1 4973 135 PATHOPHYSIOLOGICAL EFFECTS OF CONTEMPORARY LIFESTYLE ON EVOLUTIONARY-CONSERVED SURVIVAL MECHANISMS IN POLYCYSTIC OVARY SYNDROME. POLYCYSTIC OVARY SYNDROME (PCOS) IS INCREASINGLY BEING CHARACTERIZED AS AN EVOLUTIONARY MISMATCH DISORDER THAT PRESENTS WITH A COMPLEX MIXTURE OF METABOLIC AND ENDOCRINE SYMPTOMS. THE EVOLUTIONARY MODEL PROPOSES THAT PCOS ARISES FROM A COLLECTION OF INHERITED POLYMORPHISMS THAT HAVE BEEN CONSISTENTLY DEMONSTRATED IN A VARIETY OF ETHNIC GROUPS AND RACES. IN UTERO DEVELOPMENTAL PROGRAMMING OF SUSCEPTIBLE GENOMIC VARIANTS ARE THOUGHT TO PREDISPOSE THE OFFSPRING TO DEVELOP PCOS. POSTNATAL EXPOSURE TO LIFESTYLE AND ENVIRONMENTAL RISK FACTORS RESULTS IN EPIGENETIC ACTIVATION OF DEVELOPMENTALLY PROGRAMMED GENES AND DISTURBANCE OF THE HALLMARKS OF HEALTH. THE RESULTING PATHOPHYSIOLOGICAL CHANGES REPRESENT THE CONSEQUENCES OF POOR-QUALITY DIET, SEDENTARY BEHAVIOUR, ENDOCRINE DISRUPTING CHEMICALS, STRESS, CIRCADIAN DISRUPTION, AND OTHER LIFESTYLE FACTORS. EMERGING EVIDENCE SUGGESTS THAT LIFESTYLE-INDUCED GASTROINTESTINAL DYSBIOSIS PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF PCOS. LIFESTYLE AND ENVIRONMENTAL EXPOSURES INITIATE CHANGES THAT RESULT IN DISTURBANCE OF THE GASTROINTESTINAL MICROBIOME (DYSBIOSIS), IMMUNE DYSREGULATION (CHRONIC INFLAMMATION), ALTERED METABOLISM (INSULIN RESISTANCE), ENDOCRINE AND REPRODUCTIVE IMBALANCE (HYPERANDROGENISM), AND CENTRAL NERVOUS SYSTEM DYSFUNCTION (NEUROENDOCRINE AND AUTONOMIC NERVOUS SYSTEM). PCOS CAN BE A PROGRESSIVE METABOLIC CONDITION THAT LEADS TO OBESITY, GESTATIONAL DIABETES, TYPE TWO DIABETES, METABOLIC-ASSOCIATED FATTY LIVER DISEASE, METABOLIC SYNDROME, CARDIOVASCULAR DISEASE, AND CANCER. THIS REVIEW EXPLORES THE MECHANISMS THAT UNDERPIN THE EVOLUTIONARY MISMATCH BETWEEN ANCIENT SURVIVAL PATHWAYS AND CONTEMPORARY LIFESTYLE FACTORS INVOLVED IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF PCOS. 2023 2 4804 36 OBESITY AND MALE INFERTILITY: MECHANISMS AND MANAGEMENT. OBESITY IS CONSIDERED A GLOBAL HEALTH PROBLEM AFFECTING MORE THAN A THIRD OF THE POPULATION. COMPLICATIONS OF OBESITY INCLUDE CARDIOVASCULAR DISEASES, TYPE 2 DIABETES MELLITUS, MALIGNANCY (INCLUDING PROSTATIC CANCER), NEURODEGENERATION AND ACCELERATED AGEING. IN MALES, THESE FURTHER INCLUDE ERECTILE DYSFUNCTION, POOR SEMEN QUALITY AND SUBCLINICAL PROSTATITIS. ALTHOUGH POORLY UNDERSTOOD, IMPORTANT MEDIATORS OF OBESITY THAT MAY INFLUENCE THE MALE REPRODUCTIVE SYSTEM INCLUDE HYPERINSULINEMIA, HYPERLEPTINEMIA, CHRONIC INFLAMMATION AND OXIDATIVE STRESS. OBESITY IS KNOWN TO DISRUPT MALE FERTILITY AND THE REPRODUCTION POTENTIAL, PARTICULARLY THROUGH ALTERATION IN THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS, DISRUPTION OF TESTICULAR STEROIDOGENESIS AND METABOLIC DYSREGULATION, INCLUDING INSULIN, CYTOKINES AND ADIPOKINES. IMPORTANTLY, OBESITY AND ITS UNDERLYING MEDIATORS RESULT IN A NEGATIVE IMPACT ON SEMEN PARAMETERS, INCLUDING SPERM CONCENTRATION, MOTILITY, VIABILITY AND NORMAL MORPHOLOGY. MOREOVER, OBESITY INHIBITS CHROMATIN CONDENSATION, DNA FRAGMENTATION, INCREASES APOPTOSIS AND EPIGENETIC CHANGES THAT CAN BE TRANSFERRED TO THE OFFSPRING. THIS REVIEW DISCUSSES THE IMPACT OF OBESITY ON THE MALE REPRODUCTIVE SYSTEM AND FERTILITY, INCLUDING ASSOCIATED MECHANISMS. FURTHERMORE, WEIGHT MANAGEMENT STRATEGIES, LIFESTYLE CHANGES, PRESCRIPTION MEDICATION, AND COMPLEMENTARY AND ALTERNATIVE MEDICINE IN THE MANAGEMENT OF OBESITY-INDUCED SUBFERTILITY IS DISCUSSED. 2021 3 4805 37 OBESITY AND METABOLIC COMORBIDITIES: ENVIRONMENTAL DISEASES? OBESITY AND METABOLIC COMORBIDITIES REPRESENT INCREASING HEALTH PROBLEMS. ENDOCRINE DISRUPTING COMPOUNDS (EDCS) ARE EXOGENOUS AGENTS THAT CHANGE ENDOCRINE FUNCTION AND CAUSE ADVERSE HEALTH EFFECTS. MOST EDCS ARE SYNTHETIC CHEMICALS; SOME ARE NATURAL FOOD COMPONENTS AS PHYTOESTROGENS. PEOPLE ARE EXPOSED TO COMPLEX MIXTURES OF CHEMICALS THROUGHOUT THEIR LIVES. EDCS IMPACT HORMONE-DEPENDENT METABOLIC SYSTEMS AND BRAIN FUNCTION. LABORATORY AND HUMAN STUDIES PROVIDE COMPELLING EVIDENCE THAT HUMAN CHEMICAL CONTAMINATION CAN PLAY A ROLE IN OBESITY EPIDEMIC. CHEMICAL EXPOSURES MAY INCREASE THE RISK OF OBESITY BY ALTERING