1 6914 130 [VITAMIN D DEFICIENCY IN PREGNANCY AND ITS IMPACT ON THE FETUS, THE NEWBORN AND IN CHILDHOOD]. OBJECTIVE: VITAMIN D DEFICIENCY (VDD) IN PREGNANT WOMEN AND THEIR CHILDREN IS AN IMPORTANT HEALTH PROBLEM WITH SEVERE CONSEQUENCES FOR THE HEALTH OF BOTH. THUS, THE OBJECTIVES OF THIS REVIEW WERE TO REASSESS THE MAGNITUDE AND CONSEQUENCES OF VDD DURING PREGNANCY, LACTATION AND INFANCY, ASSOCIATED RISK FACTORS, PREVENTION METHODS, AND TO EXPLORE EPIGENETIC MECHANISMS IN EARLY FETAL LIFE CAPABLE OF EXPLAINING MANY OF THE NON-SKELETAL BENEFITS OF VITAMIN D (VID). DATA SOURCE: ORIGINAL AND REVIEW ARTICLES, AND CONSENSUS DOCUMENTS WITH ELEVATED LEVEL OF EVIDENCE FOR VDD-RELATED CLINICAL DECISIONS ON THE HEALTH OF PREGNANT WOMEN AND THEIR CHILDREN, AS WELL AS ARTICLES ON THE INFLUENCE OF VID ON EPIGENETIC MECHANISMS OF FETAL PROGRAMMING OF CHRONIC DISEASES IN ADULTHOOD WERE SELECTED AMONG ARTICLES PUBLISHED ON PUBMED OVER THE LAST 20 YEARS, USING THE SEARCH TERM VITD STATUS, IN COMBINATION WITH PREGNANCY, OFFSPRING HEALTH, CHILD OUTCOMES, AND PROGRAMMING. DATA SYNTHESIS: THE FOLLOWING ITEMS WERE ANALYZED: VID PHYSIOLOGY AND METABOLISM, RISK FACTORS FOR VDD AND IMPLICATIONS IN PREGNANCY, LACTATION AND INFANCY, CONCENTRATION CUTOFF TO DEFINE VDD, THE VARIABILITY OF METHODS FOR VDD DETECTION, RECOMMENDATIONS ON VID REPLACEMENT IN PREGNANT WOMEN, THE NEWBORN AND THE CHILD, AND THE EPIGENETIC INFLUENCE OF VID. CONCLUSIONS: VDD IS A COMMON CONDITION AMONG HIGH-RISK PREGNANT WOMEN AND THEIR CHILDREN. THE ROUTINE MONITORING OF SERUM 25(OH)D3 LEVELS IN ANTENATAL PERIOD IS MANDATORY. EARLY PREVENTIVE MEASURES SHOULD BE TAKEN AT THE SLIGHTEST SUSPICION OF VDD IN PREGNANT WOMEN, TO REDUCE MORBIDITY DURING PREGNANCY AND LACTATION, AS WELL AS ITS SUBSEQUENT IMPACT ON THE FETUS, THE NEWBORN AND THE CHILD. 2015 2 6911 25 [TWO GERMAN BIRTH COHORTS: GINIPLUS AND LISAPLUS]. NUMEROUS CHRONIC DISEASES IN CHILDHOOD AND ADULTHOOD HAVE THEIR ORIGINS IN PERINATAL LIFE AND ARE POTENTIALLY INFLUENCED BY TRANS-GENERATIONAL EPIGENETIC PROCESSES. THEREFORE, PROSPECTIVE BIRTH COHORTS CAN SUBSTANTIALLY CONTRIBUTE TO OUR KNOWLEDGE ABOUT THE ETIOLOGY OF DISEASES INCLUDING MODIFIABLE RISK FACTORS. THE TWO POPULATION-BASED GERMAN BIRTH COHORTS GINIPLUS AND LISAPLUS AIM TO DESCRIBE THE NATURAL COURSE OF CHRONIC DISEASES AND INTERMEDIATE PHENOTYPES IN CHILDHOOD AND ITS DETERMINANTS, AND TO IDENTIFY POTENTIAL GENETIC EFFECT