1 4121 145 MECHANISMS OF CHEMICALLY INDUCED RENAL CARCINOGENESIS IN THE LABORATORY RODENT. LABORATORY STUDIES WITH CLASSICAL RENAL CARCINOGENS IN THE RAT AND MOUSE, AS WELL AS RESEARCH INVESTIGATION WITH SOME OF THE CHEMICALS PROVING POSITIVE FOR THE KIDNEY IN NATIONAL TOXICOLOGY PROGRAM CARCINOGENICITY BIOASSAYS, HAVE DEMONSTRATED THE EXISTENCE OF A RANGE OF DIVERSE MECHANISMS UNDERLYING RODENT KIDNEY CARCINOGENESIS. THE CLASSICAL CARCINOGENS USED AS EXPERIMENTAL MODELS FOR STUDYING RENAL TUMOR PATHOGENESIS, SUCH AS THE NITROSAMINES, ARE GENOTOXIC AND INTERACT DIRECTLY WITH DNA, FORMING DNA ADDUCTS WITH MUTAGENIC POTENTIAL. IN CONTRAST, POTASSIUM BROMATE AND FERRIC NITRILOTRIACETATE (FE-NTA), ALSO EFFECTIVE RENAL CARCINOGENS, APPEAR TO CAUSE INDIRECT DAMAGE TO DNA MEDIATED BY OXIDATIVE STRESS. A NUMBER OF NONGENOTOXIC CHEMICALS ARE ASSOCIATED WITH EPIGENETIC RENAL TUMOR INDUCTION IN RODENTS, AND THE ACTIVITY OF THESE TENDS TO INVOLVE PROLONGED STIMULATION OF CELL PROLIFERATION THROUGHOUT THE DURATION OF EXPOSURE. THIS MODE OF ACTION REFLECTS A SUSTAINED REGENERATIVE RESPONSE, EITHER DUE TO DIRECT CHEMICAL TOXICITY TO THE TUBULE CELLS, AS WITH CHLOROFORM, OR TO INDIRECT CYTOTOXICITY ASSOCIATED WITH LYSOSOMAL OVERLOAD, AS IN ALPHA2U-GLOBULIN ACCUMULATION IN MALE RATS RESULTING FROM THE ADMINISTRATION OF SUCH CHEMICALS AS D-LIMONENE AND TETRACHLOROETHYLENE. THE HISTOPATHOLOGIC NATURE OF HYDROQUINONE RENAL CARCINOGENESIS SUGGESTS THAT AN ADDITIONAL EPIGENETIC PATHWAY TO RENAL TUBULE TUMOR FORMATION IN RATS MAY BE THROUGH CHEMICAL-MEDIATED EXACERBATION OF, AND INTERACTION WITH, THE AGE-RELATED SPONTANEOUS RENAL DISEASE, CHRONIC PROGRESSIVE NEPHROPATHY. THESE VARIOUS MECHANISTIC PATHWAYS HAVE IMPLICATIONS FOR THE NATURE OF THE INDUCED CANCER PROCESS WITH RESPECT TO TUMOR INCIDENCE, LATENCY, MALIGNANCY, AND SEX PREDISPOSITION. 1998 2 3418 34 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 3 818 38 CHARACTERISTICS OF THE SPECTRUM OF PROLIFERATIVE LESIONS OBSERVED IN THE KIDNEY AND URINARY BLADDER OF FISCHER 344 RATS AND B6C3F1 MICE. MANY RODENT RENAL AND BLADDER CARCINOGENS RELY UPON EPIGENETIC MECHANISMS OF CARCINOGENESIS; SUCH MECHANISMS ARE LIKELY TO INFLUENCE THE SPECTRUM OF URINARY TRACT TUMORS OBSERVED IN CONTROL AND TREATED ANIMALS. THIS IS REFLECTED IN SEVERAL FEATURES OF CHEMICALLY INDUCED RODENT URINARY TRACT NEOPLASMS, INCLUDING A LOW OVERALL TUMOR INCIDENCE, AN INCREASED PREVALENCE OF URINARY TRACT TUMORS IN RATS COMPARED TO MICE AND MALES COMPARED TO FEMALES, THE TENDENCY FOR EPITHELIAL TUMORS TO PREDOMINATE OVER NONEPITHELIAL TYPES, AND DEMONSTRATED LINKS TO CHRONIC PROGRESSIVE NEPHROPATHY AND UROLITHIASIS. SUCH TENDENCIES ARE ALSO CHARACTERISTIC OF SPONTANEOUS URINARY TRACT TUMORS IN RODENTS. DATA TO SUPPORT THESE OBSERVATIONS CAN BE DERIVED FROM LARGE HISTORICAL DATABASES SUCH AS THE TOXICOLOGY DATA MANAGEMENT SYSTEM, MAINTAINED BY NATIONAL TOXICOLOGY PROGRAM. 2002 4 761 40 CATEGORIZING THE CHARACTERISTICS OF HUMAN CARCINOGENS: A NEED FOR SPECIFICITY. THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS RECENTLY PROPOSED EMPLOYING "TEN KEY CHARACTERISTICS OF HUMAN CARCINOGENS" (TKCS) TO DETERMINE THE POTENTIAL OF AGENTS FOR HARMFUL EFFECTS. THE TKCS SEEM LIKELY TO CONFUSE THE UNSATISFACTORY CORRELATION FROM TESTING REGIMES THAT HAVE IGNORED THE DIFFERENCES EVIDENT WHEN CELLULAR CHANGES ARE COMPARED IN SHORT AND LONG-LIVED SPECIES, WITH THEIR VERY DIFFERENT STEM CELL AND SOMATIC CELL PHYLOGENIES. THE PROPOSED CHARACTERISTICS ARE SO BROAD