1 3614 121 IN VITRO CELL TRANSFORMATION ASSAYS: A VALUABLE APPROACH FOR CARCINOGENIC POTENTIALITY ASSESSMENT OF NANOMATERIALS. THIS REVIEW EXPLORES THE APPLICATION OF IN VITRO CELL TRANSFORMATION ASSAYS (CTAS) AS A SCREENING PLATFORM TO ASSESS THE CARCINOGENIC POTENTIAL OF NANOMATERIALS (NMS) RESULTING FROM CONTINUOUSLY GROWING INDUSTRIAL PRODUCTION AND USE. THE WIDESPREAD APPLICATION OF NMS IN VARIOUS FIELDS HAS RAISED CONCERNS ABOUT THEIR POTENTIAL ADVERSE EFFECTS, NECESSITATING SAFETY EVALUATIONS, PARTICULARLY IN LONG-TERM CONTINUOUS EXPOSURE SCENARIOS. CTAS PRESENT A REALISTIC SCREENING PLATFORM FOR KNOWN AND EMERGING NMS BY EXAMINING THEIR RESEMBLANCE TO THE HALLMARK OF MALIGNANCY, INCLUDING HIGH PROLIFERATION RATES, LOSS OF CONTACT INHIBITION, THE GAIN OF ANCHORAGE-INDEPENDENT GROWTH, CELLULAR INVASION, DYSREGULATION OF THE CELL CYCLE, APOPTOSIS RESISTANCE, AND ABILITY TO FORM TUMORS IN EXPERIMENTAL ANIMALS. THROUGH THE DELIBERATE TRANSFORMATION OF CELLS VIA CHRONIC NM EXPOSURE, RESEARCHERS CAN INVESTIGATE THE TUMORIGENIC PROPERTIES OF NMS AND THE UNDERLYING MECHANISMS OF CANCER DEVELOPMENT. THIS ARTICLE EXAMINES NM-INDUCED CELL TRANSFORMATION STUDIES, FOCUSING ON IDENTIFYING EXISTING KNOWLEDGE GAPS. SPECIFICALLY, IT EXPLORES THE PHYSICOCHEMICAL PROPERTIES OF NMS, EXPERIMENTAL MODELS, ASSAYS, DOSE AND TIME REQUIREMENTS FOR CELL TRANSFORMATION, AND THE UNDERLYING MECHANISMS OF MALIGNANCY. OUR REVIEW AIMS TO ADVANCE UNDERSTANDING IN THIS FIELD AND IDENTIFY AREAS FOR FURTHER INVESTIGATION. 2023 2 4312 36 MICRORNAS AS A SUITABLE BIOMARKER TO DETECT THE EFFECTS OF LONG-TERM EXPOSURES TO NANOMATERIALS. STUDIES ON TIO(2)NP AND MWCNT. THE PRESENCE OF NANOMATERIALS (NMS) IN THE ENVIRONMENT MAY REPRESENT A SERIOUS RISK TO HUMAN HEALTH, ESPECIALLY IN A SCENARIO OF CHRONIC EXPOSURE. TO EVALUATE THE POTENTIAL RELATIONSHIP BETWEEN NM-INDUCED EPIGENETIC ALTERATIONS AND CARCINOGENESIS, THE PRESENT STUDY ANALYZED A PANEL OF 33 MIRNAS RELATED TO THE CELL TRANSFORMATION PROCESS IN BEAS-2B CELLS TRANSFORMED BY TIO(2)NP AND LONG-TERM MWCNT EXPOSURE. OUR BATTERY REVEALED A LARGE IMPACT ON MIRNA EXPRESSION PROFILING IN CELLS EXPOSED TO BOTH NMS. FROM THIS ANALYSIS, A SMALL SET OF FIVE MIRNAS (MIR-23A, MIR-25, MIR-96, MIR-210, AND MIR-502) WERE IDENTIFIED AS INFORMATIVE BIOMARKERS OF THE TRANSFORMING EFFECTS INDUCED BY NM EXPOSURES. THE USEFULNESS OF THIS REDUCED MIRNA BATTERY WAS FURTHER VALIDATED IN OTHER PREVIOUSLY GENERATED TRANSFORMED CELL SYSTEMS BY LONG-TERM EXPOSURE TO OTHER NMS (CONP, ZNONP, MSINP, AND CEO(2)NP). INTERESTINGLY, THE FIVE SELECTED MIRNAS WERE CONSISTENTLY OVEREXPRESSED IN ALL CELL LINES AND NMS TESTED. THESE RESULTS CONFIRM THE SUITABILITY OF THE PROPOSED SET OF MRNAS TO IDENTIFY THE POTENTIAL TRANSFORMING ABILITY OF NMS. PARTICULAR ATTENTION SHOULD BE PAID TO THE EPIGENOME AND ESPECIALLY TO MIRNAS FOR HAZARD ASSESSMENT OF NMS, AS WELLS AS FOR THE STUDY OF THE UNDERLYING MECHANISMS OF ACTION. 