MODIFICATIONS. IN THE MID-1990S, 5,991 (GINIPLUS) AND 3,097 (LISAPLUS) HEALTHY, TERM NEWBORNS WERE RECRUITED FOR LONG-TERM FOLLOW-UP IN FOUR REGIONS OF GERMANY. THE FOLLOW-UP RATE FOR THE FIRST 10 YEARS WAS ABOUT 55%. WE ANALYZED THE GROWTH AND DEVELOPMENT OF OVERWEIGHT, INFECTIONS AND ALLERGIC DISEASES, MENTAL AND ORAL HEALTH, METABOLIC AND INFLAMMATORY PARAMETERS AND THE ROLE OF POTENTIAL RISK FACTORS INCLUDING GENETICS. THE RESULTS OF THESE TWO BIRTH COHORTS SUBSTANTIALLY CONTRIBUTE TO THE CURRENT KNOWLEDGE ABOUT THE NATURAL COURSE OF THESE HEALTH PARAMETERS. THESE DATA WERE INCLUDED IN MANY INTERNATIONAL PROJECTS AND CONSORTIA FOR PURPOSES OF INTERNATIONAL COMPARISONS OF PREVALENCE AND CONSISTENCY OF FINDINGS, AND TO INCREASE THE POWER OF THE ANALYSES. 2012 3 6490 28 TRACING SLOW PHENOPTOSIS TO THE PRENATAL STAGE IN SOCIAL VERTEBRATES. VLADIMIR SKULACHEV'S COINING OF THE TERM "PHENOPTOSIS" 25 YEARS AGO (SKULACHEV, V. P., BIOCHEMISTRY (MOSCOW), 62, 1997) HIGHLIGHTED THE THEORETICAL POSSIBILITY THAT AGING IS A PROGRAMMED PROCESS TO SPEED THE EXIT OF INDIVIDUALS POSING SOME DANGER TO THEIR SOCIAL GROUP. WHILE RAPID "ACUTE PHENOPTOSIS" MIGHT OCCUR AT ANY AGE (E.G., TO PREVENT SPREAD OF DEADLY INFECTIONS), "SLOW PHENOPTOSIS" IS GENERALLY CONSIDERED TO OCCUR LATER IN LIFE IN THE FORM OF CHRONIC AGE-RELATED DISORDERS. HOWEVER, RECENT RESEARCH INDICATES THAT RISKS FOR SUCH CHRONIC DISORDERS CAN BE GREATLY RAISED BY EARLY LIFE ADVERSITY, ESPECIALLY DURING THE PRENATAL STAGE. MUCH OF THIS RESEARCH USES INDICATORS OF BIOLOGICAL AGING, THE SPEEDING OR SLOWING OF NATURAL PHYSIOLOGICAL DETERIORATION IN RESPONSE TO ENVIRONMENTAL INPUTS, LEADING TO DIVERGENCE FROM CHRONOLOGICAL AGE. STUDIES USING BIOLOGICAL AGING INDICATORS COMMONLY FIND IT IS ACCELERATED NOT ONLY IN OLDER INDIVIDUALS WITH CHRONIC DISORDERS, BUT ALSO IN VERY YOUNG INDIVIDUALS WITH HEALTH PROBLEMS. THIS REVIEW WILL EXPLAIN HOW ACCELERATED BIOLOGICAL AGING EQUATES TO SLOW PHENOPTOSIS. ITS OCCURRENCE EVEN IN THE PRENATAL STAGE IS THEORETICALLY SUPPORTED BY W. D. HAMILTON'S PROPOSAL THAT OFFSPRINGS DETECTING THEY HAVE DANGEROUS MUTATIONS SHOULD THEN AUTOMATICALLY SPEED THEIR DEMISE, IN ORDER TO IMPROVE THEIR INCLUSIVE FITNESS BY GIVING THEIR PARENTS THE CHANCE TO PRODUCE OTHER FITTER SIBLINGS. 