THE DIFFERENTIATION OF ADIPOCYTES. EDCS CAN ALTER METHYLATION PATTERNS AND NORMAL EPIGENETIC PROGRAMMING IN CELLS. OXIDATIVE STRESS MAY BE INDUCED BY MANY OF THESE CHEMICALS, AND ACCUMULATING EVIDENCE INDICATES THAT IT PLAYS IMPORTANT ROLES IN THE ETIOLOGY OF CHRONIC DISEASES. THE INDIVIDUAL SENSITIVITY TO CHEMICALS IS VARIABLE, DEPENDING ON ENVIRONMENT AND ABILITY TO METABOLIZE HAZARDOUS CHEMICALS. A NUMBER OF GENES, ESPECIALLY THOSE REPRESENTING ANTIOXIDANT AND DETOXIFICATION PATHWAYS, HAVE POTENTIAL APPLICATION AS BIOMARKERS OF RISK ASSESSMENT. THE POTENTIAL HEALTH EFFECTS OF COMBINED EXPOSURES MAKE THE RISK ASSESSMENT PROCESS MORE COMPLEX COMPARED TO THE ASSESSMENT OF SINGLE CHEMICALS. TECHNIQUES AND METHODS NEED TO BE FURTHER DEVELOPED TO FILL DATA GAPS AND INCREASE THE KNOWLEDGE ON HARMFUL EXPOSURE COMBINATIONS. 2013 4 1919 37 ENVIRONMENTAL ENDOCRINE DISRUPTORS: NEW DIABETOGENS? THE PREVALENCE OF TYPE-2 DIABETES HAS DRAMATICALLY INCREASED WORLDWIDE DURING THE LAST FEW DECADES. WHILE LIFESTYLE FACTORS (SEDENTARINESS, NOXIOUS FOOD), TOGETHER WITH GENETIC SUSCEPTIBILITY, ARE WELL-KNOWN ACTORS, THERE IS ACCUMULATING EVIDENCE SUGGESTING THAT ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY ALSO PLAY A PATHOPHYSIOLOGICAL ROLE IN THE OCCURRENCE OF METABOLIC DISEASES. BOTH EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A ROLE FOR EARLY AND CHRONIC EXPOSURE TO LOW DOSES OF CHEMICAL POLLUTANTS WITH ENDOCRINE AND METABOLIC DISRUPTING EFFECTS. MOST ARE PRESENT IN THE FOOD CHAIN AND ACCUMULATE IN THE FAT MASS AFTER ABSORPTION. IN RODENTS, BISPHENOL A STIMULATES SYNTHESIS AND SECRETION OF PANCREATIC BETA CELLS AND DISTURBS INSULIN SIGNALING IN LIVER, MUSCLE AND ADIPOSE TISSUE THROUGH EPIGENETIC CHANGES LEADING TO INSULIN RESISTANCE AND BETA CELL IMPAIRMENT. IN HUMANS, EPIDEMIOLOGICAL REPORTS SHOW STATISTICAL LINK BETWEEN EXPOSURE TO PESTICIDES, POLYCHLORINATED BISPHENYLS, BISPHENOL A, PHTHALATES, DIOXINS OR AROMATIC POLYCYCLIC HYDROCARBIDES OR HEAVY METALS AND DT2 AFTER ACUTE ACCIDENTAL RELEASES OR EARLY IN LIFE AND/OR CHRONIC, LOW DOSES EXPOSURE. MORE PROSPECTIVE, LONGITUDINAL STUDIES ARE NEEDED TO DETERMINE THE IMPORTANCE OF SUCH ENVIRONMENTAL RISK FACTORS. 2017 5 4107 43 MECHANISMS AFFECTING NEUROENDOCRINE AND EPIGENETIC REGULATION OF BODY WEIGHT AND ONSET OF PUBERTY: POTENTIAL IMPLICATIONS IN THE CHILD BORN SMALL FOR GESTATIONAL AGE (SGA). SIGNALING PEPTIDES PRODUCED IN PERIPHERAL TISSUES SUCH AS GUT, ADIPOSE TISSUE, AND PANCREAS COMMUNICATE WITH BRAIN CENTERS, SUCH AS HYPOTHALAMUS AND HINDBRAIN TO MANAGE ENERGY HOMEOSTASIS. THESE REGULATORY MECHANISMS OF ENERGY INTAKE AND STORAGE HAVE EVOLVED DURING LONG PERIODS OF HUNGER IN THE EVOLUTION OF MAN TO PROTECT THE SPECIES FROM EXTINCTION. IT IS NOW CLEAR THAT THESE CIRCUITRIES ARE INFLUENCED BY PRENATAL AND POSTNATAL ENVIRONMENTAL FACTORS INCLUDING ENDOCRINE DISRUPTIVE CHEMICALS. HYPOTHALAMIC APPETITE REGULATORY SYSTEMS DEVELOP AND MATURE IN UTERO AND EARLY INFANCY, AND INVOLVE SIGNALING PATHWAYS THAT ARE IMPORTANT ALSO FOR THE REGULATION OF PUBERTY ONSET. RECENT STUDIES IN HUMANS AND ANIMALS HAVE SHOWN THAT METABOLIC PATHWAYS INVOLVED IN REGULATION OF GROWTH, BODY WEIGHT GAIN AND SEXUAL MATURATION ARE LARGELY AFFECTED BY EPIGENETIC PROGRAMMING THAT CAN IMPACT BOTH CURRENT AND FUTURE GENERATIONS. IN PARTICULAR, INTRAUTERINE AND EARLY INFANTILE DEVELOPMENTAL PHASES OF HIGH PLASTICITY ARE SUSCEPTIBLE TO FACTORS THAT AFFECT METABOLIC PROGRAMMING THAT THEREFORE, AFFECT METABOLIC FUNCTION THROUGHOUT LIFE. IN CHILDREN BORN SMALL FOR GESTATIONAL AGE, POOR NUTRITIONAL CONDITIONS DURING GESTATION CAN MODIFY METABOLIC SYSTEMS TO ADAPT TO EXPECTATIONS OF CHRONIC UNDERNUTRITION. THESE CHILDREN ARE POTENTIALLY POORLY EQUIPPED TO COPE WITH ENERGY-DENSE DIETS AND ARE POSSIBLY PROGRAMMED TO STORE AS MUCH ENERGY AS POSSIBLE, LEADING TO LATER OBESITY, METABOLIC SYNDROME, DISTURBED REGULATION OF NORMAL PUBERTY AND EARLY ONSET OF CARDIOVASCULAR DISEASE. MOST CASES OF DISTURBED ENERGY BALANCE ARE LIKELY A RESULT OF A COMBINATION OF GENETICS, EPIGENETICS AND ENVIRONMENT. THIS REVIEW WILL DISCUSS POTENTIAL MECHANISMS LINKING INTRAUTERINE GROWTH RETARDATION WITH CHANGES IN GROWTH, ENERGY HOMEOSTASIS AND SEXUAL MATURATION. 