1 3356 183 HISTONE H3 LYSINE 27 ACETYLATION PROFILE UNDERGOES TWO GLOBAL SHIFTS IN UNDERNOURISHED CHILDREN AND SUGGESTS ALTERED ONE-CARBON METABOLISM. BACKGROUND: STUNTING IS A CONDITION IN WHICH A CHILD DOES NOT REACH THEIR FULL GROWTH POTENTIAL DUE TO CHRONIC UNDERNUTRITION. IT ARISES DURING THE FIRST 2 YEARS OF A CHILD'S LIFE AND IS ASSOCIATED WITH DEVELOPMENTAL DEFICIENCIES AND LIFE-LONG HEALTH PROBLEMS. CURRENT INTERVENTIONS PROVIDE SOME BENEFIT, BUT NEW APPROACHES TO PREVENTION AND TREATMENT GROUNDED IN A MOLECULAR UNDERSTANDING OF STUNTING ARE NEEDED. EPIGENETIC ANALYSES ARE CRITICAL AS THEY CAN PROVIDE INSIGHT INTO HOW SIGNALS FROM A POOR ENVIRONMENT LEAD TO CHANGES IN CELL FUNCTION. RESULTS: HERE WE PROFILED HISTONE H3 ACETYLATION ON LYSINE 27 (H3K27AC) IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF 18-WEEK-OLD (N = 14) AND 1-YEAR-OLD CHILDREN (N = 22) LIVING IN AN URBAN SLUM IN DHAKA, BANGLADESH. WE SHOW THAT 18-WEEK-OLD CHILDREN DESTINED TO BECOME STUNTED HAVE ELEVATED LEVELS OF H3K27AC OVERALL, FUNCTIONAL ANALYSIS OF WHICH INDICATES ACTIVATION OF THE IMMUNE SYSTEM AND STRESS RESPONSE PATHWAYS AS A PRIMARY RESPONSE TO A POOR ENVIRONMENT WITH HIGH PATHOGEN LOAD. CONVERSELY, OVERT STUNTING AT 1-YEAR-OF AGE IS ASSOCIATED WITH GLOBALLY REDUCED H3K27AC THAT IS INDICATIVE OF METABOLIC REWIRING AND DOWNREGULATION OF THE IMMUNE SYSTEM AND DNA REPAIR PATHWAYS THAT ARE LIKELY SECONDARY RESPONSES TO CHRONIC EXPOSURE TO A POOR ENVIRONMENT WITH LIMITED NUTRIENTS. AMONG PROCESSES ALTERED IN 1-YEAR-OLD CHILDREN, WE IDENTIFIED ONE-CARBON METABOLISM, THE SIGNIFICANCE OF WHICH IS SUPPORTED BY INTEGRATIVE ANALYSIS WITH RESULTS FROM HISTONE H3 TRIMETHYLATION ON LYSINE 4 (H3K4ME3). TOGETHER, THESE RESULTS SUGGEST ALTERED ONE-CARBON METABOLISM IN THIS POPULATION OF STUNTED CHILDREN. CONCLUSIONS: THE EPIGENOMES OF STUNTED CHILDREN UNDERGO TWO GLOBAL CHANGES IN H3K27AC WITHIN THEIR FIRST YEAR OF LIFE, WHICH ARE ASSOCIATED WITH PROBABLE INITIAL HYPERACTIVE IMMUNE RESPONSES FOLLOWED BY REDUCED METABOLIC CAPACITY. LIMITATION OF ONE-CARBON METABOLITES MAY PLAY A KEY ROLE IN THE DEVELOPMENT OF STUNTING. TRIAL REGISTRATION CLINICALTRIALS.GOV NCT01375647. REGISTERED 17 JUNE 2011, RETROSPECTIVELY REGISTERED, HTTPS://CLINICALTRIALS.GOV/CT2/SHOW/NCT01375647 . 