2022 4 227 20 ADAPTATION OF AN OUTBREAKING INSECT DEFOLIATOR TO CHRONIC NUTRITIONAL STRESS. DURING INSECT OUTBREAKS, THE HIGH NUMBER OF INDIVIDUALS FEEDING ON ITS HOST PLANT CAUSES A DEPLETION OF THE FOOD SOURCE. REDUCED AVAILABILITY AND DECREASED QUALITY OF NUTRIENTS NEGATIVELY INFLUENCE LIFE-HISTORY TRAITS OF INSECTS DRIVING THEM TO DEVELOP ADAPTIVE STRATEGIES TO PERSIST IN THE ENVIRONMENT. IN A LABORATORY EXPERIMENT WITH THREE REPETITIONS, WE TESTED THE EFFECT OF CHRONIC NUTRITIONAL STRESS ON SPRUCE BUDWORM PERFORMANCE DURING THREE GENERATIONS TO DETERMINE THE ADAPTIVE STRATEGIES EMPLOYED BY THE INSECT TO DEAL WITH A SELECTION PRESSURE PRODUCED BY LOW-QUALITY DIET. OUR RESULTS SHOW THAT ALL TESTED LIFE-HISTORY TRAITS (MORTALITY, DEVELOPMENTAL TIME, PUPAL MASS, GROWTH RATE AND FEMALE FECUNDITY) BUT FEMALE FERTILITY WERE NEGATIVELY INFLUENCED BY THE LOW-QUALITY DIET SIMULATING FOOD DEPLETION DURING OUTBREAK CONDITIONS. HOWEVER, ESPECIALLY FEMALES IN THE THIRD GENERATION UNDER CHRONIC NUTRITIONAL STRESS SHOW AN ADAPTIVE RESPONSE IN LIFE-HISTORY TRAITS WHEN COMPARED TO THOSE REARED ONLY ONE GENERATION ON LOW-QUALITY DIET. LARVAL DEVELOPMENTAL TIME SIGNIFICANTLY DECREASED AND PUPAL MASS, GROWTH RATE AND FECUNDITY SIGNIFICANTLY INCREASED. THE STUDY DEMONSTRATES THE CAPACITY OF SPRUCE BUDWORM TO REACT TO CHRONIC NUTRITIONAL STRESS WITH ADAPTATIONS THAT MAY BE CAUSED BY EPIGENETIC PARENTAL EFFECTS. THIS INFORMATION CAN HELP TO UNDERSTAND THE COURSE OF AN OUTBREAK ESPECIALLY AT PEAK DENSITIES AND DURING THE COLLAPSE. 2015 5 645 22 BIRTH DEFECTS IN GAZA: PREVALENCE, TYPES, FAMILIARITY AND CORRELATION WITH ENVIRONMENTAL FACTORS. THIS IS THE FIRST REPORT OF REGISTRATION AT BIRTH, AND OF INCIDENCE OF MAJOR STRUCTURAL BIRTH DEFECTS (BD) OBTAINED IN GAZA AT AL SHIFA HOSPITAL, WHERE 28% OF TOTAL BIRTHS IN GAZA STRIP OCCUR. DOCTORS REGISTERED 4,027 DELIVERIES, WITH A PROTOCOL COMPREHENSIVE OF CLINICAL, DEMOGRAPHIC, KIN AND ENVIRONMENTAL QUESTIONS. PREVALENCE OF BD IS 14/1,000, WITHOUT ASSOCIATION WITH INTERMARRIAGE OR GENDER OF THE CHILD. PREVALENCE OF LATE MISCARRIAGES AND STILL BIRTHS ARE RESPECTIVELY 23.3/1,000 AND 7.4/1,000, AND OF PREMATURE BIRTHS 19.6/1,000. COUPLES WITH A BD CHILD HAVE ABOUT 10 TIMES HIGHER FREQUENCY OF RECURRENCE OF A BD IN THEIR PROGENY THAN THOSE WITH NORMAL CHILDREN, BUT NONE OF THEIR 694 SIBLINGS AND ONLY 10/1,000 OF THEIR 1,423 PROGENY HAD BD, SIMILAR TO THE FREQUENCY IN GENERAL POPULATION. THESE DATA SUGGEST OCCURRENCE OF NOVEL GENETIC AND EPIGENETIC EVENTS IN DETERMINATION OF BD. CHILDREN WITH BD