2012 6 5450 37 REPRODUCTIVE TOXICITY OF COMBINED EFFECTS OF ENDOCRINE DISRUPTORS ON HUMAN REPRODUCTION. CONFLUENCE OF ENVIRONMENTAL, GENETIC, AND LIFESTYLE VARIABLES IS RESPONSIBLE FOR DETERIORATION OF HUMAN FECUNDITY. ENDOCRINE DISRUPTORS OR ENDOCRINE DISRUPTING CHEMICALS (EDCS) MAY BE FOUND IN A VARIETY OF FOODS, WATER, AIR, BEVERAGES, AND TOBACCO SMOKE. IT HAS BEEN DEMONSTRATED IN EXPERIMENTAL INVESTIGATIONS THAT A WIDE RANGE OF ENDOCRINE DISRUPTING CHEMICALS HAVE NEGATIVE EFFECTS ON HUMAN REPRODUCTIVE FUNCTION. HOWEVER, EVIDENCE ON THE REPRODUCTIVE CONSEQUENCES OF HUMAN EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS IS SPARSE AND/OR CONFLICTING IN THE SCIENTIFIC LITERATURE. THE COMBINED TOXICOLOGICAL ASSESSMENT IS A PRACTICAL METHOD FOR ASSESSING THE HAZARDS OF COCKTAILS OF CHEMICALS, CO-EXISTING IN THE ENVIRONMENT. THE CURRENT REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF STUDIES EMPHASIZING THE COMBINED TOXICITY OF ENDOCRINE DISRUPTING CHEMICALS ON HUMAN REPRODUCTION. ENDOCRINE DISRUPTING CHEMICALS INTERACT WITH EACH OTHER TO DISRUPT THE DIFFERENT ENDOCRINE AXES, RESULTING IN SEVERE GONADAL DYSFUNCTIONS. TRANSGENERATIONAL EPIGENETIC EFFECTS HAVE ALSO BEEN INDUCED IN GERM CELLS, MOSTLY THROUGH DNA METHYLATION AND EPIMUTATIONS. SIMILARLY, AFTER ACUTE OR CHRONIC EXPOSURE TO ENDOCRINE DISRUPTING CHEMICALS COMBINATIONS, INCREASED OXIDATIVE STRESS (OS), ELEVATED ANTIOXIDANT ENZYMATIC ACTIVITY, DISRUPTED REPRODUCTIVE CYCLE, AND REDUCED STEROIDOGENESIS ARE OFTEN REPORTED CONSEQUENCES. THE ARTICLE ALSO DISCUSSES THE CONCENTRATION ADDITION (CA) AND INDEPENDENT ACTION (IA) PREDICTION MODELS, WHICH REVEAL THE IMPORTANCE OF VARIOUS SYNERGISTIC ACTIONS OF ENDOCRINE DISRUPTING CHEMICALS MIXTURES. MORE CRUCIALLY, THIS EVIDENCE-BASED STUDY ADDRESSES THE RESEARCH LIMITATIONS AND INFORMATION GAPS, AS WELL AS PARTICULARLY PRESENTS THE FUTURE RESEARCH VIEWS ON COMBINED ENDOCRINE DISRUPTING CHEMICALS TOXICITY ON HUMAN REPRODUCTION. 2023 7 6672 41 USE OF A MOUSE IN VITRO FERTILIZATION MODEL TO UNDERSTAND THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE HYPOTHESIS HOLDS THAT ALTERATIONS TO HOMEOSTASIS DURING CRITICAL PERIODS OF DEVELOPMENT CAN PREDISPOSE INDIVIDUALS TO ADULT-ONSET CHRONIC DISEASES SUCH AS DIABETES AND METABOLIC SYNDROME. IT REMAINS CONTROVERSIAL WHETHER PREIMPLANTATION EMBRYO MANIPULATION, CLINICALLY USED TO TREAT PATIENTS WITH INFERTILITY, DISTURBS HOMEOSTASIS AND AFFECTS LONG-TERM GROWTH AND METABOLISM. TO ADDRESS THIS CONTROVERSY, WE HAVE ASSESSED THE EFFECTS OF IN VITRO FERTILIZATION (IVF) ON POSTNATAL PHYSIOLOGY IN MICE. WE DEMONSTRATE THAT IVF AND EMBRYO CULTURE, EVEN UNDER CONDITIONS CONSIDERED OPTIMAL FOR MOUSE EMBRYO CULTURE, ALTER POSTNATAL GROWTH TRAJECTORY, FAT ACCUMULATION, AND GLUCOSE METABOLISM IN ADULT MICE. UNBIASED METABOLIC PROFILING IN SERUM AND MICROARRAY ANALYSIS OF PANCREATIC ISLETS AND INSULIN SENSITIVE TISSUES (LIVER, SKELETAL MUSCLE, AND ADIPOSE TISSUE) REVEALED BROAD CHANGES IN METABOLIC HOMEOSTASIS, CHARACTERIZED BY SYSTEMIC OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION. ADOPTING A CANDIDATE APPROACH, WE IDENTIFY THIOREDOXIN-INTERACTING PROTEIN (TXNIP), A KEY MOLECULE INVOLVED IN INTEGRATING CELLULAR NUTRITIONAL AND OXIDATIVE STATES WITH METABOLIC RESPONSE, AS A MARKER FOR PREIMPLANTATION STRESS AND DEMONSTRATE TISSUE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL TXNIP MISREGULATION IN SELECTED ADULT TISSUES. IMPORTANTLY, DYSREGULATION OF TXNIP EXPRESSION IS ASSOCIATED WITH ENRICHMENT FOR H4 ACETYLATION AT THE TXNIP PROMOTER THAT PERSISTS FROM THE BLASTOCYST STAGE THROUGH ADULTHOOD IN ADIPOSE TISSUE. OUR DATA SUPPORT THE VULNERABILITY OF PREIMPLANTATION EMBRYOS TO ENVIRONMENTAL DISTURBANCE AND DEMONSTRATE THAT CONCEPTION BY IVF CAN REPROGRAM METABOLIC HOMEOSTASIS THROUGH METABOLIC, TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS WITH LASTING EFFECTS FOR ADULT GROWTH AND FITNESS. THIS STUDY HAS WIDE CLINICAL RELEVANCE AND UNDERSCORES THE IMPORTANCE OF CONTINUED FOLLOW-UP OF IVF-CONCEIVED OFFSPRING. 