2021 2 5894 45 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS. 2018 3 6720 35 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN. 2023 4 276 37 AGE-RELATED DIFFERENCES IN MONOCYTE DNA METHYLATION AND IMMUNE FUNCTION IN HEALTHY KENYAN ADULTS AND CHILDREN. BACKGROUND: AGE-RELATED CHANGES IN ADAPTIVE AND INNATE IMMUNE CELLS HAVE BEEN ASSOCIATED WITH A DECLINE IN EFFECTIVE IMMUNITY AND CHRONIC, LOW-GRADE INFLAMMATION. EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL CHANGES IN MONOCYTES OCCUR WITH AGING, THOUGH MOST STUDIES TO DATE HAVE FOCUSED ON DIFFERENCES BETWEEN YOUNG ADULTS AND THE ELDERLY IN POPULATIONS WITH EUROPEAN ANCESTRY; FEW DATA EXIST REGARDING CHANGES THAT OCCUR IN CIRCULATING MONOCYTES DURING THE FIRST FEW DECADES OF LIFE OR IN AFRICAN POPULATIONS. WE ANALYZED DNA METHYLATION PROFILES, CYTOKINE PRODUCTION, AND INFLAMMATORY GENE EXPRESSION PROFILES IN MONOCYTES FROM YOUNG ADULTS AND CHILDREN FROM WESTERN KENYA. RESULTS: WE IDENTIFIED SEVERAL HYPO- AND HYPER-METHYLATED CPG SITES IN MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN THAT REPLICATED FINDINGS IN THE CURRENT LITERATURE OF DIFFERENTIAL DNA METHYLATION IN MONOCYTES FROM ELDERLY PERSONS VS. YOUNG ADULTS ACROSS DIVERSE POPULATIONS. DIFFERENTIALLY METHYLATED CPG SITES WERE ALSO NOTED IN GENE REGIONS IMPORTANT TO INFLAMMATION AND INNATE IMMUNE RESPONSES. MONOCYTES FROM KENYAN YOUNG ADULTS VS. CHILDREN DISPLAYED INCREASED PRODUCTION OF IL-8, IL-10, AND IL-12P70 IN RESPONSE TO TLR4 AND TLR2/1 STIMULATION AS WELL AS DISTINCT INFLAMMATORY GENE EXPRESSION PROFILES. CONCLUSIONS: THESE FINDINGS COMPLEMENT PREVIOUS REPORTS OF AGE-RELATED METHYLATION CHANGES IN ISOLATED MONOCYTES AND PROVIDE NOVEL INSIGHTS INTO THE ROLE OF AGE-ASSOCIATED CHANGES IN INNATE IMMUNE FUNCTIONS. 2021 5 3290 35 HIGH CORTISOL IN 5-YEAR-OLD CHILDREN CAUSES LOSS OF DNA METHYLATION IN SINE RETROTRANSPOSONS: A POSSIBLE ROLE FOR ZNF263 IN STRESS-RELATED DISEASES. BACKGROUND: CHILDHOOD STRESS LEADS TO INCREASED RISK OF MANY ADULT DISEASES, SUCH AS MAJOR DEPRESSION AND CARDIOVASCULAR DISEASE. STUDIES SHOW THAT ADULTS WITH EXPERIENCED CHILDHOOD STRESS HAVE SPECIFIC EPIGENETIC CHANGES, BUT TO UNDERSTAND THE PATHWAYS THAT LEAD TO DISEASE, WE ALSO NEED TO STUDY THE EPIGENETIC LINK PROSPECTIVELY IN CHILDREN. RESULTS: HERE, WE STUDIED A HOMOGENOUS GROUP OF 48 5-YEAR-OLD CHILDREN. BY COMBINING HAIR CORTISOL MEASUREMENTS (A WELL-DOCUMENTED BIOMARKER FOR CHRONIC STRESS), WITH WHOLE-GENOME DNA-METHYLATION SEQUENCING, WE SHOW THAT HIGH CORTISOL ASSOCIATES WITH A GENOME-WIDE DECREASE IN DNA METHYLATION AND TARGETS SHORT INTERSPERSED NUCLEAR