THAT THEIR USE WILL LEAD TO AN INCREASE IN THE CURRENT UNACCEPTABLY HIGH RATE OF FALSE POSITIVES. IT COULD BE AN INFORMATIVE EXPERIMENT TO TAKE WELL-ESTABLISHED APPROVED THERAPEUTICS WITH WELL-KNOWN HUMAN SAFETY PROFILES AND TEST THEM AGAINST THIS NEW TKC PARADIGM. CANCERS ARE INITIATED AND DRIVEN BY HERITABLE AND TRANSIENT CHANGES IN GENE EXPRESSION, EXPAND CLONALLY, AND PROGRESS VIA ADDITIONAL ASSOCIATED ACQUIRED MUTATIONS AND EPIGENETIC ALTERATIONS THAT PROVIDE CELLS WITH AN EVOLUTIONARY ADVANTAGE. THE GENOTOXICITY TESTING PROTOCOLS CURRENTLY EMPLOYED AND REQUIRED BY REGULATION, EMPHASIZE TESTING FOR THE MUTATIONAL POTENTIAL OF THE TEST AGENT. TWO-YEAR, CHRONIC RODENT CANCER BIOASSAYS ARE INTENDED TO TEST FOR THE ENTIRE SPECTRUM OF CARCINOGENIC TRANSFORMATION. THE USE OF CYTOTOXIC DOSES CAUSING INCREASED, SUSTAINED CELL PROLIFERATION THAT FACILITATES ACCUMULATED GENETIC DAMAGE LEADS TO A HIGH FALSE-POSITIVE RATE OF TUMOR INDUCTION. CURRENT CANCER HAZARD ASSESSMENT PROTOCOLS AND WEIGHT-OF-THE-EVIDENCE ANALYSIS OF AGENT-SPECIFIC CANCER RISK ALIGN POORLY WITH THE PATHOGENESIS OF HUMAN CARCINOMA AND SO NEED MODERNIZATION AND IMPROVEMENT IN WAYS SUGGESTED HERE. 2021 5 4823 33 OCHRATOXIN A: POTENTIAL EPIGENETIC MECHANISMS OF TOXICITY AND CARCINOGENICITY. ASSESSMENT OF THE SIGNIFICANCE TO HUMAN HEALTH OF OCHRATOXIN A (OTA) IN FOOD IS LIMITED BY A LACK OF HUMAN TOXICITY DATA. THEREFORE, OTA RISK EVALUATION RELIES MAINLY ON THE USE OF ANIMAL DATA, WITH RENAL CARCINOGENICITY IN RAT BEING CONSIDERED AS THE PIVOTAL EFFECT. THE ELUCIDATION OF THE MECHANISM OF ACTION WOULD IMPROVE THE USE OF THE CARCINOGENICITY DATA FOR RISK ASSESSMENT. DIRECT GENOTOXICITY VERSUS EPIGENETIC MECHANISMS APPEARS TO BE A KEY QUESTION. IN THIS PRESENTATION, NEW BIOCHEMICAL AND TOXICOGENOMIC RESULTS OBTAINED IN A RECENT EUROPEAN PROJECT (EU-GRANT # QLK1-CT-2001-011614) WILL BE SUMMARIZED IN THE CONTEXT OF PREVIOUSLY REPORTED MECHANISMS OF ACTION INCLUDING INHIBITION OF PROTEIN SYNTHESIS, PRODUCTION OF OXIDATIVE STRESS AND ALTERATION OF CELL SIGNALLING. AMONGST OTHERS, THE NEW DATA INDICATE THAT CHRONIC ADMINISTRATION OF A CARCINOGENIC DOSE OF OTA AFFECTED CELL-SIGNALLING PATHWAYS RESULTING IN A SIGNIFICANTLY REDUCED RENAL ANTIOXIDANT DEFENCE AND INCREASED OXIDATIVE DNA DAMAGE. THESE DATA CONFIRM PREVIOUS HYPOTHESES INVOLVING OXIDATIVE STRESS AS A POSSIBLE KEY EPIGENETIC MECHANISM OF OTA TOXICITY AND CARCINOGENICITY. 2005 6 1912 31 ENVIRONMENT, DIET AND CPG ISLAND METHYLATION: EPIGENETIC SIGNALS IN GASTROINTESTINAL NEOPLASIA. THE EPITHELIAL SURFACES OF THE MAMMALIAN ALIMENTARY TRACT ARE CHARACTERISED BY VERY HIGH RATES OF CELL PROLIFERATION AND DNA SYNTHESIS, AND IN HUMANS THEY ARE HIGHLY SUSCEPTIBLE TO CANCER. THE ROLE OF SOMATIC MUTATIONS AS DRIVERS OF CARCINOGENESIS IN THE ALIMENTARY TRACT IS WELL ESTABLISHED, BUT THE IMPORTANCE OF GENE SILENCING BY EPIGENETIC MECHANISMS IS INCREASINGLY RECOGNISED. METHYLATION OF CPG ISLANDS IS AN IMPORTANT COMPONENT OF THE EPIGENETIC CODE THAT REGULATES GENE EXPRESSION DURING DEVELOPMENT AND NORMAL CELLULAR DIFFERENTIATION, AND A NUMBER OF GENES ARE WELL KNOWN TO BECOME ABNORMALLY METHYLATED DURING THE DEVELOPMENT OF TUMOURS OF THE OESOPHAGUS, STOMACH AND COLORECTUM. ABERRANT PATTERNS OF DNA METHYLATION DEVELOP AS A RESULT OF PATHOLOGICAL PROCESSES SUCH AS CHRONIC INFLAMMATION, AND IN RESPONSE TO VARIOUS DIETARY FACTORS, INCLUDING IMBALANCES IN THE SUPPLY OF METHYL DONORS, PARTICULARLY FOLATES, AND EXPOSURE TO DNA METHYLTRANSFERASE INHIBITORS, WHICH INCLUDE POLYPHENOLS AND POSSIBLY ISOTHIOCYANATES FROM PLANT FOODS. HOWEVER THE IMPORTANCE OF THESE ENVIRONMENTAL INTERACTIONS IN HUMAN HEALTH AND DISEASE REMAINS TO BE ESTABLISHED. RECENT MOVES TO MODIFY THE EXPOSURE OF HUMAN POPULATIONS TO FOLATE, BY MANDATORY SUPPLEMENTATION OF CEREAL FOODS, EMPHASISE THE IMPORTANCE OF UNDERSTANDING THE SUSCEPTIBILITY OF THE HUMAN EPIGENOME TO DIETARY AND OTHER ENVIRONMENTAL EFFECTS. 