2014 8 375 19 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 9 5209 33 PRENATAL XENOBIOTIC EXPOSURE AND INTRAUTERINE HYPOTHALAMUS-PITUITARY-ADRENAL AXIS PROGRAMMING ALTERATION. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IS ONE OF THE MOST IMPORTANT NEUROENDOCRINE AXES AND PLAYS AN IMPORTANT ROLE IN STRESS DEFENSE RESPONSES BEFORE AND AFTER BIRTH. PRENATAL EXPOSURE TO XENOBIOTICS, INCLUDING ENVIRONMENTAL TOXINS (SUCH AS SMOKE, SULFUR DIOXIDE AND CARBON MONOXIDE), DRUGS (SUCH AS SYNTHETIC GLUCOCORTICOIDS), AND FOODS AND BEVERAGE CATEGORIES (SUCH AS ETHANOL AND CAFFEINE), AFFECTS FETAL DEVELOPMENT INDIRECTLY BY CHANGING THE MATERNAL STATUS OR DAMAGING THE PLACENTA. CERTAIN XENOBIOTICS (SUCH AS CAFFEINE, ETHANOL AND DEXAMETHASONE) MAY ALSO AFFECT THE FETUS DIRECTLY BY CROSSING THE PLACENTA INTO THE FETUS DUE TO THEIR LIPOPHILIC PROPERTIES AND LOWER MOLECULAR WEIGHTS. ALL OF THESE FACTORS PROBABLY RESULT IN INTRAUTERINE PROGRAMMING ALTERATION OF THE HPA AXIS, WHICH SHOWED A LOW BASAL ACTIVITY BUT HYPERSENSITIVITY TO CHRONIC STRESS. THESE ALTERATIONS WILL, THEREFORE, INCREASE THE SUSCEPTIBILITY TO ADULT NEUROPSYCHIATRIC (SUCH AS DEPRESSION AND SCHIZOPHRENIA) AND METABOLIC DISEASES (SUCH AS HYPERTENSION, DIABETES AND NON-ALCOHOLIC FATTY LIVER DISEASE). THE "OVER-EXPOSURE OF FETUSES TO MATERNAL GLUCOCORTICOIDS" MAY BE THE MAIN INITIATION FACTOR BY WHICH THE FETAL HPA AXIS PROGRAMMING IS ALTERED. MEANTIME, XENOBIOTICS CAN DIRECTLY INDUCE ABNORMAL EPIGENETIC MODIFICATIONS AND EXPRESSION ON THE IMPORTANT FETAL GENES (SUCH AS HIPPOCAMPAL GLUCOCORTICOID RECEPTOR, ADRENAL STEROIDOGENIC ACUTE REGULATORY PROTEIN, ET AL) OR DAMAGE BY IN SITU OXIDATIVE METABOLISM OF FETAL ADRENALS, WHICH MAY ALSO BE CONTRIBUTED TO THE PROGRAMMING ALTERATION OF FETAL HPA AXIS. 2014 10 6374 37 THE ROLE OF MITOCHONDRIA IN MYOCARDIAL DAMAGE CAUSED BY ENERGY METABOLISM DISORDERS: FROM MECHANISMS TO THERAPEUTICS. MYOCARDIAL DAMAGE IS THE MOST SERIOUS PATHOLOGICAL CONSEQUENCE OF CARDIOVASCULAR DISEASES AND AN IMPORTANT REASON FOR THEIR HIGH MORTALITY. IN RECENT YEARS, BECAUSE OF THE HIGH PREVALENCE OF SYSTEMIC ENERGY METABOLISM DISORDERS (E.G., OBESITY, DIABETES MELLITUS, AND METABOLIC SYNDROME), COMPLICATIONS OF MYOCARDIAL DAMAGE CAUSED BY THESE DISORDERS HAVE ATTRACTED WIDESPREAD ATTENTION. ENERGY METABOLISM DISORDERS ARE INDEPENDENT OF TRADITIONAL INJURY-RELATED RISK FACTORS, SUCH AS ISCHEMIA, HYPOXIA, TRAUMA, AND INFECTION. AN IMBALANCE OF MYOCARDIAL METABOLIC FLEXIBILITY AND MYOCARDIAL ENERGY DEPLETION ARE USUALLY THE INITIAL CHANGES OF MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS, AND ABNORMAL MORPHOLOGY AND FUNCTIONAL DESTRUCTION OF THE MITOCHONDRIA ARE THEIR IMPORTANT FEATURES. SPECIFICALLY, MITOCHONDRIA ARE THE CENTERS OF ENERGY METABOLISM, AND RECENT EVIDENCE HAS SHOWN THAT DECREASED MITOCHONDRIAL FUNCTION, CAUSED BY AN IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL, MAY PLAY A KEY ROLE IN MYOCARDIAL INJURY CAUSED BY ENERGY METABOLISM DISORDERS. UNDER CHRONIC ENERGY STRESS, MITOCHONDRIA UNDERGO PATHOLOGICAL FISSION, WHILE MITOPHAGY, MITOCHONDRIAL FUSION, AND BIOGENESIS ARE INHIBITED, AND MITOCHONDRIAL PROTEIN BALANCE AND TRANSFER ARE DISTURBED, RESULTING IN THE ACCUMULATION OF NONFUNCTIONAL AND DAMAGED MITOCHONDRIA. CONSEQUENTLY, DAMAGED MITOCHONDRIA LEAD TO MYOCARDIAL ENERGY DEPLETION AND THE ACCUMULATION OF LARGE AMOUNTS OF REACTIVE OXYGEN SPECIES, FURTHER AGGRAVATING THE IMBALANCE IN MITOCHONDRIAL QUALITY CONTROL AND FORMING A VICIOUS CYCLE. IN ADDITION, IMPAIRED MITOCHONDRIA COORDINATE CALCIUM HOMEOSTASIS IMBALANCE, AND EPIGENETIC ALTERATIONS PARTICIPATE IN THE PATHOGENESIS OF MYOCARDIAL DAMAGE. THESE PATHOLOGICAL CHANGES INDUCE RAPID PROGRESSION OF MYOCARDIAL DAMAGE, EVENTUALLY LEADING TO HEART FAILURE OR SUDDEN CARDIAC DEATH. TO INTERVENE MORE SPECIFICALLY IN THE MYOCARDIAL DAMAGE CAUSED BY METABOLIC DISORDERS, WE NEED TO UNDERSTAND THE SPECIFIC ROLE OF MITOCHONDRIA IN THIS CONTEXT IN DETAIL. ACCORDINGLY, PROMISING THERAPEUTIC STRATEGIES HAVE BEEN PROPOSED. WE ALSO SUMMARIZE THE EXISTING THERAPEUTIC STRATEGIES TO PROVIDE A REFERENCE FOR CLINICAL TREATMENT AND DEVELOPING NEW THERAPIES. 