WERE BORN WITH HIGHER FREQUENCY (P < 0 001) IN FAMILIES WHERE ONE OR BOTH PARENTS WERE UNDER "WHITE PHOSPHORUS" ATTACK, THAT IN THE GENERAL POPULATION. BOMBING OF THE FAMILY HOME AND REMOVAL OF THE RUBBLE WERE ALSO FREQUENTLY REPORTED BY COUPLES WITH BD OCCURRENCE. THESE DATA SUGGESTS A CAUSATIVE/FAVORING ROLE OF ACUTE EXPOSURE OF PARENTS TO THE WEAPONS-ASSOCIATED CONTAMINANTS, AND/OR OF THEIR CHRONIC EXPOSURE FROM THEIR PERSISTENCE IN THE ENVIRONMENT ON THE EMBRYONIC DEVELOPMENT OF THEIR CHILDREN. 2012 6 4834 29 ON THE INTERPLAY BETWEEN THE MEDICINE OF HILDEGARD OF BINGEN AND MODERN MEDICINE: THE ROLE OF ESTROGEN RECEPTOR AS AN EXAMPLE OF BIODYNAMIC INTERFACE FOR STUDYING THE CHRONIC DISEASE'S COMPLEXITY. INTRODUCTION: HILDEGARD OF BINGEN (1098-1179) INTERPRETED THE ORIGINS OF CHRONIC DISEASE HIGHLIGHTING AND ANTICIPATING, ALTHOUGH ONLY IN A LIMITED FASHION, THE IMPORTANCE THAT COMPLEX INTERACTIONS AMONG NUMEROUS GENETIC, INTERNAL MILIEU AND EXTERNAL ENVIRONMENTAL FACTORS HAVE IN DETERMINING THE DISEASE PHENOTYPE. TODAY, WE RECOGNIZE THOSE FACTORS, CAPABLE OF MEDIATING THE TRANSMISSION OF MESSAGES BETWEEN HUMAN BODY AND ENVIRONMENT AND VICE VERSA, AS BIODYNAMIC INTERFACES. AIM: WE ANALYZED, IN THE LIGHT OF MODERN SCIENTIFIC EVIDENCE, HILDEGARD OF BINGEN'S MEDICAL APPROACH AND HER ORIGINAL HUMORAL THEORY IN ORDER TO IDENTIFY POSSIBLE INSIGHTS INCLUDED IN HER MEDICINE THAT COULD BE REFERRED TO IN THE CONTEXT OF MODERN EVIDENCE-BASED MEDICINE. IN PARTICULAR, THE ABBESS'S HUMORAL THEORY SUGGESTS THE IDENTIFICATION OF BIODYNAMIC INTERFACES WITH SEX HORMONES AND THEIR RECEPTORS. FINDINGS: WE FOUND THAT THE HILDEGARDIAN HOLISTIC VISION OF THE ORGANISM-ENVIRONMENT RELATIONSHIP CAN ACTUALLY REPRESENT A VISIONARY APPROACH TO MODERN ENDOCRINOLOGY AND THAT SEX HORMONES, IN PARTICULAR ESTROGENS, COULD REPRESENT AN EXAMPLE OF A BIODYNAMIC INTERFACE. ESTROGEN RECEPTORS ARE FOUND IN REGIONS OF THE BRAIN INVOLVED IN EMOTIONAL AND COGNITIVE REGULATION, CONTROLLING THE MOLECULAR MECHANISM OF BRAIN FUNCTION. ESTROGEN RECEPTORS ARE INVOLVED IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IN THE EPIGENETIC REGULATION OF RESPONSES TO PHYSIOLOGICAL, SOCIAL, AND HORMONAL STIMULI. FURTHERMORE, ESTROGEN AFFECTS GENE METHYLATION ON ITS OWN AND RELATED RECEPTOR PROMOTERS IN DISCRETE REGIONS OF THE DEVELOPING BRAIN. THIS SCENARIO WAS STRIKINGLY PERCEIVED BY THE ABBESS IN THE XIITH CENTURY, AND DEPICTED AS