ELEMENTS (SINES; A TYPE OF RETROTRANSPOSON) AND GENES IMPORTANT FOR CALCIUM TRANSPORT: PHENOMENA COMMONLY AFFECTED IN STRESS-RELATED DISEASES AND IN BIOLOGICAL AGING. MORE IMPORTANTLY, WE IDENTIFY A ZINC-FINGER TRANSCRIPTION FACTOR, ZNF263, WHOSE BINDING SITES WHERE HIGHLY OVERREPRESENTED IN REGIONS EXPERIENCING METHYLATION LOSS. THIS TYPE OF ZINC-FINGER PROTEIN HAS PREVIOUSLY SHOWN TO BE INVOLVED IN THE DEFENSE AGAINST RETROTRANSPOSONS. CONCLUSIONS: OUR RESULTS SHOW THAT STRESS IN PRESCHOOL CHILDREN LEADS TO CHANGES IN DNA METHYLATION SIMILAR TO THOSE SEEN IN BIOLOGICAL AGING. WE SUGGEST THAT THIS MAY AFFECT FUTURE DISEASE SUSCEPTIBILITY BY ALTERATIONS IN THE EPIGENETIC MECHANISMS THAT KEEP RETROTRANSPOSONS DORMANT. FUTURE TREATMENTS FOR STRESS- AND AGE-RELATED DISEASES MAY THEREFORE SEEK TO TARGET ZINC-FINGER PROTEINS THAT EPIGENETICALLY CONTROL RETROTRANSPOSON REACTIVATION, SUCH AS ZNF263. 2015 6 1567 41 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 7 1503 39 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION. 2009 8 3652 41 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION. 2021 9 2507 34 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH. 2010 10 5398 36 REDUCED MOUSE ALLERGEN IS ASSOCIATED WITH EPIGENETIC CHANGES IN REGULATORY GENES, BUT NOT MOUSE SENSITIZATION, IN ASTHMATIC CHILDREN. CHRONIC EXPOSURE TO MOUSE ALLERGEN MAY CONTRIBUTE GREATLY TO THE INNER-CITY ASTHMA BURDEN. WE HYPOTHESIZED THAT REDUCING MOUSE ALLERGEN EXPOSURE MAY MODULATE THE IMMUNOPATHOLOGY UNDERLYING SYMPTOMATIC PEDIATRIC ALLERGIC ASTHMA, AND THAT THIS OCCURS THROUGH EPIGENETIC REGULATION. TO TEST THIS HYPOTHESIS, WE STUDIED A COHORT OF MOUSE SENSITIZED, PERSISTENT ASTHMATIC INNER-CITY CHILDREN UNDERGOING MOUSE ALLERGEN-TARGETED INTEGRATED PEST MANAGEMENT (IPM) VS EDUCATION IN A RANDOMIZED CONTROLLED INTERVENTION TRIAL. WE FOUND THAT DECREASING MOUSE ALLERGEN EXPOSURE, BUT NOT COCKROACH, WAS ASSOCIATED WITH REDUCED FOXP3 BUCCAL DNA PROMOTER METHYLATION, BUT THIS WAS UNRELATED TO MOUSE SPECIFIC IGE PRODUCTION. THIS FINDING SUGGESTS THAT THE ENVIRONMENTAL EPIGENETIC REGULATION OF AN IMMUNOMODULATORY GENE MAY OCCUR FOLLOWING CHANGING ALLERGEN EXPOSURES IN SOME HIGHLY EXPOSED COHORTS. GIVEN THE CLINICAL AND PUBLIC HEALTH IMPORTANCE OF INNER-CITY PEDIATRIC ASTHMA AND THE POTENTIAL IMPACT OF ENVIRONMENTAL INTERVENTIONS, FURTHER STUDIES WILL BE NEEDED TO CORROBORATE CHANGES IN EPIGENETIC REGULATION FOLLOWING CHANGING EXPOSURES OVER TIME, AND DETERMINE THEIR IMPACT ON ASTHMA MORBIDITY IN SUSCEPTIBLE CHILDREN. 