2023 11 5033 35 PESTICIDES AND HUMAN CHRONIC DISEASES: EVIDENCES, MECHANISMS, AND PERSPECTIVES. ALONG WITH THE WIDE USE OF PESTICIDES IN THE WORLD, THE CONCERNS OVER THEIR HEALTH IMPACTS ARE RAPIDLY GROWING. THERE IS A HUGE BODY OF EVIDENCE ON THE RELATION BETWEEN EXPOSURE TO PESTICIDES AND ELEVATED RATE OF CHRONIC DISEASES SUCH AS DIFFERENT TYPES OF CANCERS, DIABETES, NEURODEGENERATIVE DISORDERS LIKE PARKINSON, ALZHEIMER, AND AMYOTROPHIC LATERAL SCLEROSIS (ALS), BIRTH DEFECTS, AND REPRODUCTIVE DISORDERS. THERE IS ALSO CIRCUMSTANTIAL EVIDENCE ON THE ASSOCIATION OF EXPOSURE TO PESTICIDES WITH SOME OTHER CHRONIC DISEASES LIKE RESPIRATORY PROBLEMS, PARTICULARLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), CARDIOVASCULAR DISEASE SUCH AS ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE, CHRONIC NEPHROPATHIES, AUTOIMMUNE DISEASES LIKE SYSTEMIC LUPUS ERYTHEMATOUS AND RHEUMATOID ARTHRITIS, CHRONIC FATIGUE SYNDROME, AND AGING. THE COMMON FEATURE OF CHRONIC DISORDERS IS A DISTURBANCE IN CELLULAR HOMEOSTASIS, WHICH CAN BE INDUCED VIA PESTICIDES' PRIMARY ACTION LIKE PERTURBATION OF ION CHANNELS, ENZYMES, RECEPTORS, ETC., OR CAN AS WELL BE MEDIATED VIA PATHWAYS OTHER THAN THE MAIN MECHANISM. IN THIS REVIEW, WE PRESENT THE HIGHLIGHTED EVIDENCE ON THE ASSOCIATION OF PESTICIDE'S EXPOSURE WITH THE INCIDENCE OF CHRONIC DISEASES AND INTRODUCE GENETIC DAMAGES, EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS AND UNFOLDED PROTEIN RESPONSE (UPR), IMPAIRMENT OF UBIQUITIN PROTEASOME SYSTEM, AND DEFECTIVE AUTOPHAGY AS THE EFFECTIVE MECHANISMS OF ACTION. 2013 12 1638 40 DOES EARLY WEANING SHAPE FUTURE ENDOCRINE AND METABOLIC DISORDERS? LESSONS FROM ANIMAL MODELS. OBESITY AND ITS COMPLICATIONS OCCUR AT ALARMING RATES WORLDWIDE. EPIDEMIOLOGICAL DATA HAVE ASSOCIATED PERINATAL CONDITIONS, SUCH AS MALNUTRITION, WITH THE DEVELOPMENT OF SOME DISORDERS, SUCH AS OBESITY, DYSLIPIDEMIA, DIABETES, AND CARDIOVASCULAR DISEASES, IN CHILDHOOD AND ADULTHOOD. EXCLUSIVE BREASTFEEDING HAS BEEN ASSOCIATED WITH PROTECTION AGAINST LONG-TERM CHRONIC DISEASES. HOWEVER, IN HUMANS, THE INTERRUPTION OF BREASTFEEDING BEFORE THE RECOMMENDED PERIOD OF 6 MONTHS IS A COMMON PRACTICE AND CAN INCREASE THE RISK OF SEVERAL METABOLIC DISTURBANCES. NUTRITIONAL AND ENVIRONMENTAL CHANGES WITHIN A CRITICAL WINDOW OF DEVELOPMENT, SUCH AS PREGNANCY AND BREASTFEEDING, CAN INDUCE PERMANENT CHANGES IN METABOLISM THROUGH EPIGENETIC MECHANISMS, LEADING TO DISEASES LATER IN LIFE VIA A PHENOMENON KNOWN AS PROGRAMMING OR DEVELOPMENTAL PLASTICITY. HOWEVER, LITTLE IS KNOWN REGARDING THE UNDERLYING MECHANISMS BY WHICH PRECOCIOUS WEANING CAN RESULT IN ADIPOSE TISSUE DYSFUNCTION AND ENDOCRINE PROFILE ALTERATIONS. HERE, THE AUTHORS GIVE A COMPREHENSIVE REPORT OF THE DIFFERENT ANIMAL MODELS OF EARLY WEANING AND PROGRAMMING THAT CAN RESULT IN THE DEVELOPMENT OF METABOLIC SYNDROME. IN RATS, FOR EXAMPLE, PHARMACOLOGICAL AND NONPHARMACOLOGICAL EARLY WEANING MODELS ARE ASSOCIATED WITH THE DEVELOPMENT OF OVERWEIGHT AND VISCERAL FAT ACCUMULATION, LEPTIN AND INSULIN RESISTANCE, AND NEUROENDOCRINE AND HEPATIC CHANGES IN ADULT PROGENY. SEX-RELATED DIFFERENCES SEEM TO INFLUENCE THIS PHENOTYPE. THEREFORE, PRECOCIOUS WEANING SEEMS TO BE OBESOGENIC FOR OFFSPRING. A BETTER UNDERSTANDING OF THIS CONDITION SEEMS ESSENTIAL TO REDUCING THE RISK FOR DISEASES. ADDITIONALLY, THIS KNOWLEDGE CAN GENERATE NEW INSIGHTS INTO THERAPEUTIC STRATEGIES FOR OBESITY MANAGEMENT, IMPROVING HEALTH OUTCOMES. 2020 13 6406 33 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 14 1376 36 DEVELOPMENTAL PROGRAMMING OF BODY COMPOSITION: UPDATE ON EVIDENCE AND MECHANISMS. PURPOSE OF REVIEW: A GROWING BODY OF EPIDEMIOLOGICAL AND EXPERIMENTAL DATA INDICATE THAT NUTRITIONAL OR ENVIRONMENTAL STRESSORS DURING EARLY DEVELOPMENT CAN INDUCE LONG-TERM ADAPTATIONS THAT INCREASE RISK OF OBESITY, DIABETES, CARDIOVASCULAR DISEASE, AND OTHER CHRONIC CONDITIONS-A PHENOMENON TERMED "DEVELOPMENTAL PROGRAMMING." A COMMON PHENOTYPE IN HUMANS AND ANIMAL MODELS IS ALTERED BODY COMPOSITION, WITH REDUCED MUSCLE AND BONE MASS, AND INCREASED FAT MASS. IN THIS REVIEW, WE SUMMARIZE THE RECENT LITERATURE LINKING PRENATAL FACTORS TO FUTURE BODY COMPOSITION AND EXPLORE CONTRIBUTING