2008 7 1340 29 DESIGNING SAFER DRUGS: (Q)SAR-BASED IDENTIFICATION OF MUTAGENS AND CARCINOGENS. MUTAGENICITY AND CARCINOGENICITY ARE CHRONIC EFFECTS OF PRIMARY CONCERN FOR HUMAN HEALTH. A UNIFYING APPROACH TO THEIR MECHANISTIC UNDERSTANDING IS THE RECOGNITION THAT MANY CHEMICALS PROVOKE BOTH EFFECTS BY ELECTROPHILIC ATTACK TO THE BIOLOGICAL MACROMOLECULES, AS SUCH OR AFTER METABOLISM (GENOTOXIC CARCINOGENICITY). QSARS OF INDIVIDUAL CLASSES OF GENOTOXIC CARCINOGENS HAVE CONTRIBUTED TO THE ELUCIDATION OF THE CHEMICAL DETERMINANTS OF THIS ACTIVITY. LITTLE WORK HAS BEEN DONE ON THE EPIGENETIC CARCINOGENS, ACTING THROUGH NON-GENOTOXIC, VERY SPECIFIC MECHANISMS. HOWEVER, THE EXISTING QSARS FOR INDIVIDUAL CHEMICAL CLASSES ARE TOO FEW TO BE OF REAL USEFULNESS IN THE SCREENING OF MASSES OF CANDIDATE DRUGS. MODELS FOR PREDICTING THE CARCINOGENICITY OF "ANY TYPE" OF CHEMICALS HAVE BEEN PROPOSED: PROSPECTIVE PREDICTION EXERCISES POINTED TO THE SERIOUS LIMITATIONS OF MOST OF THESE APPROACHES. THE BEST ALTERNATIVE IS PROVIDED BY PANELS OF HUMAN EXPERTS. THE ABOVE PREDICTION EXERCISES CONSIDERED SAMPLES OF GENERAL CHEMICALS, THUS WE SPECIFICALLY ADDRESSED IN THIS PAPER THE ISSUE OF PHARMACEUTICAL DRUGS. WE APPLIED OUR EXPERT KNOWLEDGE TO A DATABASE OF DRUGS WHOSE CARCINOGENICITY/NONCARCINOGENICITY STATUS WAS KNOWN. WHEREAS MOST OF THE NONCARCINOGENS WERE CORRECTLY IDENTIFIED, OUR PREDICTION OF CARCINOGENS WAS LESS SUCCESSFUL THAN WITH THE GENERAL CHEMICALS. SEVERAL CARCINOGENIC DRUGS DID NOT SHOW RECOGNIZED STRUCTURAL ALERTS, AND SUPPOSEDLY ACTED BY EPIGENETIC MECHANISMS. WHEREAS THE CONTRIBUTION OF HUMAN EXPERTS IS HIGHLY VALUABLE IN THIS PHASE (E.G. PRIORITY SETTING), MORE WORK IS NECESSARY ON: A) EPIGENETIC CARCINOGENS; B) EFFICIENT COMPUTERIZED MODELS. 2003 8 266 50 ADVERSE OUTCOME PATHWAYS FOR IONIZING RADIATION AND BREAST CANCER INVOLVE DIRECT AND INDIRECT DNA DAMAGE, OXIDATIVE STRESS, INFLAMMATION, GENOMIC INSTABILITY, AND INTERACTION WITH HORMONAL REGULATION OF THE BREAST. KNOWLEDGE ABOUT ESTABLISHED BREAST CARCINOGENS CAN SUPPORT IMPROVED AND MODERNIZED TOXICOLOGICAL TESTING METHODS BY IDENTIFYING KEY MECHANISTIC EVENTS. IONIZING RADIATION (IR) INCREASES THE RISK OF BREAST CANCER, ESPECIALLY FOR WOMEN AND FOR EXPOSURE AT YOUNGER AGES, AND EVIDENCE OVERALL SUPPORTS A LINEAR DOSE-RESPONSE RELATIONSHIP. WE USED THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK TO OUTLINE AND EVALUATE THE EVIDENCE LINKING IONIZING RADIATION WITH BREAST CANCER FROM MOLECULAR INITIATING EVENTS TO THE ADVERSE OUTCOME THROUGH INTERMEDIATE KEY EVENTS, CREATING A QUALITATIVE AOP. WE IDENTIFIED KEY EVENTS BASED ON REVIEW ARTICLES, SEARCHED PUBMED FOR RECENT LITERATURE ON KEY EVENTS AND IR, AND IDENTIFIED ADDITIONAL PAPERS USING REFERENCES. WE MANUALLY CURATED PUBLICATIONS AND EVALUATED DATA QUALITY. IONIZING RADIATION DIRECTLY AND INDIRECTLY CAUSES DNA DAMAGE AND INCREASES PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES (RONS). RONS LEAD TO DNA DAMAGE AND EPIGENETIC CHANGES LEADING TO MUTATIONS AND GENOMIC INSTABILITY (GI). PROLIFERATION AMPLIFIES THE EFFECTS