1 6301 165 THE PUTATIVE ROLE OF ENVIRONMENTAL MERCURY IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF AUTISM SPECTRUM DISORDERS AND SUBTYPES. EXPOSURE TO ORGANIC FORMS OF MERCURY HAS THE THEORETICAL CAPACITY TO GENERATE A RANGE OF IMMUNE ABNORMALITIES COUPLED WITH CHRONIC NITRO-OXIDATIVE STRESS SEEN IN CHILDREN WITH AUTISM SPECTRUM DISORDER (ASD). THE PAPER DISCUSSES POSSIBLE MECHANISMS EXPLAINING THE NEUROTOXIC EFFECTS OF MERCURY AND POSSIBLE ASSOCIATIONS BETWEEN MERCURY EXPOSURE AND ASD SUBTYPES. ENVIRONMENTAL MERCURY IS NEUROTOXIC AT DOSES WELL BELOW THE CURRENT REFERENCE LEVELS CONSIDERED TO BE SAFE, WITH EVIDENCE OF NEUROTOXICITY IN CHILDREN EXPOSED TO ENVIRONMENTAL SOURCES INCLUDING FISH CONSUMPTION AND ETHYLMERCURY-CONTAINING VACCINES. POSSIBLE NEUROTOXIC MECHANISMS OF MERCURY INCLUDE DIRECT EFFECTS ON SULFHYDRYL GROUPS, PERICYTES AND CEREBRAL ENDOTHELIAL CELLS, ACCUMULATION WITHIN ASTROCYTES, MICROGLIAL ACTIVATION, INDUCTION OF CHRONIC OXIDATIVE STRESS, ACTIVATION OF IMMUNE-INFLAMMATORY PATHWAYS AND IMPAIRMENT OF MITOCHONDRIAL FUNCTIONING. (EPI-)GENETIC FACTORS WHICH MAY INCREASE SUSCEPTIBILITY TO THE TOXIC EFFECTS OF MERCURY IN ASD INCLUDE THE FOLLOWING: A GREATER PROPENSITY OF MALES TO THE LONG-TERM NEUROTOXIC EFFECTS OF POSTNATAL EXPOSURE AND GENETIC POLYMORPHISMS IN GLUTATHIONE TRANSFERASES AND OTHER GLUTATHIONE-RELATED GENES AND IN SELENOPROTEINS. FURTHERMORE, IMMUNE AND INFLAMMATORY RESPONSES TO IMMUNISATIONS WITH MERCURY-CONTAINING ADJUVANTS ARE STRONGLY INFLUENCED BY POLYMORPHISMS IN THE HUMAN LEUKOCYTE ANTIGEN (HLA) REGION AND BY GENES ENCODING EFFECTOR PROTEINS SUCH AS CYTOKINES AND PATTERN RECOGNITION RECEPTORS. SOME EPIDEMIOLOGICAL STUDIES INVESTIGATING A POSSIBLE RELATIONSHIP BETWEEN HIGH ENVIRONMENTAL EXPOSURE TO METHYLMERCURY AND IMPAIRED NEURODEVELOPMENT HAVE REPORTED A POSITIVE DOSE-DEPENDENT EFFECT. RETROSPECTIVE STUDIES, ON THE OTHER HAND, REPORTED NO RELATIONSHIP BETWEEN A RANGE OF ETHYLMERCURY-CONTAINING VACCINES AND CHRONIC NEUROPATHOLOGY OR ASD. ON THE BASIS OF THESE RESULTS, WE WOULD ARGUE THAT MORE CLINICALLY RELEVANT RESEARCH IS REQUIRED TO EXAMINE WHETHER ENVIRONMENTAL MERCURY IS ASSOCIATED WITH ASD OR SUBTYPES. SPECIFIC RECOMMENDATIONS FOR FUTURE RESEARCH ARE DISCUSSED. 2018 2 4626 39 NEURODEVELOPMENTAL DISORDERS AND ENVIRONMENTAL TOXICANTS: EPIGENETICS AS AN UNDERLYING MECHANISM. THE INCREASING PREVALENCE OF NEURODEVELOPMENTAL DISORDERS, ESPECIALLY AUTISM SPECTRUM DISORDERS (ASD) AND ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD), CALLS FOR MORE RESEARCH INTO THE IDENTIFICATION OF ETIOLOGIC AND RISK FACTORS. THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE (DOHAD) HYPOTHESIZES THAT THE ENVIRONMENT DURING FETAL AND CHILDHOOD DEVELOPMENT AFFECTS THE RISK FOR MANY CHRONIC DISEASES IN LATER STAGES OF LIFE, INCLUDING NEURODEVELOPMENTAL DISORDERS. EPIGENETICS, A TERM DESCRIBING MECHANISMS THAT CAUSE CHANGES IN THE CHROMOSOME STATE WITHOUT AFFECTING DNA SEQUENCES, IS SUGGESTED TO BE THE UNDERLYING MECHANISM, ACCORDING TO THE DOHAD HYPOTHESIS. MOREOVER, MANY NEURODEVELOPMENTAL DISORDERS ARE ALSO