MECHANISMS. RECENT FINDINGS: MANY PRENATAL EXPOSURES, INCLUDING INTRAUTERINE GROWTH RESTRICTION, EXTREMES OF BIRTH WEIGHT, MATERNAL OBESITY, AND MATERNAL DIABETES, ARE ASSOCIATED WITH INCREASED FAT MASS, REDUCED MUSCLE MASS, AND DECREASED BONE DENSITY, WITH EFFECTS REPORTED THROUGHOUT INFANCY AND CHILDHOOD, AND PERSISTING INTO MIDDLE AGE. MECHANISMS AND MEDIATORS INCLUDE MATERNAL DIET, BREASTMILK COMPOSITION, METABOLITES, APPETITE REGULATION, GENETIC AND EPIGENETIC INFLUENCES, STEM CELL COMMITMENT AND FUNCTION, AND MITOCHONDRIAL METABOLISM. DIFFERENCES IN BODY COMPOSITION ARE A COMMON PHENOTYPE FOLLOWING DISRUPTIONS TO THE PRENATAL ENVIRONMENT, AND MAY CONTRIBUTE TO DEVELOPMENTAL PROGRAMMING OF OBESITY AND DIABETES RISK. 2019 15 5136 32 POTENTIAL MECHANISMS LINKING PSYCHOLOGICAL STRESS TO BONE HEALTH. CHRONIC PSYCHOLOGICAL STRESS AFFECTS MANY BODY SYSTEMS, INCLUDING THE SKELETON, THROUGH VARIOUS MECHANISMS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF THE FACTORS MEDIATING THE RELATIONSHIP BETWEEN PSYCHOLOGICAL STRESS AND BONE HEALTH. THESE FACTORS CAN BE DIVIDED INTO PHYSIOLOGICAL AND BEHAVIOURAL CHANGES INDUCED BY PSYCHOLOGICAL STRESS. THE PHYSIOLOGICAL FACTORS INVOLVE ENDOCRINOLOGICAL CHANGES, SUCH AS INCREASED GLUCOCORTICOIDS, PROLACTIN, LEPTIN AND PARATHYROID HORMONE LEVELS AND REDUCED GONADAL HORMONES. LOW-GRADE INFLAMMATION AND HYPERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM DURING PSYCHOLOGICAL STRESS ARE ALSO PHYSIOLOGICAL CHANGES DETRIMENTAL TO BONE HEALTH. THE BEHAVIOURAL CHANGES DURING MENTAL STRESS, SUCH AS ALTERED DIETARY PATTERN, CIGARETTE SMOKING, ALCOHOLISM AND PHYSICAL INACTIVITY, ALSO THREATEN THE SKELETAL SYSTEM. PSYCHOLOGICAL STRESS MAY BE PARTLY RESPONSIBLE FOR EPIGENETIC REGULATION OF SKELETAL DEVELOPMENT. IT MAY ALSO MEDIATE THE RELATIONSHIP BETWEEN SOCIOECONOMIC STATUS AND BONE HEALTH. HOWEVER, MORE DIRECT EVIDENCE IS REQUIRED TO PROVE THESE HYPOTHESES. IN CONCLUSION, CHRONIC PSYCHOLOGICAL STRESS SHOULD BE RECOGNISED AS A RISK FACTOR OF OSTEOPOROSIS AND STRESS-COPING METHODS SHOULD BE INCORPORATED AS PART OF THE COMPREHENSIVE OSTEOPOROSIS-PREVENTING STRATEGY. 2021 16 6169 28 THE GUT MICROBIOTA AND HEALTHY AGING: A MINI-REVIEW. THE GUT MICROBIOTA SHOWS A WIDE INTER-INDIVIDUAL VARIATION, BUT ITS WITHIN-INDIVIDUAL VARIATION IS RELATIVELY STABLE OVER TIME. A FUNCTIONAL CORE MICROBIOME, PROVIDED BY ABUNDANT BACTERIAL TAXA, SEEMS TO BE COMMON TO VARIOUS HUMAN HOSTS REGARDLESS OF THEIR GENDER, GEOGRAPHIC LOCATION, AND AGE. WITH ADVANCING CHRONOLOGICAL AGE, THE GUT MICROBIOTA BECOMES MORE DIVERSE AND VARIABLE. HOWEVER, WHEN MEASURES OF BIOLOGICAL AGE ARE USED WITH ADJUSTMENT FOR CHRONOLOGICAL AGE, OVERALL RICHNESS DECREASES, WHILE A CERTAIN GROUP OF BACTERIA ASSOCIATED WITH FRAILTY INCREASES. THIS HIGHLIGHTS THE IMPORTANCE OF CONSIDERING BIOLOGICAL OR FUNCTIONAL MEASURES OF AGING. STUDIES USING MODEL ORGANISMS INDICATE THAT AGE-RELATED GUT DYSBIOSIS MAY CONTRIBUTE TO UNHEALTHY AGING AND REDUCED LONGEVITY. THE GUT MICROBIOME DEPENDS ON THE HOST NUTRIENT SIGNALING PATHWAYS FOR ITS BENEFICIAL EFFECTS ON HOST HEALTH AND LIFESPAN, AND GUT DYSBIOSIS DISRUPTING THE INTERDEPENDENCE MAY DIMINISH THE BENEFICIAL EFFECTS OR EVEN HAVE REVERSE EFFECTS. GUT DYSBIOSIS CAN TRIGGER THE INNATE IMMUNE RESPONSE AND CHRONIC LOW-GRADE INFLAMMATION, LEADING TO MANY AGE-RELATED DEGENERATIVE PATHOLOGIES AND UNHEALTHY AGING. THE GUT MICROBIOTA COMMUNICATES WITH THE HOST THROUGH VARIOUS BIOMOLECULES, NUTRIENT SIGNALING-INDEPENDENT PATHWAYS, AND EPIGENETIC MECHANISMS. DISTURBANCE OF THESE COMMUNICATIONS BY AGE-RELATED GUT DYSBIOSIS CAN AFFECT THE HOST HEALTH AND LIFESPAN. THIS MAY EXPLAIN THE IMPACT OF THE GUT MICROBIOME ON HEALTH AND AGING. 