OF DNA DAMAGE AND MUTATIONS LEADING TO THE AO OF BREAST CANCER. SEPARATELY, RONS AND DNA DAMAGE ALSO INCREASE INFLAMMATION. INFLAMMATION CONTRIBUTES TO DIRECT AND INDIRECT EFFECTS (EFFECTS IN CELLS NOT DIRECTLY REACHED BY IR) VIA POSITIVE FEEDBACK TO RONS AND DNA DAMAGE, AND SEPARATELY INCREASES PROLIFERATION AND BREAST CANCER THROUGH PRO-CARCINOGENIC EFFECTS ON CELLS AND TISSUE. FOR EXAMPLE, GENE EXPRESSION CHANGES ALTER INFLAMMATORY MEDIATORS, RESULTING IN IMPROVED SURVIVAL AND GROWTH OF CANCER CELLS AND A MORE HOSPITABLE TISSUE ENVIRONMENT. ALL OF THESE EVENTS OVERLAP AT MULTIPLE POINTS WITH EVENTS CHARACTERISTIC OF "BACKGROUND" INDUCTION OF BREAST CARCINOGENESIS, INCLUDING HORMONE-RESPONSIVE PROLIFERATION, OXIDATIVE ACTIVITY, AND DNA DAMAGE. THESE OVERLAPS MAKE THE BREAST PARTICULARLY SUSCEPTIBLE TO IONIZING RADIATION AND REINFORCE THAT THESE BIOLOGICAL ACTIVITIES ARE IMPORTANT CHARACTERISTICS OF CARCINOGENS. AGENTS THAT INCREASE THESE BIOLOGICAL PROCESSES SHOULD BE CONSIDERED POTENTIAL BREAST CARCINOGENS, AND PREDICTIVE METHODS ARE NEEDED TO IDENTIFY CHEMICALS THAT INCREASE THESE PROCESSES. TECHNIQUES ARE AVAILABLE TO MEASURE RONS, DNA DAMAGE AND MUTATION, CELL PROLIFERATION, AND SOME INFLAMMATORY PROTEINS OR PROCESSES. IMPROVED ASSAYS ARE NEEDED TO MEASURE GI AND CHRONIC INFLAMMATION, AS WELL AS THE INTERACTION WITH HORMONALLY DRIVEN DEVELOPMENT AND PROLIFERATION. SEVERAL METHODS MEASURE DIVERSE EPIGENETIC CHANGES, BUT IT IS NOT CLEAR WHICH CHANGES ARE RELEVANT TO BREAST CANCER. IN ADDITION, MOST TOXICOLOGICAL ASSAYS ARE NOT CONDUCTED IN MAMMARY TISSUE, AND SO IT IS A PRIORITY TO EVALUATE IF RESULTS FROM OTHER TISSUES ARE GENERALIZABLE TO BREAST, OR TO CONDUCT ASSAYS IN BREAST TISSUE. DEVELOPING AND APPLYING THESE ASSAYS TO IDENTIFY EXPOSURES OF CONCERN WILL FACILITATE EFFORTS TO REDUCE SUBSEQUENT BREAST CANCER RISK. 2020 9 389 27 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 10 4719 27 NONCODING RNA AND EPIGENETIC GENE REGULATION IN RENAL DISEASES. KIDNEYS HAVE A MAJOR ROLE IN NORMAL PHYSIOLOGY AND METABOLIC HOMEOSTASIS. LOSS OR IMPAIRMENT OF KIDNEY FUNCTION IS A COMMON OCCURRENCE IN SEVERAL METABOLIC DISORDERS, INCLUDING HYPERTENSION AND DIABETES. CHRONIC KIDNEY DISEASE (CKD) AFFECT NEARLY 10% OF THE POPULATION WORLDWIDE; RANKS 18TH IN THE LIST OF CAUSES OF DEATH; AND CONTRIBUTES TO A SIGNIFICANT PROPORTION OF HEALTHCARE COSTS. THE TISSUE REPAIR AND REGENERATIVE POTENTIAL OF KIDNEYS ARE LIMITED AND THEY DECLINE DURING AGING. RECENT STUDIES HAVE DEMONSTRATED A KEY ROLE FOR EPIGENETIC PROCESSES AND PLAYERS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NONCODING (NC)RNA, AND SO ON, IN BOTH KIDNEY DEVELOPMENT AND DISEASE. IN THIS REVIEW, WE HIGHLIGHT THESE RECENT FINDINGS WITH AN EMPHASIS ON ABERRANT EPIGENETIC CHANGES THAT ACCOMPANY RENAL DISEASES, KEY TARGETS, AND THEIR THERAPEUTIC VALUE. 2017 11 5281 30 PROMOTION AND SELECTION BY SERUM GROWTH FACTORS DRIVE FIELD CANCERIZATION, WHICH IS ANTICIPATED IN VIVO BY TYPE 2 DIABETES AND OBESITY. INDIVIDUALS SUFFERING FROM TYPE 2 DIABETES OR OBESITY EXHIBIT A SIGNIFICANT INCREASE IN THE INCIDENCE OF VARIOUS TYPES OF CANCER. IT IS GENERALLY ACCEPTED THAT THOSE CONDITIONS ARISE FROM OVERNUTRITION AND A SEDENTARY LIFESTYLE, WHICH LEAD TO INSULIN RESISTANCE CHARACTERIZED BY OVERPRODUCTION OF INSULIN ACTING AS A GROWTH FACTOR. THERE IS A CONSENSUS BASED LARGELY ON EPIDEMIOLOGICAL DATA THAT CHRONIC OVERPRODUCTION OF INSULIN IS RESPONSIBLE FOR THE INCREASED INCIDENCE OF CANCER. A MODEL SYSTEM IN