2021 3 3955 18 LONG MARCH TOWARD SAFE AND EFFECTIVE ANALGESIA BY ENHANCING GENE EXPRESSION OF KCC2: FIRST STEPS TAKEN. LOW INTRANEURONAL CHLORIDE IN SPINAL CORD DORSAL HORN PAIN RELAY NEURONS IS CRITICAL FOR PHYSIOLOGIC TRANSMISSION OF PRIMARY PAIN AFFERENTS BECAUSE LOW INTRANEURONAL CHLORIDE DICTATES WHETHER GABA-ERGIC AND GLYCIN-ERGIC NEUROTRANSMISSION IS INHIBITORY. IF THE NEURONAL CHLORIDE ELEVATES TO PATHOLOGIC LEVELS, THEN SPINAL CORD PRIMARY PAIN RELAY BECOMES LEAKY AND EXHIBITS THE BEHAVIORAL HALLMARKS OF PATHOLOGIC PAIN, NAMELY HYPERSENSITIVITY AND ALLODYNIA. LOW CHLORIDE IN SPINAL CORD DORSAL HORN NEURONS IS MAINTAINED BY PROPER GENE EXPRESSION OF KCC2 AND SUSTAINED PHYSIOLOGIC FUNCTION OF THE KCC2 CHLORIDE EXTRUDING ELECTRONEUTRAL TRANSPORTER. PERIPHERAL NERVE INJURY AND OTHER FORMS OF NEURAL INJURY EVOKE GREATLY DIMINISHED KCC2 GENE EXPRESSION AND SUBSEQUENT CORRUPTION OF INHIBITORY NEUROTRANSMISSION IN THE SPINAL CORD DORSAL HORN, THUS CAUSING DERAILMENT OF THE GATE FUNCTION FOR PAIN. HERE I REVIEW KEY DISCOVERIES THAT HAVE HELPED US UNDERSTAND THESE FUNDAMENTALS, AND FOCUS ON RECENT INSIGHTS RELATING TO THE DISCOVERY OF KCC2 GENE EXPRESSION ENHANCING COMPOUNDS VIA COMPOUND SCREENS IN NEURONS. ONE SUCH STUDY CHARACTERIZED THE KINASE INHIBITOR, KENPAULLONE, MORE IN-DEPTH, REVEALING ITS FUNCTION AS A ROBUST AND LONG-LASTING ANALGESIC IN PRECLINICAL MODELS OF NERVE INJURY AND CANCER BONE PAIN, ALSO ELUCIDATING ITS MECHANISM OF ACTION VIA GSK3BETA INHIBITION, DIMINISHING DELTA-CATENIN PHOSPHORYLATION, AND FACILITATING ITS NUCLEAR TRANSFER AND SUBSEQUENT ENHANCEMENT OF KCC2 GENE EXPRESSION BY DE-REPRESSING KAISO EPIGENETIC TRANSCRIPTIONAL REGULATOR. FUTURE DIRECTIONS RE KCC2 GENE EXPRESSION ENHANCEMENT ARE DISCUSSED, NAMELY COMBINATION WITH OTHER ANALGESICS AND ANALGESIC METHODS, SUCH AS SPINAL CORD STIMULATION AND ELECTROACUPUNCTURE, GENE THERAPY, AND LEVERAGING KCC2 GENE EXPRESSION-ENHANCING NANOMATERIALS. 2022 4 3671 31 INFLAMMATION AND CANCER. INFECTION AND INFLAMMATION ACCOUNT FOR APPROXIMATELY 25% OF CANCER-CAUSING FACTORS. INFLAMMATION-RELATED CANCERS ARE CHARACTERIZED BY MUTAGENIC DNA LESIONS, SUCH AS 8-OXO-7,8-DIHYDRO-2'-DEOXYGUANOSINE (8-OXODG) AND 8-NITROGUANINE. OUR PREVIOUS STUDIES DEMONSTRATED THE FORMATION OF 8-OXODG AND 8-NITROGUANINE IN THE TISSUES OF CANCER AND PRECANCEROUS LESIONS DUE TO INFECTION (E.G., OPISTHORCHIS VIVERRINI-RELATED CHOLANGIOCARCINOMA, SCHISTOSOMA