RELATED TO EPIGENETIC ABNORMALITIES. EXPERIMENTAL AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT EXPOSURE TO PRENATAL ENVIRONMENTAL TOXICANTS IS ASSOCIATED WITH NEURODEVELOPMENTAL DISORDERS. IN ADDITION, THERE IS ALSO EVIDENCE THAT ENVIRONMENTAL TOXICANTS CAN RESULT IN EPIGENETIC ALTERATIONS, NOTABLY DNA METHYLATION. IN THIS REVIEW, WE FIRST FOCUS ON THE RELATIONSHIP BETWEEN NEURODEVELOPMENTAL DISORDERS AND ENVIRONMENTAL TOXICANTS, IN PARTICULAR MATERNAL SMOKING, PLASTIC-DERIVED CHEMICALS (BISPHENOL A AND PHTHALATES), PERSISTENT ORGANIC POLLUTANTS, AND HEAVY METALS. WE THEN REVIEW STUDIES SHOWING THE EPIGENETIC EFFECTS OF THOSE ENVIRONMENTAL FACTORS IN HUMANS THAT MAY AFFECT NORMAL NEURODEVELOPMENT. 2017 3 3511 48 IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI): FROM MOLECULAR EPIDEMIOLOGY TO MOLECULAR MEDICINE. INHERITED OR ACQUIRED IMPAIRMENT OF XENOBIOTICS METABOLISM IS A POSTULATED MECHANISM UNDERLYING ENVIRONMENT-ASSOCIATED PATHOLOGIES SUCH AS MULTIPLE CHEMICAL SENSITIVITY, FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, DENTAL AMALGAM DISEASE, AND OTHERS, ALSO COLLECTIVELY NAMED IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI). IN VIEW OF THE POOR CURRENT KNOWLEDGE OF THEIR ETIOLOGY AND PATHOGENESIS, AND THE ABSENCE OF RECOGNISED GENETIC AND METABOLIC MARKERS OF THE DISEASES. THEY ARE OFTEN CONSIDERED "MEDICALLY UNEXPLAINED SYNDROMES",. THESE DISABLING CONDITIONS SHARE THE FEATURES OF POLYSYMPTOMATIC MULTI-ORGAN SYNDROMES, CONSIDERED BY PART OF THE MEDICAL COMMUNITY TO BE ABERRANT RESPONSES TRIGGERED BY EXPOSURE TO LOW-DOSE ORGANIC AND INORGANIC CHEMICALS AND METALS, IN CONCENTRATIONS FAR BELOW AVERAGE REFERENCE LEVELS ADMITTED FOR ENVIRONMENTAL TOXICANTS. A GENETIC PREDISPOSITION TO ALTERED BIOTRANSFORMATION OF ENVIRONMENTAL CHEMICALS, DRUGS, AND METALS, AND OF ENDOGENOUS LOW-MOLECULAR WEIGHT METABOLITES, CAUSED BY POLYMORPHISMS OF GENES CODING FOR XENOBIOTIC METABOLIZING ENZYMES, THEIR RECEPTORS AND TRANSCRIPTION FACTORS APPEARS TO BE INVOLVED IN THE SUSCEPTIBILITY TO THESE ENVIRONMENT-ASSOCIATED PATHOLOGIES, ALONG WITH EPIGENETIC FACTORS. FREE RADICAL/ANTIOXIDANT HOMEOSTASIS MAY ALSO BE HEAVILY IMPLICATED, INDIRECTLY BY AFFECTING THE REGULATION OF XENOBIOTIC METABOLIZING ENZYMES, AND DIRECTLY BY CAUSING INCREASED LEVELS OF OXIDATIVE PRODUCTS, IMPLICATED IN THE CHRONIC DAMAGE OF CELLS AND TISSUES, WHICH IS IN PART CORRELATED WITH CLINICAL SYMPTOMS. MORE SYSTEMATIC STUDIES OF MOLECULAR EPIDEMIOLOGY, TOXICO- AND PHARMACO-GENOMICS, ELUCIDATING THE MECHANISMS OF REGULATION, EXPRESSION, INDUCTION, AND ACTIVITY OF ANTIOXIDANT/DETOXIFYING ENZYMES, AND THE POSSIBLE ROLE OF INFLAMMATORY MEDIATORS, PROMISE A BETTER UNDERSTANDING OF THIS PATHOLOGICALLY INCREASED SENSITIVITY TO LOW-LEVEL CHEMICAL STIMULI, AND A SOLID BASIS FOR EFFECTIVE INDIVIDUALIZED ANTIOXIDANT- AND/OR CHELATOR-BASED TREATMENTS. 