A COMPLEX INTERPLAY AMONG DIFFERENT HUMORS AND FLEGMATA THAT SHE RECOGNIZED TO BE SEX SPECIFIC AND ENVIRONMENTALLY REGULATED. VIEWPOINT: CONSIDERING THE FUNCTION PLAYED BY HORMONES, ANALYZED THROUGH THE LAST SCIENTIFIC EVIDENCE, AND SCIENTIFIC LITERATURE ON BIODYNAMIC INTERFACES, WE COULD SUGGEST HILDEGARDIAN INSIGHTS AND THEORIES AS THE FIRST ATTEMPT TO DESCRIBE THE MODERN HOLISTIC, SEX-BASED MEDICINE. CONCLUSION: HILDEGARD ANTICIPATED A CONCEPT OF PATHOGENESIS THAT SEES A CENTRAL ROLE FOR ENDOCRINOLOGY IN SEX-SPECIFIC DISEASE. FURTHERMORE, ESTROGENS AND ESTROGEN RECEPTORS COULD REPRESENT A GOOD EXAMPLE OF MOLECULAR INTERFACES CAPABLE OF MODULATING THE INTERACTION BETWEEN THE ORGANISM INTERNAL MILIEU AND THE ENVIRONMENTAL FACTORS. 2022 7 3899 26 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 8 4019 22 LOW-DOSE OR LOW-DOSE-RATE IONIZING RADIATION-INDUCED BIOEFFECTS IN ANIMAL MODELS. ANIMAL EXPERIMENTAL STUDIES INDICATE THAT ACUTE OR CHRONIC LOW-DOSE IONIZING RADIATION (LDIR) ( 100 AGENTS CLASSIFIED AS GROUP 1, CARCINOGENIC TO HUMANS (IARC MONOGRAPHS VOLUME 100, PARTS A-F). THIS EXERCISE WAS COMPLICATED BY THE ABSENCE OF A BROADLY ACCEPTED, SYSTEMATIC METHOD FOR EVALUATING MECHANISTIC DATA TO SUPPORT CONCLUSIONS REGARDING HUMAN HAZARD FROM EXPOSURE TO CARCINOGENS. OBJECTIVES AND METHODS: IARC THEREFORE CONVENED TWO WORKSHOPS IN WHICH AN INTERNATIONAL WORKING GROUP OF EXPERTS IDENTIFIED 10 KEY CHARACTERISTICS, ONE OR MORE OF WHICH ARE COMMONLY EXHIBITED BY ESTABLISHED HUMAN CARCINOGENS. DISCUSSION: THESE CHARACTERISTICS PROVIDE THE BASIS FOR AN OBJECTIVE APPROACH TO IDENTIFYING AND ORGANIZING RESULTS FROM PERTINENT MECHANISTIC STUDIES. THE 10 CHARACTERISTICS ARE THE ABILITIES OF AN AGENT TO 1) ACT AS AN ELECTROPHILE EITHER DIRECTLY OR AFTER METABOLIC ACTIVATION; 2) BE GENOTOXIC; 3) ALTER DNA REPAIR OR CAUSE GENOMIC INSTABILITY; 4) INDUCE EPIGENETIC ALTERATIONS; 5) INDUCE OXIDATIVE STRESS; 6) INDUCE CHRONIC INFLAMMATION; 7) BE IMMUNOSUPPRESSIVE; 8) MODULATE RECEPTOR-MEDIATED EFFECTS; 9) CAUSE IMMORTALIZATION; AND 10) ALTER CELL PROLIFERATION, CELL DEATH, OR NUTRIENT SUPPLY. CONCLUSION: WE DESCRIBE THE USE OF THE 10 KEY CHARACTERISTICS TO CONDUCT A SYSTEMATIC LITERATURE SEARCH FOCUSED ON RELEVANT END POINTS AND CONSTRUCT A GRAPHICAL REPRESENTATION OF THE IDENTIFIED MECHANISTIC INFORMATION. NEXT, WE USE BENZENE AND POLYCHLORINATED BIPHENYLS AS EXAMPLES TO ILLUSTRATE HOW THIS APPROACH