2018 17 4798 45 NUTRITIONALLY MEDIATED PROGRAMMING OF THE DEVELOPING IMMUNE SYSTEM. A GROWING BODY OF EVIDENCE HIGHLIGHTS THE IMPORTANCE OF A MOTHER'S NUTRITION FROM PRECONCEPTION THROUGH LACTATION IN PROGRAMMING THE EMERGING ORGAN SYSTEMS AND HOMEOSTATIC PATHWAYS OF HER OFFSPRING. THE DEVELOPING IMMUNE SYSTEM MAY BE PARTICULARLY VULNERABLE. INDEED, EXAMPLES OF NUTRITION-MEDIATED IMMUNE PROGRAMMING CAN BE FOUND IN THE LITERATURE ON INTRA-UTERINE GROWTH RETARDATION, MATERNAL MICRONUTRIENT DEFICIENCIES, AND INFANT FEEDING. CURRENT MODELS OF IMMUNE ONTOGENY DEPICT A "LAYERED" EXPANSION OF INCREASINGLY COMPLEX DEFENSES, WHICH MAY BE PERMANENTLY ALTERED BY MATERNAL MALNUTRITION. ONE PROGRAMMING MECHANISM INVOLVES ACTIVATION OF THE MATERNAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO NUTRITIONAL STRESS. FETAL OR NEONATAL EXPOSURE TO ELEVATED STRESS HORMONES IS LINKED IN ANIMAL STUDIES TO PERMANENT CHANGES IN NEUROENDOCRINE-IMMUNE INTERACTIONS, WITH DIVERSE MANIFESTATIONS SUCH AS AN ATTENUATED INFLAMMATORY RESPONSE OR REDUCED RESISTANCE TO TUMOR COLONIZATION. MATERNAL MALNUTRITION MAY ALSO HAVE A DIRECT INFLUENCE, AS EVIDENCED BY NUTRIENT-DRIVEN EPIGENETIC CHANGES TO DEVELOPING T REGULATORY CELLS AND SUBSEQUENT RISK OF ALLERGY OR ASTHMA. A 3RD PROGRAMMING PATHWAY INVOLVES PLACENTAL OR BREAST MILK TRANSFER OF MATERNAL IMMUNE FACTORS WITH IMMUNOMODULATORY FUNCTIONS (E.G. CYTOKINES). MATERNAL MALNUTRITION CAN DIRECTLY AFFECT TRANSFER MECHANISMS OR INFLUENCE THE QUALITY OR QUANTITY OF TRANSFERRED FACTORS. THE PUBLIC HEALTH IMPLICATIONS OF NUTRITION-MEDIATED IMMUNE PROGRAMMING ARE OF PARTICULAR IMPORTANCE IN THE DEVELOPING WORLD, WHERE PREVALENT MATERNAL UNDERNUTRITION IS COUPLED WITH PERSISTENT INFECTIOUS CHALLENGES. HOWEVER, EARLY ALTERATIONS TO THE IMMUNE SYSTEM, RESULTING FROM EITHER NUTRITIONAL DEFICIENCIES OR EXCESSES, HAVE BROAD RELEVANCE FOR IMMUNE-MEDIATED DISEASES, SUCH AS ASTHMA, AND CHRONIC INFLAMMATORY CONDITIONS LIKE CARDIOVASCULAR DISEASE. 2011 18 3397 33 HOW ADVANCED ARE WE ON THE CONSEQUENCES OF ORAL EXPOSURE TO FOOD CONTAMINANTS ON THE OCCURRENCE OF CHRONIC NON COMMUNICABLE DISEASES? THE DEVELOPMENT OF AN INDIVIDUAL DURING FETAL LIFE AND CHILDHOOD IS CHARACTERIZED BY RAPID GROWTH AS WELL AS GRADUAL MATURATION OF ORGANS AND SYSTEMS. BEYOND THE NUTRITIONAL INTAKE IN ESSENTIAL NUTRIENTS, FOOD CONTAMINANTS CAN PERMANENTLY INFLUENCE THE WAY ORGANS MATURE AND FUNCTION. THESE PROCESSES ARE CALLED "PROGRAMMING" AND PLAY AN ESSENTIAL ROLE IN THE OCCURRENCE OF NON-COMMUNICABLE CHRONIC DISEASES THROUGHOUT THE LIFESPAN. POPULATIONS AS PREGNANT WOMEN, FETUSES AND YOUNG CHILDREN ARE VULNERABLE AND PARTICULARLY SENSITIVE TO FOOD CONTAMINANTS WHICH CAN INDUCE EPIGENETIC MODIFICATIONS TRANSMISSIBLE TO FUTURE GENERATIONS. AMONG THESE CONTAMINANTS, PESTICIDES ARE FOUND IN MOST FOOD MATRICES EXPOSING HUMANS TO COCKTAILS OF MOLECULES THROUGH VARIABLE CONCENTRATIONS AND DURATION OF EXPOSURE. THE MAILLARD REACTION PRODUCTS (MRPS) REPRESENT OTHER FOOD CONTAMINANTS RESULTING FROM HEAT TREATMENT OF FOOD. MODERN DIET, RICH IN FATS AND SUGARS, IS ALSO RICH IN NEOFORMED PATHOGENIC COMPOUNDS, ADVANCED GLYCATION END PRODUCTS (AGES), THE LEVELS OF WHICH DEPEND ON THE HEAT TREATMENT OF FOODS AND EATING HABITS AND WHOSE EFFECTS ON HEALTH ARE CONTROVERSIAL. IN THIS REVIEW, WE HAVE CHOSEN TO PRESENT THE CURRENT KNOWLEDGE ON THE IMPACTS OF SELECTED PESTICIDES AND MRPS, ON THE RISK OF DEVELOPING DURING LIFE NON-COMMUNICABLE CHRONIC DISEASES SUCH AS IBD, METABOLIC DISORDERS OR ALLERGIES. A LARGE REVIEW OF LITERATURE WAS PERFORMED VIA PUBMED, AND THE MOST APPROPRIATE STUDIES WERE SUMMARISED. 2022 19 4977 49 PATHOPHYSIOLOGY AND EVOLUTIONARY ASPECTS OF DIETARY FATS AND LONG-CHAIN POLYUNSATURATED FATTY ACIDS ACROSS THE LIFE CYCLE. DIETARY FAT IS OUR SECOND MOST IMPORTANT ENERGY-PRODUCING MACRONUTRIENT. IT ALSO CONTAINS FATTY ACIDS AND VITAMINS ESSENTIAL FOR GROWTH, DEVELOPMENT, AND MAINTENANCE OF GOOD HEALTH. DIETARY FAT QUANTITY AND QUALITY HAVE BEEN SUBJECT TO TREMENDOUS CHANGE OVER THE PAST 10,000 YEARS. THIS HAS, TOGETHER WITH OTHER MAN-MADE CHANGES IN OUR ENVIRONMENT, CAUSED A CONFLICT WITH OUR SLOWLY ADAPTING GENOME THAT IS IMPLICATED IN "TYPICALLY WESTERN" DISEASES. RATHER THAN REDUCING OUR LIFE EXPECTANCY, THESE DISEASES NOTABLY DIMINISH OUR NUMBER OF YEARS IN HEALTH. IMPORTANT CHANGES IN DIETARY FAT QUALITY ARE THE INCREASED INTAKES OF CERTAIN SATURATED FATTY ACIDS (SAFA) AND LINOLEIC ACID (LA), INTRODUCTION OF INDUSTRIALLY PRODUCED TRANS FATTY ACIDS, AND REDUCED INTAKES OF OMEGA3 FATTY ACIDS, NOTABLY ALPHA-LINOLENIC ACID (ALA) FROM VEGETABLE SOURCES