2010 4 679 23 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021 5 6833 34 [HYPOTHETICAL LINK BETWEEN ENDOMETRIOSIS AND XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD]. ENDOMETRIOSIS IS AN OESTROGEN-DEPENDENT INFLAMMATORY DISEASE AFFECTING 10 % OF REPRODUCTIVE-AGED WOMEN. OFTEN ACCOMPANIED BY CHRONIC PELVIC PAIN AND INFERTILITY, ENDOMETRIOSIS RIGOROUSLY INTERFERES WITH WOMEN'S QUALITY OF LIFE. ALTHOUGH THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS REMAINS UNCLEAR, A GROWING BODY OF EVIDENCE POINTS TO THE IMPLICATION OF ENVIRONMENTAL TOXICANTS. OVER THE LAST DECADE, AN INCREASE IN THE INCIDENCE OF ENDOMETRIOSIS HAS BEEN REPORTED AND COINCIDES WITH THE INTRODUCTION OF GENETICALLY MODIFIED FOODS IN OUR DIET. EVEN THOUGH ASSESSMENTS OF GENETICALLY MODIFIED FOOD RISK HAVE NOT INDICATED ANY HAZARD ON HUMAN HEALTH, XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD, SUCH AS PESTICIDES RESIDUES AND XENOPROTEINS, COULD BE HARMFUL IN THE LONG-TERM. THE "LOW-DOSE HYPOTHESIS", ACCUMULATION AND BIOTRANSFORMATION OF PESTICIDES-ASSOCIATED GENETICALLY MODIFIED FOOD AND THE MULTIPLIED TOXICITY OF PESTICIDES-FORMULATION ADJUVANTS SUPPORT THIS HYPOTHESIS. THIS REVIEW SUMMARIZES TOXIC EFFECTS (IN VITRO AND ON ANIMAL MODELS) OF SOME XENOBIOTICS-ASSOCIATED GENETICALLY MODIFIED FOOD, SUCH AS GLYPHOSATE AND CRY1AB PROTEIN, AND EXTRAPOLATES ON THEIR POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS. THEIR ROLES AS IMMUNE TOXICANTS, PRO-OXIDANTS, ENDOCRINE DISRUPTORS AND EPIGENETIC MODULATORS ARE DISCUSSED. 2010 6 1364 42 DEVELOPMENTAL NEUROENDOCRINOLOGY OF EARLY-LIFE STRESS: IMPACT ON CHILD DEVELOPMENT AND BEHAVIOR. OUR INTERNAL BALANCE, OR HOMEOSTASIS, IS THREATENED OR PERCEIVED AS THREATENED BY STRESSFUL STIMULI, THE STRESSORS. THE STRESS SYSTEM IS A HIGHLY CONSERVED SYSTEM THAT ADJUSTS HOMEOSTASIS TO THE RESTING STATE. THROUGH THE CONCURRENT ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE LOCUS COERULEUS/NOREPINEPHRINE-AUTONOMIC NERVOUS SYSTEMS, THE STRESS SYSTEM PROVIDES THE APPROPRIATE PHYSICAL AND BEHAVIORAL RESPONSES, COLLECTIVELY TERMED AS "STRESS RESPONSE", TO RESTORE HOMEOSTASIS. IF THE STRESS RESPONSE IS PROLONGED, EXCESSIVE OR EVEN INADEQUATE, SEVERAL ACUTE OR CHRONIC STRESS-RELATED PATHOLOGIC CONDITIONS MAY DEVELOP IN CHILDHOOD, ADOLESCENCE AND ADULT LIFE. ON THE OTHER HAND, EARLY-LIFE EXPOSURE TO STRESSORS HAS BEEN RECOGNIZED AS A MAJOR CONTRIBUTING FACTOR UNDERLYING THE PATHOGENESIS OF NON-COMMUNICABLE DISORDERS, INCLUDING NEURODEVELOPMENTAL DISORDERS. ACCUMULATING EVIDENCE SUGGESTS THAT EARLY-LIFE STRESS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER AND AUTISM SPECTRUM DISORDER IN THE OFFSPRING, ALTHOUGH FINDINGS ARE STILL CONTROVERSIAL. NEVERTHELESS, AT THE MOLECULAR LEVEL, EARLY-LIFE STRESSORS ALTER THE CHEMICAL STRUCTURE OF CYTOSINES LOCAT- ED IN THE REGULATORY REGIONS OF GENES, MOSTLY THROUGH THE ADDITION OF METHYL GROUPS. THESE EPIGENETIC MODIFICATIONS RESULT IN THE SUPPRESSION OF GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. IN ADDITION TO DNA METHYLATION, SEVERAL LINES OF EVIDENCE SUPPORT THE ROLE OF NON-CODING RNAS IN THE EVOLVING FIELD OF EPIGENETICS. IN THIS REVIEW ARTICLE, WE PRESENT THE ANATOMICAL AND FUNCTIONAL COMPO- NENTS OF THE STRESS SYSTEM, DISCUSS THE PROPER, IN TERMS OF QUALITY AND QUANTITY, STRESS RESPONSE, AND PROVIDE AN UPDATE ON THE IMPACT OF EARLY-LIFE STRESS ON CHILD DEVELOPMENT AND BEHAVIOR. 