CULTURE OF NIH 3T3 CELLS INDUCES THE COLLECTIVE EFFECTS OF SERUM GROWTH FACTORS ON PROGRESSION THROUGH THE STAGES OF FIELD CANCERIZATION. IT SHOWS THAT THE DRIVING FORCE OF PROGRESSION IS PROMOTION OF CELL GROWTH UNDER SELECTION AT HIGH CELL DENSITY, WITH NO REQUIREMENT FOR EXOGENOUS CARCINOGENIC AGENTS. THE EARLY EFFECT IS GRADUAL SELECTION AMONG MANY PREEXISTING, LOW-PENETRANCE PRENEOPLASTIC MUTATIONS OR STABLE EPIGENETIC VARIANTS, FOLLOWED BY SPORADIC, HIGH-PENETRANCE TRANSFORMING VARIANTS, ALL DEPENDENT ON ENDOGENOUS PROCESSES. THE SIGNIFICANCE OF THE RESULTS FOR CANCER IN DIABETIC AND OBESE INDIVIDUALS IS THAT THE INITIAL STAGES OF THE PROCESS INVOLVE MULTIORGAN METABOLIC INTERACTIONS THAT PRODUCE A SYSTEMIC INSULIN RESISTANCE WITH CHRONIC OVERPRODUCTION OF INSULIN AND LOCALIZED FIELD CANCERIZATION. HYPOMAGNESEMIA IS PREVALENT IN THE FOREGOING METABALO/SYSTEMIC DISORDERS, AND MAY ALSO PROVIDE A SELECTIVE MICROENVIRONMENT FOR TUMOR DEVELOPMENT. 2013 12 1326 24 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES. 2012 13 45 28 A COMPREHENSIVE REVIEW ON RNA INTERFERENCE-MEDIATED TARGETING OF INTERLEUKINS AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN COLON CANCER. COLON CANCER IS THE WORLD'S FOURTH LEADING CAUSE OF DEATH. IT IS CANCER OF THE LATTER PART OF THE LARGE INTESTINE, I.E. THE COLON. CHRONIC INFLAMMATION OVER A LONG PERIOD ALSO LEADS TO THE DEVELOPMENT OF CANCER. CANCER IN THE COLON REGION IS ARDUOUS TO DIAGNOSE AND IS DETECTED AT A LATER STAGE WHEN IT METASTASIZES TO OTHER PARTS OF THE BODY LIKE THE LIVER, LUNGS, PERITONEUM, ETC. COLON CANCER IS A GREAT EXAMPLE OF SOLID TUMOURS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH CONVENTIONAL THERAPIES ARE EFFECTIVE, THEY LOSE THEIR EFFECTIVENESS BEYOND A CERTAIN POINT. RELAPSE OF THE DISEASE OCCURS FREQUENTLY. RNA INTERFERENCE (RNAI) IS EMERGING AS A GREAT TOOL TO SPECIFICALLY ATTACK THE CANCER CELLS OF A TARGET SITE LIKE THE COLON. RNAI DEALS WITH EPIGENETIC CHANGES MADE IN THE DEFECTIVE CELLS WHICH ULTIMATELY LEADS TO THEIR DEATH WITHOUT HARMING THE HEALTHY CELLS. IN THIS REVIEW, TWO TYPES OF EPIGENETIC MODULATORS HAVE BEEN CONSIDERED, NAMELY SIRNA AND MIRNA, AND THEIR EFFECT ON INTERLEUKINS. INTERLEUKINS, A CLASS OF CYTOKINES, ARE MAJOR INFLAMMATORY RESPONSES OF THE BODY THAT ARE RELEASED BY IMMUNE CELLS LIKE LEUKOCYTES AND MACROPHAGES. SOME OF THESE INTERLEUKINS ARE PRO-INFLAMMATORY, THEREBY PROMOTING INFLAMMATION WHICH EVENTUALLY CAUSES CANCER. RNAI CAN PREVENT COLON CANCER BY INHIBITING PRO-INFLAMMATORY INTERLEUKINS. 2023 14 6296 41 THE PROSPECTS FOR A SIMPLIFIED AND INTERNATIONALLY HARMONIZED APPROACH TO THE DETECTION OF POSSIBLE HUMAN CARCINOGENS AND MUTAGENS. IT IS PROPOSED THAT THE MANY SETS OF REGULATORY GUIDELINES FOR THE ASSESSMENT OF CHEMICAL CARCINOGENICITY AND MUTAGENICITY SHOULD BE SIMPLIFIED AND HARMONIZED IN LIGHT OF CURRENT EXPERIMENTAL DATA. DATA ARE DISCUSSED WHICH ILLUSTRATE THAT AN ABSOLUTE DISTINCTION WOULD BE DRAWN BETWEEN ASSAYS CONDUCTED IN VITRO FROM THOSE IN VIVO, AND THAT THE GENOTOXICITY OF A CHEMICAL CAN BE ADEQUATELY DEFINED USING A COMBINATION OF THE SALMONELLA MUTATION ASSAY AND ONE FOR THE ASSESSMENT OF CHROMOSOME ABERRATIONS IN VITRO. IT IS SPECIFICALLY RECOMMENDED THAT ONCE A CHEMICAL HAS SHOWN A CLEAR POSITIVE RESPONSE IN VITRO, FURTHER SHORT-TERM ASSAYS SHOULD BE CONDUCTED IN VIVO; THIS AVOIDS CONSIDERING THE 'WEIGHT OF EVIDENCE' OF IN VITRO DATA, THE DANGERS OF WHICH ARE ILLUSTRATED. IT HAS NOW BEEN UNEQUIVOCALLY ESTABLISHED THAT NOT ALL