FINALLY, WE EMPHASIZE THE IMPORTANCE OF STUDYING BOTH SEXES IN THESE STUDIES, AS SEX DIFFERENCES APPEAR TO BE A COMMON FEATURE OF THE RESPONSE TO PRENATAL STRESS. 2018 20 2069 44 EPIGENETIC CONTROL OF SKELETAL MUSCLE REGENERATION: INTEGRATING GENETIC DETERMINANTS AND ENVIRONMENTAL CHANGES. DURING EMBRYONIC DEVELOPMENT, PLURIPOTENT CELLS ARE GENETICALLY COMMITTED TO SPECIFIC LINEAGES BY THE EXPRESSION OF CELL-TYPE-SPECIFIC TRANSCRIPTIONAL ACTIVATORS THAT DIRECT THE FORMATION OF SPECIALIZED TISSUES AND ORGANS IN RESPONSE TO DEVELOPMENTAL CUES. CHROMATIN-MODIFYING PROTEINS ARE EMERGING AS ESSENTIAL COMPONENTS OF THE EPIGENETIC MACHINERY, WHICH ESTABLISHES THE NUCLEAR LANDSCAPE THAT ULTIMATELY DETERMINES THE FINAL IDENTITY AND FUNCTIONAL SPECIALIZATION OF ADULT CELLS. RECENT EVIDENCE HAS REVEALED THAT DISCRETE POPULATIONS OF ADULT CELLS CAN RETAIN THE ABILITY TO ADOPT ALTERNATIVE CELL FATES IN RESPONSE TO ENVIRONMENTAL CUES. THESE CELLS INCLUDE CONVENTIONAL ADULT STEM CELLS AND A STILL POORLY DEFINED COLLECTION OF CELL TYPES ENDOWED WITH FACULTATIVE PHENOTYPE AND FUNCTIONAL PLASTICITY. UNDER PHYSIOLOGICAL CONDITIONS OR ADAPTIVE STATES, THESE CELLS COOPERATE TO SUPPORT TISSUE AND ORGAN HOMEOSTASIS, AND TO PROMOTE GROWTH OR COMPENSATORY REGENERATION. HOWEVER, DURING CHRONIC DISEASES AND AGING THESE CELLS CAN ADOPT A PATHOLOGICAL PHENOTYPE AND MEDIATE MALADAPTIVE RESPONSES, SUCH AS THE FORMATION OF FIBROTIC SCARS AND FAT DEPOSITION THAT PROGRESSIVELY REPLACES STRUCTURAL AND FUNCTIONAL UNITS OF TISSUES AND ORGANS. THE MOLECULAR DETERMINANTS OF THESE PHENOTYPIC TRANSITIONS ARE ONLY EMERGING FROM RECENT STUDIES THAT REVEAL HOW DYNAMIC CHROMATIN STATES CAN GENERATE FLEXIBLE EPIGENETIC LANDSCAPES, WHICH CONFER ON CELLS THE ABILITY TO RETAIN PARTIAL PLURIPOTENCY AND ADAPT TO ENVIRONMENTAL CHANGES. THIS REVIEW SUMMARIZES OUR CURRENT KNOWLEDGE ON THE ROLE OF THE EPIGENETIC MACHINERY AS A 'FILTER' BETWEEN GENETIC COMMITMENT AND ENVIRONMENTAL SIGNALS IN CELL TYPES THAT CAN ALTERNATIVELY PROMOTE SKELETAL MUSCLE REGENERATION OR FIBRO-ADIPOGENIC DEGENERATION. 2013