2017 11 887 32 CHRONIC CORTISOL EXPOSURE IN EARLY DEVELOPMENT LEADS TO NEUROENDOCRINE DYSREGULATION IN ADULTHOOD. OBJECTIVE: CHRONIC EARLY LIFE STRESS CAN AFFECT DEVELOPMENT OF THE NEUROENDOCRINE STRESS SYSTEM, LEADING TO ITS PERSISTENT DYSREGULATION AND CONSEQUENTLY INCREASED DISEASE RISK IN ADULTHOOD. ONE CONTRIBUTING FACTOR IS THOUGHT TO BE EPIGENETIC PROGRAMMING IN RESPONSE TO CHRONIC CORTISOL EXPOSURE DURING EARLY DEVELOPMENT. WE HAVE PREVIOUSLY SHOWN THAT ZEBRAFISH EMBRYOS TREATED CHRONICALLY WITH CORTISOL DEVELOP INTO ADULTS WITH CONSTITUTIVELY ELEVATED WHOLE-BODY CORTISOL AND ABERRANT IMMUNE GENE EXPRESSION. HERE WE FURTHER CHARACTERIZE THAT PHENOTYPE BY ASSESSING PERSISTENT EFFECTS OF THE TREATMENT ON CORTISOL TISSUE DISTRIBUTION AND DYNAMICS, CHROMATIN ACCESSIBILITY, AND ACTIVITIES OF GLUCOCORTICOID-RESPONSIVE REGULATORY GENES KLF9 AND FKBP5. TO THAT END CORTISOL LEVELS IN DIFFERENT TISSUES OF FED AND FASTED ADULTS WERE MEASURED USING ELISA, OPEN CHROMATIN IN ADULT BLOOD CELLS WAS MAPPED USING ATAC-SEQ, AND GENE ACTIVITY IN ADULT BLOOD AND BRAIN CELLS WAS MEASURED USING QRT-PCR. RESULTS: ADULTS DERIVED FROM CORTISOL-TREATED EMBRYOS HAVE ELEVATED WHOLE-BODY CORTISOL WITH ABERRANTLY REGULATED TISSUE DISTRIBUTION AND DYNAMICS THAT CORRELATE WITH DIFFERENTIAL ACTIVITY OF KLF9 AND FKBP5 IN BLOOD AND BRAIN. 2020 12 3914 42 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK. 2015 13 1408 49 DIETARY INTAKE IS ASSOCIATED WITH RESPIRATORY HEALTH OUTCOMES AND DNA METHYLATION IN CHILDREN WITH ASTHMA. BACKGROUND: ASTHMA IS AN INCREASINGLY COMMON CHRONIC DISEASE AMONG CHILDREN, AND DATA POINT TOWARD A COMPLEX MECHANISM INVOLVING GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. EPIGENETIC MODIFICATIONS SUCH AS DNA HYPO- OR HYPER-METHYLATION HAVE BEEN SHOWN TO OCCUR IN RESPONSE TO ENVIRONMENTAL EXPOSURES INCLUDING DIETARY NUTRIENTS. METHODS: WITHIN THE CONTEXT OF THE ASTHMA RANDOMIZED TRIAL OF INDOOR WOOD SMOKE (ARTIS) STUDY, WE INVESTIGATED RELATIONSHIPS BETWEEN DIET, ASTHMA HEALTH MEASURES, AND DNA METHYLATION. ASTHMA HEALTH MEASURES INCLUDED A QUALITY OF LIFE INSTRUMENT, DIURNAL PEAK FLOW VARIABILITY (DPFV) AND FORCED EXPIRATORY VOLUME IN THE FIRST SECOND (FEV(1)). DIETARY INTAKE WAS ASSESSED WITH A FOOD FREQUENCY QUESTIONNAIRE. METHYLATION LEVELS OF LINE-1 REPETITIVE ELEMENT AND TWO PROMOTER CPG SITES FOR INTERFERON