2023 7 5756 38 SOCIOECONOMIC DEPRIVATION, ADVERSE CHILDHOOD EXPERIENCES AND MEDICAL DISORDERS IN ADULTHOOD: MECHANISMS AND ASSOCIATIONS. SEVERE SOCIOECONOMIC DEPRIVATION (SED) AND ADVERSE CHILDHOOD EXPERIENCES (ACE) ARE SIGNIFICANTLY ASSOCIATED WITH THE DEVELOPMENT IN ADULTHOOD OF (I) ENHANCED INFLAMMATORY STATUS AND/OR HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSFUNCTION AND (II) NEUROLOGICAL, NEUROPROGRESSIVE, INFLAMMATORY AND AUTOIMMUNE DISEASES. THE MECHANISMS BY WHICH THESE ASSOCIATIONS TAKE PLACE ARE DETAILED. THE TWO SETS OF CONSEQUENCES ARE THEMSELVES STRONGLY ASSOCIATED, WITH THE FIRST SET LIKELY CONTRIBUTING TO THE SECOND. MECHANISMS ENABLING BIDIRECTIONAL COMMUNICATION BETWEEN THE IMMUNE SYSTEM AND THE BRAIN ARE DESCRIBED, INCLUDING COMPLEX SIGNALLING PATHWAYS FACILITATED BY FACTORS AT THE LEVEL OF IMMUNE CELLS. ALSO DETAILED ARE MECHANISMS UNDERPINNING THE ASSOCIATION BETWEEN SED, ACE AND THE GENESIS OF PERIPHERAL INFLAMMATION, INCLUDING EPIGENETIC CHANGES TO IMMUNE SYSTEM-RELATED GENE EXPRESSION. THE DURATION AND MAGNITUDE OF INFLAMMATORY RESPONSES CAN BE INFLUENCED BY GENETIC FACTORS, INCLUDING SINGLE NUCLEOTIDE POLYMORPHISMS, AND BY EPIGENETIC FACTORS, WHEREBY PRO-INFLAMMATORY CYTOKINES, REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES AND NUCLEAR FACTOR-KAPPAB AFFECT GENE DNA METHYLATION AND HISTONE ACETYLATION AND ALSO INDUCE SEVERAL MICRORNAS INCLUDING MIR-155, MIR-181B-1 AND MIR-146A. ADULT HPA AXIS ACTIVITY IS REGULATED BY (I) GENETIC FACTORS, SUCH AS GLUCOCORTICOID RECEPTOR POLYMORPHISMS; (II) EPIGENETIC FACTORS AFFECTING GLUCOCORTICOID RECEPTOR FUNCTION OR EXPRESSION, INCLUDING THE METHYLATION STATUS OF ALTERNATIVE PROMOTER REGIONS OF NR3C1 AND THE METHYLATION OF FKBP5 AND HSD11BETA2; (III) CHRONIC INFLAMMATION AND CHRONIC NITROSATIVE AND OXIDATIVE STRESS. FINALLY, IT IS SHOWN HOW SEVERE PSYCHOLOGICAL STRESS ADVERSELY AFFECTS MITOCHONDRIAL STRUCTURE AND FUNCTIONING AND IS ASSOCIATED WITH CHANGES IN BRAIN MITOCHONDRIAL DNA COPY NUMBER AND TRANSCRIPTION; MITOCHONDRIA CAN ACT AS COURIERS OF CHILDHOOD STRESS INTO ADULTHOOD. 2019 8 6300 51 THE PUTATIVE ROLE OF ENVIRONMENTAL ALUMINIUM IN THE DEVELOPMENT OF CHRONIC NEUROPATHOLOGY IN ADULTS AND CHILDREN. HOW STRONG IS THE EVIDENCE AND WHAT COULD BE THE MECHANISMS INVOLVED? THE CONCEPTUALISATION OF AUTISTIC SPECTRUM DISORDER AND ALZHEIMER'S DISEASE HAS UNDERGONE SOMETHING OF A PARADIGM SHIFT IN RECENT YEARS AND RATHER THAN BEING VIEWED AS SINGLE ILLNESSES WITH A UNITARY PATHOGENESIS AND PATHOPHYSIOLOGY THEY ARE INCREASINGLY CONSIDERED TO BE HETEROGENEOUS SYNDROMES WITH A COMPLEX MULTIFACTORIAL AETIOPATHOGENESIS, INVOLVING A HIGHLY COMPLEX AND DIVERSE COMBINATION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ONE SUCH ENVIRONMENTAL FACTOR IMPLICATED AS A POTENTIAL CAUSE IN BOTH SYNDROMES IS ALUMINIUM, AS AN ELEMENT OR AS PART OF A SALT, RECEIVED, FOR EXAMPLE, IN ORAL FORM OR AS AN ADJUVANT. SUCH ADMINISTRATION HAS THE POTENTIAL TO INDUCE PATHOLOGY VIA