IN VITRO GENOTOXINS PROVE CARCINOGENIC TO MAMMALS. IT IS THEREFORE RECOMMENDED THAT ALL NEW IN VITRO GENOTOXINS SHOULD BE ASSESSED IN VIVO USING THE MOUSE BONE MARROW MICRONUCLEUS ASSAY, AND IF A NEGATIVE RESPONSE IS OBSERVED, A LIVER GENOTOXICITY TEST. AT PRESENT AN ASSAY FOR THE INDUCTION OF UNSCHEDULED DNA SYNTHESIS (UDS) IN THE LIVER IS THE MOST WELL DEVELOPED FOR THIS PURPOSE. CURRENT DATA INDICATE THAT AN IN VITRO GENOTOXIN FOUND TO BE INACTIVE IN THESE TWO IN VIVO ASSAYS WILL BE NEITHER CARCINOGENIC NOR MUTAGENIC TO THE GERM CELLS OF MAMMALS. EQUALLY, GENOTOXICITY PRODUCED IN MAMMALS INDICATES A CARCINOGENIC AND MUTAGENIC POTENTIAL WHICH CAN USUALLY ONLY BE COUNTERED BY APPROPRIATE CHRONIC BIOASSAYS. THE USE OF SHORT-TERM IN VIVO ASSAYS IN THIS CRITICAL ROLE REQUIRES ATTENTION TO THE SELECTION OF APPROPRIATE DOSE-LEVELS AND ROUTES OF EXPOSURE - THESE ISSUES ARE DISCUSSED. THE ABOVE TESTING STRATEGY WILL NOT DETECT CERTAIN ANIMAL CARCINOGENS, SOME OF WHICH ARE SPECIFICALLY DISCUSSED. THESE CARCINOGENS HAVE BEEN VARIOUSLY REFERRED TO IN THE LITERATURE AS EPIGENETIC/NON-GENOTOXIC/HORMONAL/TOXIC/AMBIGUOUS OR AMBIVALENT CARCINOGENS. IT IS SUGGESTED THAT THEY PRESENT A MINOR POTENTIAL HAZARD TO MAN WHEN COMPARED WITH THAT OF GENOTOXIC CARCINOGENS AND THAT THEIR SHORT-TERM DETECTION CAN ONLY BE ACHIEVED BY THE DEVELOPMENT OF NEW WHOLE MAMMAL ASSAYS EMPLOYING NON-GENETIC ENDPOINTS. THIS IS IN CONTRAST TO THE PRESENT TENDENCY TO EMPLOY ADDITIONAL GENOTOXICITY ASSAYS FOR THEIR DETECTION IN THE UNJUSTIFIED BELIEF THAT THEY POSSESS AN EXQUISITE SPECIFICITY OF GENOTOXIC ACTION. THIS ARTICLE REPRESENTS A PERSONAL VIEW, BUT THE TESTING STRATEGY PROPOSED IS BASED TO A LARGE EXTENT ON THE ORIGINAL THREE-TIER APPROACH OF BRIDGES.(ABSTRACT TRUNCATED AT 400 WORDS) 1986 15 1824 26 EFFECTS OF ENVIRONMENTAL CONDITIONS ON NEPHRON NUMBER: MODELING MATERNAL DISEASE AND EPIGENETIC REGULATION IN RENAL DEVELOPMENT. A GROWING BODY OF EVIDENCE SUGGESTS THAT LOW NEPHRON NUMBERS AT BIRTH CAN INCREASE THE RISK OF CHRONIC KIDNEY DISEASE OR HYPERTENSION LATER IN LIFE. ENVIRONMENTAL STRESSORS, SUCH AS MATERNAL MALNUTRITION, MEDICATION AND SMOKING, CAN INFLUENCE RENAL SIZE AT BIRTH. USING METANEPHRIC ORGAN CULTURES TO MODEL SINGLE-VARIABLE ENVIRONMENTAL CONDITIONS, MODELS OF MATERNAL DISEASE WERE EVALUATED FOR PATTERNS OF DEVELOPMENTAL IMPAIRMENT. WHILE HYPERTHERMIA HAD LIMITED EFFECTS ON RENAL DEVELOPMENT, FETAL IRON DEFICIENCY WAS ASSOCIATED WITH SEVERE IMPAIRMENT OF RENAL GROWTH AND NEPHROGENESIS WITH AN ALL-PROXIMAL PHENOTYPE. CULTURING KIDNEY EXPLANTS UNDER HIGH GLUCOSE CONDITIONS LED TO CELLULAR AND TRANSCRIPTOMIC CHANGES RESEMBLING HUMAN DIABETIC NEPHROPATHY. SHORT-TERM HIGH GLUCOSE CULTURE CONDITIONS WERE SUFFICIENT FOR LONG-TERM ALTERATIONS IN DNA METHYLATION-ASSOCIATED EPIGENETIC MEMORY. FINALLY, THE ROLE OF EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT WAS TESTED USING A SMALL COMPOUND LIBRARY. AMONG THE SELECTED EPIGENETIC INHIBITORS, VARIOUS COMPOUNDS ELICITED AN EFFECT ON RENAL GROWTH, SUCH AS HDAC (ENTINOSTAT, TH39), HISTONE DEMETHYLASE (DEFERASIROX, DEFEROXAMINE) AND HISTONE METHYLTRANSFERASE (CYPROHEPTADINE) INHIBITORS. THUS, METANEPHRIC ORGAN CULTURES PROVIDE A VALUABLE SYSTEM FOR STUDYING METABOLIC CONDITIONS AND A TOOL FOR SCREENING FOR EPIGENETIC MODIFIERS IN RENAL DEVELOPMENT. 