AND EICOSAPENTAENOIC ACID (EPA) AND DOCOSAHEXAENOIC ACID (DHA) FROM FISH. THE PATHOPHYSIOLOGICAL EFFECTS OF THESE CHANGES ARE DIVERSE, BUT ARE INCREASINGLY ASCRIBED TO INDUCTION OF A PROINFLAMMATORY STATE THAT PROGRESSES EASILY TO CHRONIC LOW-GRADE INFLAMMATION. THE LATTER MIGHT AFFECT VIRTUALLY ALL ORGANS AND SYSTEMS, POSSIBLY BEGINNING AT CONCEPTION, AND POSSIBLY EVEN PRIOR TO GAMETOGENESIS THROUGH EPIGENETIC ALTERATIONS. LOW-GRADE INFLAMMATION MIGHT BE A COMMON DENOMINATOR OF THE METABOLIC SYNDROME AND ITS SEQUELAE (E.G., CORONARY ARTERY DISEASE (CAD), DIABETES MELLITUS TYPE 2, SOME TYPES OF CANCER, AND PREGNANCY COMPLICATIONS), SOME PSYCHIATRIC DISEASES (E.G., MAJOR AND POSTPARTUM DEPRESSION, SCHIZOPHRENIA, AND AUTISM), AND NEURODEGENERATIVE DISEASES (E.G., ALZHEIMER'S DISEASE, PARKINSON'S DISEASE). THE LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LCPUFA) ARACHIDONIC ACID (AA), EPA, AND DHA ARE INTIMATELY RELATED TO THE INITIATION AND RESOLUTION OF INFLAMMATORY RESPONSES. THE CURRENT BALANCE BETWEEN AA AND EPA + DHA IS HOWEVER DISTURBED BY THE DOMINANCE OF AA, WHICH ORIGINATES FROM THE DIET OR SYNTHESIS FROM LA. LCPUFA ARE TOGETHER WITH THEIR HIGHLY POTENT METABOLITES (PROSTAGLANDINS, THROMBOXANES, LEUKOTRIENES, RESOLVINS, AND (NEURO)PROTECTINS) INVOLVED IN THE FUNCTIONING OF MEMBRANE-BOUND RECEPTORS, TRANSPORTERS, ION CHANNELS, AND ENZYMES, AND ALSO IN SIGNAL TRANSDUCTION AND GENE EXPRESSION. AMONG THEIR MANY TARGETS ARE NUCLEAR RECEPTORS WHICH, UPON LIGATION WITH LCPUFA AND THEIR METABOLITES, FUNCTION AS TRANSCRIPTION FACTORS OF A VARIETY OF GENES FUNCTIONING IN MANY PATHWAYS. FOR INSTANCE, THE TARGETED PEROXISOME PROLIFERATORS-ACTIVATED RECEPTORS (PPARS) ARE STRATEGIC INTERMEDIATES IN THE COORDINATED EXPRESSION OF PROTEINS WITH FUNCTIONS IN, FOR EXAMPLE, LIPID AND GLUCOSE HOMEOSTASIS AND INFLAMMATORY REACTIONS. MANY INTERVENTIONS HAVE BEEN CONDUCTED WITH LCPUFA, ESPECIALLY EPA AND DHA, AIMING AT PRIMARY AND SECONDARY CAD PREVENTIONS, IMPROVEMENT OF FETAL AND NEWBORN (BRAIN) DEVELOPMENT BY SUPPLEMENTATION DURING PREGNANCY OR EARLY POSTNATAL LIFE, AND IN PSYCHIATRIC DISEASES. CONSENSUS HAS BEEN REACHED THAT THOSE IN CAD AND DEPRESSION ARE POSITIVE, ALTHOUGH MORE LARGE-SCALE TRIALS ARE NEEDED. MANY RECOMMENDATIONS FOR THE INTAKES OF SATURATED FAT, TRANS FAT AND EPA + DHA HAVE BEEN ISSUED, NOTABLY FOR CAD PREVENTION, AND ALSO FOR EPA + DHA INTAKES BY PREGNANT WOMEN AND FOR AA, EPA, AND DHA INTAKES BY NEWBORNS. THE ULTIMATE GOAL MIGHT, HOWEVER, BE TO RETURN TO THE FAT QUALITY OF OUR ANCIENT DIET ON WHICH OUR GENES HAVE EVOLVED DURING THE PAST MILLION YEARS OF EVOLUTION, WHILE THIS ACTUALLY APPLIES FOR OUR ENTIRE DIETARY COMPOSITION AND LIFESTYLE, AS TRANSLATED TO THE CULTURE OF THE CURRENT SOCIETY. 2010 20 2699 39 EXCESS BODY WEIGHT: NOVEL INSIGHTS INTO ITS ROLES IN OBESITY COMORBIDITIES. EXCESS BODY WEIGHT IS A GLOBAL HEALTH PROBLEM DUE TO SEDENTARY LIFESTYLE AND UNHEALTHY DIET, AFFECTING 2 BILLION POPULATION WORLDWIDE. OBESITY IS A MAJOR RISK FACTOR FOR METABOLIC DISEASES. NOTABLY, THE METABOLIC RISK OF OBESITY LARGELY DEPENDS ON BODY WEIGHT DISTRIBUTION, OF WHICH VISCERAL ADIPOSE TISSUES BUT NOT SUBCUTANEOUS FATS ARE CLOSELY ASSOCIATED WITH OBESITY COMORBIDITIES, INCLUDING TYPE 2 DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASE AND CERTAIN TYPES OF CANCER. LATEST MULTI-OMICS AND MECHANISTICAL STUDIES REPORTED THE CRUCIAL INVOLVEMENT OF GENETIC AND EPIGENETIC ALTERATIONS, ADIPOKINES DYSREGULATION, IMMUNITY CHANGES, IMBALANCE OF WHITE AND BROWN ADIPOSE TISSUES, AND GUT MICROBIAL DYSBIOSIS IN MEDIATING THE PATHOGENIC ASSOCIATION BETWEEN VISCERAL ADIPOSE TISSUES AND COMORBIDITIES. IN THIS REVIEW, WE EXPLORE THE EPIDEMIOLOGY OF EXCESS BODY WEIGHT AND THE UP-TO-DATE MECHANISM OF HOW EXCESS BODY WEIGHT AND OBESITY LEAD TO CHRONIC COMPLICATIONS. WE ALSO EXAMINE THE UTILIZATION OF VISCERAL FAT MEASUREMENT AS AN ACCURATE CLINICAL PARAMETER FOR RISK ASSESSMENT IN HEALTHY INDIVIDUALS AND CLINICAL OUTCOME PREDICTION IN OBESE SUBJECTS. IN ADDITION, CURRENT APPROACHES FOR THE PREVENTION AND TREATMENT OF EXCESS BODY WEIGHT AND ITS RELATED METABOLIC COMORBIDITIES ARE FURTHER DISCUSSED. 2023