SEVERAL ROUTES SUCH AS PROVOKING DYSFUNCTION AND/OR ACTIVATION OF GLIAL CELLS WHICH PLAY AN INDISPENSABLE ROLE IN THE REGULATION OF CENTRAL NERVOUS SYSTEM HOMEOSTASIS AND NEURODEVELOPMENT. OTHER ROUTES INCLUDE THE GENERATION OF OXIDATIVE STRESS, DEPLETION OF REDUCED GLUTATHIONE, DIRECT AND INDIRECT REDUCTIONS IN MITOCHONDRIAL PERFORMANCE AND INTEGRITY, AND INCREASING THE PRODUCTION OF PROINFLAMMATORY CYTOKINES IN BOTH THE BRAIN AND PERIPHERALLY. THE MECHANISMS WHEREBY ENVIRONMENTAL ALUMINIUM COULD CONTRIBUTE TO THE DEVELOPMENT OF THE HIGHLY SPECIFIC PATTERN OF NEUROPATHOLOGY SEEN IN ALZHEIMER'S DISEASE ARE DESCRIBED. ALSO DETAILED ARE SEVERAL MECHANISMS WHEREBY SIGNIFICANT QUANTITIES OF ALUMINIUM INTRODUCED VIA IMMUNISATION COULD PRODUCE CHRONIC NEUROPATHOLOGY IN GENETICALLY SUSCEPTIBLE CHILDREN. ACCORDINGLY, IT IS RECOMMENDED THAT THE USE OF ALUMINIUM SALTS IN IMMUNISATIONS SHOULD BE DISCONTINUED AND THAT ADULTS SHOULD TAKE STEPS TO MINIMISE THEIR EXPOSURE TO ENVIRONMENTAL ALUMINIUM. 2017 9 3210 36 HEALTH EFFECTS ASSOCIATED WITH PRE- AND PERINATAL EXPOSURE TO ARSENIC. INORGANIC ARSENIC IS A WELL-ESTABLISHED HUMAN CARCINOGEN, ABLE TO INDUCE GENETIC AND EPIGENETIC ALTERATIONS. MORE THAN 200 MILLION PEOPLE WORLDWIDE ARE EXPOSED TO ARSENIC CONCENTRATIONS IN DRINKING WATER EXCEEDING THE RECOMMENDED WHO THRESHOLD (10MUG/L). ADDITIONALLY, CHRONIC EXPOSURE TO LEVELS BELOW THIS THRESHOLD IS KNOWN TO RESULT IN LONG-TERM HEALTH EFFECTS IN HUMANS. THE ARSENIC-RELATED HEALTH EFFECTS IN HUMANS ARE ASSOCIATED WITH ITS BIOTRANSFORMATION PROCESS, WHEREBY THE RESULTING METABOLITES CAN INDUCE MOLECULAR DAMAGE THAT ACCUMULATES OVER TIME. THE EFFECTS DERIVED FROM THESE ALTERATIONS INCLUDE GENOMIC INSTABILITY ASSOCIATED WITH OXIDATIVE DAMAGE, ALTERATION OF GENE EXPRESSION (INCLUDING CODING AND NON-CODING RNAS), GLOBAL AND LOCALIZED EPIGENETIC REPROGRAMMING, AND HISTONE POSTTRANSLATIONAL MODIFICATIONS. THESE ALTERATIONS DIRECTLY AFFECT MOLECULAR PATHWAYS INVOLVED IN THE ONSET AND PROGRESSION OF MANY CONDITIONS THAT CAN ARISE EVEN DECADES AFTER THE EXPOSURE OCCURS. IMPORTANTLY, ARSENIC METABOLITES GENERATED DURING ITS BIOTRANSFORMATION CAN ALSO PASS THROUGH THE PLACENTAL BARRIER, RESULTING IN FETAL EXPOSURE TO THIS CARCINOGEN AT SIMILAR LEVELS TO THOSE OF THE MOTHER. AS SUCH, MORE IMMEDIATE EFFECTS OF THE ARSENIC-INDUCED MOLECULAR DAMAGE CAN BE OBSERVED AS DETRIMENTAL EFFECTS ON FETAL DEVELOPMENT, PREGNANCY, AND BIRTH OUTCOMES. IN THIS REVIEW, WE FOCUS ON THE GENETIC AND EPIGENETIC DAMAGE ASSOCIATED WITH EXPOSURE TO LOW LEVELS OF ARSENIC, PARTICULARLY THOSE AFFECTING EARLY DEVELOPMENTAL STAGES. WE ALSO PRESENT HOW THESE ALTERATIONS OCCURRING DURING EARLY LIFE CAN IMPACT THE DEVELOPMENT OF CERTAIN DISEASES IN ADULT LIFE. 2021 10 6863 28 [ONE AUTISM, SEVERAL AUTISMS. PHENOTYPICAL VARIABILITY IN AUTISM SPECTRUM DISORDERS]. INTRODUCTION: AUTISM SPECTRUM DISORDERS (ASD) ARE A HETEROGENEOUS GROUP OF DISORDERS THAT BEGIN IN THE EARLY MONTHS OF LIFE AND FOLLOW A CHRONIC PROGRESSION. THEY HAVE A BIOLOGICAL ORIGIN, WITH COMPLEX AETIOLOGICAL FACTORS THAT INVOLVE DIFFERENT