MAY WORK IN PRACTICE. THE APPROACH DESCRIBED IS SIMILAR IN MANY RESPECTS TO THOSE CURRENTLY BEING IMPLEMENTED BY THE U.S. EPA'S INTEGRATED RISK INFORMATION SYSTEM PROGRAM AND THE U.S. NATIONAL TOXICOLOGY PROGRAM. CITATION: SMITH MT, GUYTON KZ, GIBBONS CF, FRITZ JM, PORTIER CJ, RUSYN I, DEMARINI DM, CALDWELL JC, KAVLOCK RJ, LAMBERT P, HECHT SS, BUCHER JR, STEWART BW, BAAN R, COGLIANO VJ, STRAIF K. 2016. KEY CHARACTERISTICS OF CARCINOGENS AS A BASIS FOR ORGANIZING DATA ON MECHANISMS OF CARCINOGENESIS. ENVIRON HEALTH PERSPECT 124:713-721; HTTP://DX.DOI.ORG/10.1289/EHP.1509912. 2016 19 4736 27 NOVEL EPIGENETIC BIOMARKERS MEDIATING BISPHENOL A EXPOSURE AND METABOLIC PHENOTYPES IN FEMALE MICE. THERE IS COMPELLING EVIDENCE THAT EPIGENETIC MODIFICATIONS LINK DEVELOPMENTAL ENVIRONMENTAL INSULTS TO ADULT DISEASE SUSCEPTIBILITY. ANIMAL STUDIES HAVE ASSOCIATED PERINATAL BISPHENOL A (BPA) EXPOSURE TO ALTERED DNA METHYLATION, BUT THESE STUDIES ARE OFTEN LIMITED TO CANDIDATE GENE AND GLOBAL NON-LOCI-SPECIFIC APPROACHES. BY USING AN EPIGENOME-WIDE DISCOVERY PLATFORM, WE ELUCIDATED EPIGENETIC ALTERATIONS IN LIVER TISSUE FROM ADULT MICE OFFSPRING (10 MONTHS) FOLLOWING PERINATAL BPA EXPOSURE AT HUMAN PHYSIOLOGICALLY RELEVANT DOSES (50-NG, 50-MUG, AND 50-MG BPA/KG DIET). BIOLOGICAL PATHWAY ANALYSIS IDENTIFIED AN ENRICHMENT OF SIGNIFICANT DIFFERENTIALLY METHYLATED REGIONS IN METABOLIC PATHWAYS AMONG FEMALES. FURTHERMORE, THROUGH THE USE OF TOP ENRICHED BIOLOGICAL PATHWAYS, 4 CANDIDATE GENES WERE CHOSEN TO ASSESS DNA METHYLATION AS A MEDIATING FACTOR LINKING THE ASSOCIATION OF PERINATAL BPA EXPOSURE TO METABOLIC PHENOTYPES PREVIOUSLY OBSERVED IN FEMALE OFFSPRING. DNA METHYLATION STATUS AT JANUS KINASE-2 (JAK-2), RETINOID X RECEPTOR (RXR), REGULATORY FACTOR X-ASSOCIATED PROTEIN (RFXAP), AND TRANSMEMBRANE PROTEIN 238 (TMEM238) WAS USED WITHIN A MEDIATIONAL REGRESSION ANALYSIS. DNA METHYLATION IN ALL FOUR OF THE CANDIDATE GENES WAS IDENTIFIED AS A MEDIATOR IN THE MECHANISTIC PATHWAY OF DEVELOPMENTAL BPA EXPOSURE AND FEMALE-SPECIFIC ENERGY EXPENDITURE, BODY WEIGHT, AND BODY FAT PHENOTYPES. DATA GENERATED FROM THIS STUDY ARE CRUCIAL FOR DECIPHERING THE MECHANISTIC ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC DISEASE AND THE DEVELOPMENT OF EPIGENETIC-BASED PREVENTION AND THERAPEUTIC STRATEGIES FOR COMPLEX HUMAN DISEASE. 2017 20 6815 17 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES. 2011