2021 16 1515 29 DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A GLOBAL EPIDEMIC, AND ITS MAJOR RISK FACTORS INCLUDE OBESITY AND TYPE 2 DIABETES. OBESITY NOT ONLY PROMOTES METABOLIC DYSREGULATION AND THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE BUT ALSO MAY INDEPENDENTLY LEAD TO CKD BY A VARIETY OF MECHANISMS, INCLUDING ENDOCRINE AND METABOLIC DYSFUNCTION, INFLAMMATION, OXIDATIVE STRESS, ALTERED RENAL HEMODYNAMICS, AND LIPOTOXICITY. DELETERIOUS RENAL EFFECTS OF OBESITY CAN ALSO BE TRANSMITTED FROM ONE GENERATION TO THE NEXT, AND IT IS INCREASINGLY RECOGNIZED THAT OFFSPRING OF OBESE MOTHERS ARE PREDISPOSED TO CKD. EPIGENETIC MODIFICATIONS ARE CHANGES THAT REGULATE GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. OF THESE, DNA METHYLATION IS THE MOST STUDIED. EPIGENETIC IMPRINTS, PARTICULARLY DNA METHYLATION, ARE LAID DOWN DURING CRITICAL PERIODS OF FETAL DEVELOPMENT, AND THEY MAY PROVIDE A MECHANISM BY WHICH MATERNAL-FETAL TRANSMISSION OF CHRONIC DISEASE OCCURS. OUR CURRENT REVIEW EXPLORES THE EVIDENCE FOR THE ROLE OF DNA METHYLATION IN THE DEVELOPMENT OF CKD, DIABETIC KIDNEY DISEASE, DIABETES, AND OBESITY. DNA METHYLATION HAS BEEN IMPLICATED IN RENAL FIBROSIS-THE FINAL PATHOPHYSIOLOGIC PATHWAY IN THE DEVELOPMENT OF END-STAGE KIDNEY DISEASE-WHICH SUPPORTS THE NOTION THAT DEMETHYLATING AGENTS MAY PLAY A POTENTIAL THERAPEUTIC ROLE IN PREVENTING DEVELOPMENT AND PROGRESSION OF CKD.-LARKIN, B. P., GLASTRAS, S. J., CHEN, H., POLLOCK, C. A., SAAD, S. DNA METHYLATION AND THE POTENTIAL ROLE OF DEMETHYLATING AGENTS IN PREVENTION OF PROGRESSIVE CHRONIC KIDNEY DISEASE. 2018 17 6308 33 THE REGULATION OF APOPTOSIS IN KIDNEY DEVELOPMENT: IMPLICATIONS FOR NEPHRON NUMBER AND PATTERN? APOPTOSIS IS ESSENTIAL TO REMODEL DEVELOPING STRUCTURES AND ELIMINATE SUPERFLUOUS CELLS IN A CONTROLLED MANNER DURING NORMAL DEVELOPMENT, AND CONTINUES TO BE AN IMPORTANT COMPONENT OF TISSUE REMODELING AND REGENERATION DURING AN ORGANISM'S LIFESPAN, OR AS A RESPONSE TO INJURY. THIS MINI REVIEW WILL DISCUSS RECENT STUDIES THAT HAVE PROVIDED INSIGHTS INTO THE ROLES OF APOPTOSIS IN THE DETERMINATION OF NEPHRON NUMBER AND PATTERN, DURING NORMAL AND ABNORMAL KIDNEY DEVELOPMENT. THE REGULATION OF CONGENITAL NEPHRON ENDOWMENT HAS IMPLICATIONS FOR RISK OF CHRONIC KIDNEY DISEASE IN LATER LIFE, WHEREAS ABNORMALITIES IN NEPHRON PATTERN ARE ASSOCIATED WITH CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (THE LEADING CAUSE OF RENAL DISEASE IN CHILDREN). TIGHT REGULATION OF APOPTOSIS IS REQUIRED IN NORMAL RENAL MORPHOGENESIS, ALTHOUGH MANY QUESTIONS REMAIN REGARDING THE REGULATION OF APOPTOSIS BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS, IN ADDITION TO THE FUNCTIONAL REQUIREMENT OF DIFFERENT COMPONENTS OF THE APOPTOTIC PATHWAY. 2014 18 1487 30 DNA DAMAGE AND EPIGENETIC CHANGES IN KIDNEY DISEASES - FOCUSED ON TRANSCRIPTION FACTORS IN PODOCYTES. RECENTLY IT HAS BEEN SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF CARIDIOVASCULAR AND METABOLIC DISEASES, INCLUDING DIABETES, OBESITY, ATHEROSCLEROSIS, HEART FAILURE, HYPERTENSION AND KIDNEY DISEASES. IN THESE CHRONIC DISEASES, VARIOUS EXOGENOUS AND ENDOGENOUS STRESSES CAUSE DNA DAMAGE, FOLLOWED BY DNA REPAIR PROCESS. ACCUMULATION OF DNA DAMAGES AND IMPAIRED REPAIR PROCESS CAN LEAD TO EPIGENETIC CHANGES, WHICH MAY CONTRIBUTE TO ONSET AND PROGRESSION OF DISEASES. RECENTLY WE HAVE SHOWN THAT THERAPEUTIC EFFECT OF TRANSCRIPTION FACTOR KLF4 (KRUPPEL-LIKE FACTOR 4) IN KIDNEY GLOMERULAR EPITHELIAL CELLS (PODOCYTES) ON PROTEINURIC KIDNEY DISEASES THROUGH EPIGENETIC MECHANISMS. OUR RESULT SUGGESTS THE POSSIBILITY OF TRANSCRIPTION FACTORS AS A TARGET OF SELECTIVE EPIGENETIC THERAPY. MOREOVER, WE