GAMMA (IFNGAMMA, -186 AND -54) FROM BUCCAL CELL DNA WERE MEASURED USING PYROSEQUENCING ASSAYS. RESULTS: DATA WERE COLLECTED ON 32 CHILDREN WITH ASTHMA LIVING IN WESTERN MONTANA WHO WERE RECRUITED TO THE ARTIS STUDY. SELENIUM AND SEVERAL METHYL DONOR DIETARY NUTRIENTS WERE POSITIVELY ASSOCIATED WITH THE ASTHMA QUALITY OF LIFE MEASURE. INTAKE OF METHYL DONATING NUTRIENTS INCLUDING FOLATE WAS POSITIVELY ASSOCIATED LINE-1 METHYLATION AND NEGATIVELY ASSOCIATED WITH IFNGAMMA CPG-186. HIGHER LEVELS OF LINE-1 METHYLATION WERE ASSOCIATED WITH GREATER DPFV. CONCLUSION: WE IDENTIFIED SEVERAL NUTRIENTS THAT WERE ASSOCIATED WITH IMPROVED QUALITY OF LIFE MEASURES AMONG CHILDREN WITH ASTHMA. THE IFNGAMMA PROMOTER CPG SITE -186 BUT NOT -54 WAS ASSOCIATED WITH THE INTAKE OF SELECTED DIETARY NUTRIENTS. HOWEVER, IN THIS SMALL POPULATION OF CHILDREN WITH ASTHMA, THE IFNGAMMA PROMOTER CPG SITES WERE NOT ASSOCIATED WITH RESPIRATORY HEALTH MEASURES SO IT REMAINS UNCLEAR THROUGH WHICH EPIGENETIC MECHANISM THESE NUTRIENTS ARE IMPACTING THE QUALITY OF LIFE MEASURE. THESE FINDINGS ADD TO THE EVIDENCE THAT DIETARY NUTRIENTS, PARTICULARLY FOODS CONTAINING METHYL DONORS, MAY BE IMPORTANT FOR EPIGENETIC REGULATION AS IT PERTAINS TO THE CONTROL OF ASTHMA. TRIAL REGISTRATION CLINCIALTRIALS.GOV NCT00807183. REGISTERED 10 DECEMBER 2008. 2017 14 5737 42 SMOKING AND HEALTH: ASSOCIATION BETWEEN TELOMERE LENGTH AND FACTORS IMPACTING ON HUMAN DISEASE, QUALITY OF LIFE AND LIFE SPAN IN A LARGE POPULATION-BASED COHORT UNDER THE EFFECT OF SMOKING DURATION. REACTIVE OXYGEN SPECIES (ROS) ARE OF PRIMARY IMPORTANCE AS THEY CAUSE DAMAGE TO LIPIDS, PROTEINS, AND DNA EITHER ENDOGENOUSLY BY CELLULAR MECHANISM, OR THROUGH EXOGENOUS EXPOSURE TO ENVIRONMENTAL INJURY FACTORS, INCLUDING OXIDATION INSULT FACTORS, SUCH AS TOBACCO SMOKE. CURRENTLY 46.3 MILLION ADULTS (25.7 PERCENT OF THE POPULATION) ARE SMOKERS. THIS INCLUDES 24 MILLION MEN (28.1 PERCENT OF THE TOTAL) AND MORE THAN 22 MILLION WOMEN (23.5 PERCENT). THE PREVALENCE IS HIGHEST AMONG PERSONS 25-44 YEARS OF AGE. CIGARETTE SMOKERS HAVE A HIGHER RISK OF DEVELOPING SEVERAL CHRONIC DISORDERS. THESE INCLUDE FATTY BUILDUPS IN ARTERIES, SEVERAL TYPES OF CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (LUNG PROBLEMS). AS PERIPHERAL LEUKOCYTES HAVE BEEN THE MAIN TARGET OF HUMAN TELOMERE RESEARCH, MOST OF WHAT IS KNOWN ABOUT HUMAN TELOMERE DYNAMICS IN VIVO IS BASED ON THESE CELLS. LEUKOCYTE TELOMERE LENGTH (TL) IS A COMPLEX TRAIT THAT IS SHAPED BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. IN THIS ARTICLE, WE CONSIDER THAT SMOKING MODIFIES LEUKOCYTE TL IN HUMANS AND CONTRIBUTES TO ITS VARIABILITY AMONG INDIVIDUALS, ALTHOUGH THE SMOKING EFFECT ON TL AND ITS RELATION WITH OTHER METABOLIC INDICES MAY ACCELERATE BIOLOGICAL AGING AND DEVELOPMENT OF SMOKING-INDUCED CHRONIC DISEASES IN A LARGE HUMAN POPULATION-BASED COHORTS WITH SMOKING BEHAVIOR. RECENT STUDIES CONFIRMED THAT INDIVIDUALS WITH SHORTER TELOMERES PRESENT A HIGHER PREVALENCE OF ARTERIAL LESIONS AND HIGHER RISK OF CARDIOVASCULAR DISEASE MORTALITY. THIS STUDY ORIGINALLY SUGGESTS THAT EFFICIENT THERAPEUTIC PROTECTION OF TL AND STRUCTURE IN RESPONSE TO STRESSES THAT ARE KNOWN TO REDUCE TL, SUCH AS OXIDATIVE DAMAGE OR INFLAMMATION ASSOCIATED WITH TOBACCO SMOKING, WOULD LEAD TO BETTER TELOMERE MAINTENANCE. RECENTLY, WE HAVE DISCOVERED THE POTENTIAL USE OF TELOMERE-RESTORATIVE IMIDAZOLE-CONTAINING DIPEPTIDE (NON-HYDROLIZED CARNOSINE, CARCININE) BASED THERAPY FOR BETTER SURVIVAL OF SMOKERS. WE CONCLUDE THAT A BETTER THERAPEUTIC OR NUTRITIONAL MAINTENANCE OF TL MAY CONFER HEALTHY AGING IN SMOKERS AND EXCEPTIONAL LONGEVITY IN REGULARLY ROS-EXPOSED HUMAN SURVIVORS. 2011 15 6195 33 THE IMPACT OF RECENT ALCOHOL USE ON GENOME WIDE DNA METHYLATION SIGNATURES. CHRONIC ALCOHOL INTAKE IS ASSOCIATED WITH A WIDE VARIETY OF ADVERSE HEALTH OUTCOMES INCLUDING DEPRESSION, DIABETES, AND HEART DISEASE. UNFORTUNATELY, THE MOLECULAR MECHANISMS THROUGH WHICH THESE EFFECTS ARE CONVEYED ARE NOT CLEARLY UNDERSTOOD. TO EXAMINE THE POTENTIAL ROLE OF EPIGENETIC FACTORS IN THIS PROCESS, WE EXAMINED THE RELATIONSHIP OF RECENT ALCOHOL INTAKE TO GENOME WIDE METHYLATION PATTERNS USING THE ILLUMINA 450 METHYLATION BEAD CHIP AND LYMPHOBLAST DNA DERIVED FROM 165 FEMALE SUBJECTS PARTICIPATING IN THE IOWA ADOPTION STUDIES. WE FOUND THAT THE PATTERN OF ALCOHOL USE OVER THE 6-MONTHS IMMEDIATELY PRIOR TO PHLEBOTOMY WAS ASSOCIATED WITH, SEVERITY-DEPENDENT CHANGES IN THE DEGREE OF GENOME WIDE METHYLATION THAT PREFERENTIALLY HYPERMETHYLATE THE CENTRAL PORTION OF CPG ISLANDS WITH METHYLATION AT CG05600126, A PROBE IN ABR, AND THE 5' UNTRANSLATED REGION OF BLCAP ATTAINING GENOME WIDE SIGNIFICANCE IN TWO POINT AND SLIDING WINDOW ANALYSES OF PROBE METHYLATION DATA, RESPECTIVELY. WE CONCLUDE THAT RECENT ALCOHOL USE IS ASSOCIATED WITH WIDESPREAD CHANGES IN DNA METHYLATION IN WOMEN AND THAT FURTHER STUDY TO CONFIRM THESE FINDINGS AND DETERMINE THEIR RELATIONSHIP TO SOMATIC FUNCTION ARE IN ORDER. 