GENETIC, EPIGENETIC AND ENVIRONMENTAL MECHANISMS THAT INTERACT WITH ONE ANOTHER. AIM: TO REVIEW THE MAIN FACTORS THAT VARY THE PRESENTATION OF AUTISM TAKING INTO ACCOUNT THE MOST RECENT SCIENTIFIC EVIDENCE. DEVELOPMENT: ASPECTS RELATED WITH THE DEVELOPMENT OF SYMPTOMS, GENDER, COMORBIDITY, AGE AND AETIOLOGY DETERMINE THE VARIABILITY IN THE CLINICAL PRESENTATION OF ASD. CONCLUSIONS: AUTISM IS HIGHLY HETEROGENEOUS AND IS PHENOTYPICALLY RELATED, AT LEAST IN PART, WITH A WIDE RANGE OF CAUSATIONS, WHICH RESEARCHERS HAVE BEGUN TO UNRAVEL BUT WHICH ARE STILL LARGELY UNKNOWN. AETIOLOGICAL RESEARCH, ESPECIALLY IN THE AREA OF GENETICS, WILL MAKE IT POSSIBLE TO IDENTIFY DIFFERENT HOMOGENEOUS SUBGROUPS WITH THEIR CORRESPONDING PHENOTYPES, WHILE ALSO OPENING UP THE WAY TO POSSIBLE THERAPEUTIC ALTERNATIVES IN THE FUTURE. 2016 11 5164 40 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 12 6133 41 THE EPIGENETIC ROLE OF VITAMIN C IN NEURODEVELOPMENT. THE MATERNAL DIET DURING PREGNANCY IS A KEY DETERMINANT OF OFFSPRING HEALTH. EARLY STUDIES HAVE LINKED POOR MATERNAL NUTRITION DURING GESTATION WITH A PROPENSITY FOR THE DEVELOPMENT OF CHRONIC CONDITIONS IN OFFSPRING. THESE CONDITIONS INCLUDE CARDIOVASCULAR DISEASE, TYPE 2 DIABETES AND EVEN COMPROMISED MENTAL HEALTH. WHILE MULTIPLE FACTORS MAY CONTRIBUTE TO THESE OUTCOMES, DISTURBED EPIGENETIC PROGRAMMING DURING EARLY DEVELOPMENT IS ONE POTENTIAL BIOLOGICAL MECHANISM. THE EPIGENOME IS PROGRAMMED PRIMARILY IN UTERO, AND DURING THIS TIME, THE DEVELOPING FETUS IS HIGHLY SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS NUTRITIONAL INSULTS. DURING NEURODEVELOPMENT, EPIGENETIC PROGRAMMING COORDINATES THE FORMATION OF PRIMITIVE CENTRAL NERVOUS SYSTEM STRUCTURES, NEUROGENESIS, AND NEUROPLASTICITY. DYSREGULATED EPIGENETIC PROGRAMMING HAS BEEN IMPLICATED IN THE AETIOLOGY OF SEVERAL NEURODEVELOPMENTAL DISORDERS SUCH AS TATTON-BROWN-RAHMAN SYNDROME. ACCORDINGLY, THERE IS GREAT INTEREST IN DETERMINING HOW MATERNAL NUTRIENT AVAILABILITY IN PREGNANCY MIGHT AFFECT THE EPIGENETIC STATUS OF OFFSPRING, AND HOW SUCH INFLUENCES MAY PRESENT PHENOTYPICALLY. IN RECENT YEARS, A NUMBER OF EPIGENETIC ENZYMES THAT ARE ACTIVE DURING EMBRYONIC DEVELOPMENT HAVE BEEN FOUND TO REQUIRE VITAMIN C AS A COFACTOR. THESE ENZYMES INCLUDE THE TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASES (TETS) AND THE JUMONJI C DOMAIN-CONTAINING HISTONE LYSINE DEMETHYLASES THAT CATALYSE THE OXIDATIVE REMOVAL OF METHYL GROUPS ON CYTOSINES AND HISTONE LYSINE RESIDUES, RESPECTIVELY. THESE ENZYMES ARE INTEGRAL TO EPIGENETIC REGULATION AND HAVE FUNDAMENTAL ROLES IN CELLULAR DIFFERENTIATION, THE MAINTENANCE OF PLURIPOTENCY AND DEVELOPMENT. THE DEPENDENCE OF THESE ENZYMES ON VITAMIN C FOR OPTIMAL CATALYTIC ACTIVITY ILLUSTRATES A POTENTIALLY CRITICAL CONTRIBUTION OF THE NUTRIENT DURING MAMMALIAN DEVELOPMENT. THESE INSIGHTS ALSO HIGHLIGHT A POTENTIAL RISK ASSOCIATED WITH VITAMIN C INSUFFICIENCY DURING PREGNANCY. THE LINK BETWEEN VITAMIN C INSUFFICIENCY AND DEVELOPMENT IS PARTICULARLY APPARENT IN THE CONTEXT OF NEURODEVELOPMENT AND HIGH VITAMIN C CONCENTRATIONS IN THE BRAIN ARE INDICATIVE OF IMPORTANT FUNCTIONAL REQUIREMENTS IN THIS ORGAN. ACCORDINGLY, THIS REVIEW CONSIDERS THE EVIDENCE FOR THE POTENTIAL IMPACT OF MATERNAL VITAMIN C STATUS ON NEURODEVELOPMENTAL EPIGENETICS. 