HAVE REPORTED THAT RENIN-ANGIOTENSIN SYSTEM (RAS) BLOCKERS, WHICH ARE WIDELY PRESCRIBED FOR THE TREATMENT OF CARDIOVASCULAR DISEASES, CAN RESTORE EPIGENETIC CHANGES THROUGH KLF4 IN PART. THESE RESULTS SUGGEST THAT ACTIVATION OF RAS CAUSES EPIGENETIC CHANGES IN DISEASE STATES, AND ELUCIDATION OF THE PRECISE MECHANISM MAY LEAD TO ESTABLISHMENT OF NOVEL THERAPEUTIC TARGET OF KIDNEY DISEASES. IN THIS REVIEW WE FOCUS ON DNA DAMAGE REPAIR SYSTEM AND EPIGENETIC MODULATORS IN DISEASE STATES, AND SPECULATE A CANDIDATE FOR EPIGENETIC THERAPY OF KIDNEY DISEASES. 2016 19 5288 24 PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE. THERE IS GROWING EVIDENCE FOR A ROLE FOR EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN MOST CASES OFAUTOIMMUNE DISEASE THE PRECISE EPIGENETIC MECHANISM INVOLVED REMAINS TO BE RESOLVED, HOWEVER DNA HYPOMETHYLATION ACCOMPANIED BY HYPOACETYLATION OFHISTONE H3/H4 IS COMMONLY OBSERVED. DUE TO THE REVERSIBLE NATURE OF EPIGENETIC MARKS THEIR MAINTENANCE ENZYMES SUCH AS DNA METHYLTRANSFERASES (DNMTS), HISTONE DEACETYLASES (HDACS) AND HISTONE LYSINE METHYLTRANSFERASES (HKMT) ARE ATTRACTIVE DRUG TARGETS. SMALL MOLECULE INHIBITORS OF HISTONE MODIFICATION AND DNA METHYLATION MAINTENANCE ARE INCREASINGLY BECOMING AVAILABLE AND WILL BE USEFUL CHEMICAL BIOLOGICAL TOOLS TO DISSECT EPIGENETIC MECHANISMS IN THESE DISEASES. HOWEVER, ALTHOUGH EPIGENETIC THERAPIES USED IN CANCER TREATMENT ARE A PROMISING STARTING POINT FOR THE EXPLORATION OF AUTOIMMUNE DISEASE TREATMENT, THERE IS A REQUIREMENT FOR MORE SPECIFIC AND LESS TOXIC AGENTS FOR THESE CHRONIC DISEASES OR FOR USE AS CHEMOPREVENTATIVE AGENTS. 2011 20 3826 38 INVESTIGATION OF EPIGENETICS IN KIDNEY CELL BIOLOGY. EPIGENETICS IS THE STUDY OF HERITABLE CHANGES IN DNA OR ITS ASSOCIATED PROTEINS EXCEPT MUTATIONS IN GENE SEQUENCE. EPIGENETIC REGULATION PLAYS FUNDAMENTAL ROLES IN THE PROCESSES OF KIDNEY CELL BIOLOGY THROUGH THE ACTION OF DNA METHYLATION, CHROMATIN MODIFICATIONS VIA EPIGENETIC REGULATORS AND INTERACTION VIA TRANSCRIPTION FACTORS, AND NONCODING RNA SPECIES. KIDNEY DISEASES, INCLUDING ACUTE KIDNEY INJURY, CHRONIC KIDNEY DISEASE, NEPHRITIC AND NEPHROTIC SYNDROMES, PYELONEPHRITIS AND POLYCYSTIC KIDNEY DISEASES ARE DRIVEN BY ABERRANT ACTIVITY IN NUMEROUS SIGNALING PATHWAYS IN EVEN INDIVIDUAL KIDNEY CELL. EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, NONCODING RNAS, AND PROTEIN POSTTRANSLATIONAL MODIFICATIONS, COULD DISRUPT ESSENTIAL PATHWAYS THAT PROTECT THE RENAL CELLS FROM UNCONTROLLED GROWTH, APOPTOSIS AND ESTABLISHMENT OF OTHER RENAL ASSOCIATED SYNDROMES, WHICH HAVE BEEN RECOGNIZED AS ONE OF THE CRITICAL MECHANISMS FOR REGULATING FUNCTIONAL CHANGES THAT DRIVE AND MAINTAIN THE KIDNEY DISEASE PHENOTYPE. IN THIS CHAPTER, WE BRIEFLY SUMMARIZE THE EPIGENETIC MECHANISMS IN KIDNEY CELL BIOLOGY AND EPIGENETIC BASIS OF KIDNEY DEVELOPMENT, AND INTRODUCE EPIGENETIC TECHNIQUES THAT CAN BE USED IN INVESTIGATING THE MOLECULAR MECHANISM OF KIDNEY CELL BIOLOGY AND KIDNEYS DISEASES, PRIMARILY FOCUSING ON THE INTEGRATION OF DNA METHYLATION AND CHROMATIN IMMUNOPRECIPITATION TECHNOLOGIES INTO KIDNEY DISEASE ASSOCIATED STUDIES. FUTURE STUDIES USING THESE EMERGING TECHNOLOGIES WILL ELUCIDATE HOW ALTERATIONS IN THE RENAL CELL EPIGENOME COOPERATE WITH GENETIC ABERRATIONS FOR KIDNEY DISEASE INITIATION AND PROGRESSION. INCORPORATING EPIGENOMIC TESTING INTO THE CLINICAL RESEARCH IS ESSENTIAL TO FUTURE STUDIES WITH EPIGENETICS BIOMARKERS AND PRECISION MEDICINE USING EMERGING EPIGENETIC THERAPIES. 2019