2012 16 422 41 ANNEXIN-A1 DEFICIENCY ATTENUATES STRESS-INDUCED TUMOR GROWTH VIA FATTY ACID METABOLISM IN MICE: AN INTEGRATED MULTIPLE OMICS ANALYSIS ON THE STRESS- MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. BACKGROUND: HIGH EMOTIONAL OR PSYCHOPHYSICAL STRESS LEVELS HAVE BEEN CORRELATED WITH AN INCREASED RISK AND PROGRESSION OF VARIOUS DISEASES. HOW STRESS IMPACTS THE GUT MICROBIOTA TO INFLUENCE METABOLISM AND SUBSEQUENT CANCER PROGRESSION IS UNCLEAR. METHODS: FECES AND SERUM SAMPLES FROM BALB/C ANXA1(+/+) AND ANXA1(-/-) MICE WITH OR WITHOUT CHRONIC RESTRAINT STRESS WERE USED FOR 16S RRNA GENE SEQUENCING AND GC-MS METABOLOMICS ANALYSIS TO INVESTIGATE THE EFFECT OF STRESS ON MICROBIOME AND METABOLOMICS DURING STRESS AND BREAST TUMORIGENESIS. BREAST TUMORS SAMPLES FROM STRESSED AND NON-STRESSED MICE WERE USED TO PERFORM WHOLE-GENOME BISULFITE SEQUENCING (WGBS) AND RNASEQ ANALYSIS TO CONSTRUCT THE POTENTIAL NETWORK FROM CANDIDATE HUB GENES. FINALLY, MACHINE LEARNING AND INTEGRATED ANALYSIS WERE USED TO MAP THE AXIS FROM CHRONIC RESTRAINT STRESS TO BREAST CANCER DEVELOPMENT. RESULTS: WE REPORT THAT CHRONIC STRESS PROMOTES BREAST TUMOR GROWTH VIA A STRESS-MICROBIOME-METABOLITE-EPIGENETIC-ONCOLOGY (SMMEO) AXIS. CHRONIC RESTRAINT STRESS IN MICE ALTERS THE MICROBIOME COMPOSITION AND FATTY ACIDS METABOLISM AND INDUCES AN EPIGENETIC SIGNATURE IN TUMORS XENOGRAFTED AFTER STRESS. SUBSEQUENT MACHINE LEARNING AND SYSTEMIC MODELING ANALYSES IDENTIFIED A SIGNIFICANT CORRELATION AMONG MICROBIOME COMPOSITION, METABOLITES, AND DIFFERENTIALLY METHYLATED REGIONS IN STRESSED TUMORS. MOREOVER, SILENCING ANNEXIN-A1 INHIBITS THE CHANGES IN THE GUT MICROBIOME AND FATTY ACID METABOLISM AFTER STRESS AS WELL AS BASAL AND STRESS-INDUCED TUMOR GROWTH. CONCLUSIONS: THESE DATA SUPPORT A PHYSIOLOGICAL AXIS LINKING THE MICROBIOME AND METABOLITES TO CANCER EPIGENETICS AND INFLAMMATION. THE IDENTIFICATION OF THIS AXIS COULD PROPEL THE NEXT PHASE OF EXPERIMENTAL DISCOVERY IN FURTHER UNDERSTANDING THE UNDERLYING MOLECULAR MECHANISM OF TUMORIGENESIS CAUSED BY PHYSIOLOGICAL STRESS. 2022 17 4093 31 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 18 2483 28 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 19 5638 41 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS. 2013 20 2901 35 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007