2022 13 3123 42 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 14 6034 37 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 15 1530 38 DNA METHYLATION CHANGES INDUCED BY PRENATAL TOXIC METAL EXPOSURE: AN OVERVIEW OF EPIDEMIOLOGICAL EVIDENCE. ACCUMULATING EVIDENCE SUGGESTS THAT EXPOSURE TO UNFAVORABLE CONDITIONS EARLY IN LIFE CAN SUBSTANTIALLY CONTRIBUTE TO THE RISK OF CHRONIC DISORDERS LATER IN LIFE ('DEVELOPMENTAL PROGRAMMING' PHENOMENON). THE MECHANISTIC BASIS FOR THIS PHENOMENON REMAINS POORLY UNDERSTOOD SO FAR, ALTHOUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNA-MEDIATED GENE REGULATION APPARENTLY PLAY A CRUCIAL ROLE. THE KEY ROLE OF EPIGENETIC MODIFICATIONS TRIGGERED BY UNFAVORABLE ENVIRONMENTAL CUES DURING SENSITIVE DEVELOPMENTAL PERIODS IN LINKING ADVERSE EARLY-LIFE EVENTS TO LATER-LIFE HEALTH OUTCOMES IS EVIDENT FROM A LARGE BODY OF STUDIES, INCLUDING METHYLOME-WIDE ASSOCIATION STUDIES AND RESEARCH OF CANDIDATE GENES. TOXIC METALS (TMS), SUCH AS HEAVY METALS, INCLUDING LEAD, CHROMIUM, CADMIUM, ARSENIC, MERCURY, ETC., ARE AMONG ENVIRONMENTAL CONTAMINANTS CURRENTLY MOST SIGNIFICANTLY IMPACTING HUMAN HEALTH STATUS. SINCE TMS CAN CROSS THE PLACENTAL BARRIER AND ACCUMULATE IN FETAL TISSUES, EXPOSURE TO HIGH DOSES OF THESE XENOBIOTICS EARLY IN DEVELOPMENT IS CONSIDERED TO BE AMONG IMPORTANT FACTORS CONTRIBUTING TO THE DEVELOPMENTAL PROGRAMMING OF ADULT-LIFE DISEASES IN MODERN SOCIETIES. IN THIS MINI-REVIEW, WE SUMMARIZE EPIDEMIOLOGICAL FINDINGS INDICATING THAT PRENATAL TM EXPOSURE CAN INDUCE EPIGENETIC DYSREGULATION, THEREBY POTENTIALLY AFFECTING ADULT HEALTH OUTCOMES. 2021 16 1360 44 DEVELOPMENTAL ASPECTS OF A LIFE COURSE APPROACH TO HEALTHY AGEING. WE EXAMINE THE MECHANISTIC BASIS AND WIDER IMPLICATIONS OF ADOPTING A DEVELOPMENTAL PERSPECTIVE ON HUMAN AGEING. PREVIOUS MODELS OF AGEING HAVE CONCENTRATED ON ITS GENETIC BASIS, OR THE DETRIMENTAL EFFECTS OF ACCUMULATED DAMAGE, BUT ALSO HAVE RAISED ISSUES ABOUT WHETHER AGEING CAN BE VIEWED AS ADAPTIVE ITSELF, OR IS A CONSEQUENCE OF OTHER ADAPTIVE PROCESSES, FOR EXAMPLE IF MAINTENANCE AND REPAIR PROCESSES IN THE PERIOD UP TO REPRODUCTION ARE TRADED OFF AGAINST LATER DECLINE IN FUNCTION. A LIFE COURSE MODEL PLACES AGEING IN THE CONTEXT OF THE ATTAINMENT OF PEAK CAPACITY FOR A BODY SYSTEM, STARTING IN EARLY DEVELOPMENT WHEN PLASTICITY PERMITS CHANGES IN STRUCTURE AND FUNCTION INDUCED BY A RANGE OF ENVIRONMENTAL STIMULI, FOLLOWED BY A PERIOD OF DECLINE, THE RATE OF WHICH DEPENDS ON THE PEAK ATTAINED AS WELL AS THE LATER LIFE CONDITIONS. SUCH PATH DEPENDENCY IN THE RATE OF AGEING MAY OFFER NEW INSIGHTS INTO ITS MODIFICATION. FOCUSING ON MUSCULOSKELETAL AND CARDIOVASCULAR FUNCTION, WE DISCUSS THIS MODEL AND THE POSSIBLE UNDERLYING MECHANISMS, INCLUDING ENDOTHELIAL FUNCTION, OXIDATIVE STRESS, STEM CELLS AND NUTRITIONAL FACTORS SUCH AS VITAMIN D STATUS. EPIGENETIC CHANGES INDUCED DURING DEVELOPMENTAL PLASTICITY, AND IMMUNE FUNCTION MAY PROVIDE A COMMON MECHANISTIC PROCESS UNDERLYING A LIFE COURSE MODEL OF AGEING. THE LIFE COURSE TRAJECTORY DIFFERS IN HIGH AND LOW RESOURCE SETTINGS. NEW INSIGHTS INTO THE DEVELOPMENTAL COMPONENTS OF THE LIFE COURSE MODEL OF AGEING MAY LEAD TO THE DESIGN OF BIOMARKERS OF LATER CHRONIC DISEASE RISK AND TO NEW INTERVENTIONS TO PROMOTE HEALTHY AGEING, WITH IMPORTANT IMPLICATIONS FOR PUBLIC HEALTH. 2016 17 5810 29 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 18 1453 29 DISCOVERING HOW ENVIRONMENTAL EXPOSURES ALTER GENES COULD LEAD TO NEW TREATMENTS FOR CHRONIC ILLNESSES. EMERGING RESEARCH DEMONSTRATES THAT DIET, POLLUTION, AND OTHER ENVIRONMENTAL TRIGGERS CAN ALTER BOTH THE FUNCTION AND EXPRESSION OF HUMAN GENES AND LEAD TO A HEIGHTENED DISEASE RISK. THESE ENVIRONMENT-GENE INTERACTIONS CAN CAUSE SO-CALLED EPIGENETIC CHANGES IN GENE EXPRESSION-PATTERNS OF WHICH GENES ARE SWITCHED "ON" OR "OFF"-THAT MAY ACCOUNT FOR THE RISING MORTALITY FROM CHRONIC DISEASES IN INDUSTRIALIZED NATIONS. IN THIS PAPER, WE CALL FOR A NEW TRANSDISCIPLINARY APPROACH TO PUBLIC HEALTH THAT WOULD EXAMINE HOW ENVIRONMENTAL EXPOSURES, BOTH PHYSICAL AND SOCIAL, INFLUENCE GENE EXPRESSION AND A PERSON'S SUSCEPTIBILITY TO CHRONIC DISEASE. THIS INITIATIVE COULD LEAD TO NEW WAYS TO PREVENT AND TREAT SUCH ILLNESSES. 2011 19 2901 40 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 20 1324 35 DEOXYRIBONUCLEIC ACID (DNA) METHYLATION IN CHILDREN EXPOSED TO AIR POLLUTION: A POSSIBLE MECHANISM UNDERLYING RESPIRATORY HEALTH EFFECTS DEVELOPMENT. AIR POLLUTION IS A SUBSTANTIAL ENVIRONMENTAL THREAT TO CHILDREN AND ACTS AS ACUTE AND CHRONIC DISEASE RISK FACTORS ALIKE. SEVERAL STUDIES HAVE PREVIOUSLY EVALUATED EPIGENETIC MODIFICATIONS CONCERNING ITS EXPOSURE ACROSS VARIOUS LIFE STAGES. HOWEVER, FINDINGS ON EPIGENETIC MODIFICATIONS AS THE CONSEQUENCES OF AIR POLLUTION DURING CHILDHOOD ARE RATHER MINIMAL. THIS REVIEW EVALUATED HIGHLY RELEVANT STUDIES IN THE FIELD TO ANALYZE THE EXISTING LITERATURE REGARDING EXPOSURE TO AIR POLLUTION, WITH A FOCUS ON EPIGENETIC ALTERATIONS DURING CHILDHOOD AND THEIR CONNECTIONS WITH RESPIRATORY HEALTH EFFECTS. THE SEARCH WAS CONDUCTED USING READILY AVAILABLE ELECTRONIC DATABASES (PUBMED AND SCIENCEDIRECT) TO SCREEN FOR CHILDREN'S STUDIES ON EPIGENETIC MECHANISMS FOLLOWING EITHER PRE- OR POST-NATAL EXPOSURE TO AIR POLLUTANTS. STUDIES RELEVANT ENOUGH AND MATCHED THE PREDETERMINED CRITERIA WERE CHOSEN TO BE REVIEWED. NON-ENGLISH ARTICLES AND STUDIES THAT DID NOT REPORT BOTH AIR MONITORING AND EPIGENETIC OUTCOMES IN THE SAME ARTICLE WERE EXCLUDED. THE REVIEW FOUND THAT EPIGENETIC CHANGES HAVE BEEN LINKED WITH EXPOSURE TO AIR POLLUTANTS DURING EARLY LIFE WITH EVIDENCE AND REPORTS OF HOW THEY MAY DEREGULATE THE EPIGENOME BALANCE, THUS INDUCING DISEASE PROGRESSION IN THE FUTURE. EPIGENETIC STUDIES EVOLVE AS A PROMISING NEW APPROACH IN DECIPHERING THE UNDERLYING IMPACTS OF AIR POLLUTION ON DEOXYRIBONUCLEIC ACID (DNA) DUE TO LINKS ESTABLISHED BETWEEN SOME OF THESE EPIGENETIC MECHANISMS AND ILLNESSES. 2021