HAEMATOBIUM-ASSOCIATED BLADDER CANCER, HELICOBACTER PYLORI-INFECTED GASTRIC CANCER, HUMAN PAPILLOMAVIRUS-RELATED CERVICAL CANCER, EPSTEIN-BARR VIRUS-INFECTED NASOPHARYNGEAL CARCINOMA) AND PRO-INFLAMMATORY FACTORS (E.G., ASBESTOS, NANOMATERIALS, AND INFLAMMATORY DISEASES SUCH AS BARRETT'S ESOPHAGUS AND ORAL LEUKOPLAKIA). INTERESTINGLY, SEVERAL OF OUR STUDIES SUGGESTED THAT INFLAMMATION-ASSOCIATED DNA DAMAGE IN CANCER STEM-LIKE CELLS LEADS TO CANCER DEVELOPMENT WITH AGGRESSIVE CLINICAL FEATURES. REACTIVE OXYGEN/NITROGEN SPECIES FROM INFLAMMATION DAMAGE NOT ONLY DNA BUT ALSO OTHER BIOMACROMOLECULES, SUCH AS PROTEINS AND LIPIDS, RESULTING IN THEIR DYSFUNCTION. WE IDENTIFIED OXIDATIVELY DAMAGED PROTEINS IN CANCER TISSUES BY 2D OXYBLOT FOLLOWED BY MALDI-TOF/TOF. AS AN EXAMPLE, OXIDATIVELY DAMAGED TRANSFERRIN RELEASED IRON ION, WHICH MAY MEDIATE FENTON REACTIONS AND GENERATE ADDITIONAL REACTIVE OXYGEN SPECIES. DYSFUNCTION OF ANTI-OXIDATIVE PROTEINS DUE TO THIS DAMAGE MIGHT INCREASE OXIDATIVE STRESS. SUCH DAMAGE IN BIOMACROMOLECULES MAY FORM A VICIOUS CYCLE OF OXIDATIVE STRESS, LEADING TO CANCER DEVELOPMENT. EPIGENETIC ALTERATIONS SUCH AS DNA METHYLATION AND MICRORNA DYSREGULATION PLAY VITAL ROLES IN CARCINOGENESIS, ESPECIALLY IN INFLAMMATION-RELATED CANCERS. WE EXAMINED EPIGENETIC ALTERATIONS, DNA METHYLATION AND MICRORNA DYSREGULATION, IN EPSTEIN-BARR VIRUS-RELATED NASOPHARYNGEAL CARCINOMA IN THE ENDEMIC AREA OF SOUTHERN CHINA AND FOUND SEVERAL DIFFERENTIALLY METHYLATED TUMOR SUPPRESSOR GENE CANDIDATES BY USING A NEXT-GENERATION SEQUENCER. AMONG THESE CANDIDATES, WE REVEALED HIGHER METHYLATION RATES OF RAS-LIKE ESTROGEN-REGULATED GROWTH INHIBITOR (RERG) IN BIOPSY SPECIMENS OF NASOPHARYNGEAL CARCINOMA MORE CONVENIENTLY BY USING RESTRICTION ENZYME-BASED REAL-TIME PCR. THIS RESULT MAY HELP TO IMPROVE CANCER SCREENING STRATEGIES. WE PROFILED MICRORNAS OF NASOPHARYNGEAL CARCINOMA TISSUES USING MICROARRAYS. QUANTITATIVE RT-PCR ANALYSIS CONFIRMED THE CONCORDANT DOWNREGULATION OF MIR-497 IN CANCER TISSUES AND PLASMA, SUGGESTING THAT PLASMA MIR-497 COULD BE USED AS A DIAGNOSTIC BIOMARKER FOR NASOPHARYNGEAL CARCINOMA. CHRONIC INFLAMMATION PROMOTES GENETIC AND EPIGENETIC ABERRATIONS, WITH VARIOUS PATHOGENESES. THESE CHANGES MAY BE USEFUL BIOMARKERS IN LIQUID BIOPSY FOR EARLY DETECTION AND PREVENTION OF CANCER. 2018 5 5010 23 PEROXIDATION OF LINOLEIC, ARACHIDONIC AND OLEIC ACID IN RELATION TO THE INDUCTION OF OXIDATIVE DNA DAMAGE AND CYTOGENETIC EFFECTS. IN THE PRESENT STUDY, THE POSSIBLE ROLE OF THE POLYUNSATURATED FATTY ACIDS LINOLEIC AND ARACHIDONIC ACID IN THE CHEMICAL INDUCTION OF CARCINOGENESIS HAS BEEN INVESTIGATED. ANALYSIS OF 7,8-DIHYDRO-8-OXO-2'-DEOXYGUANOSINE (8-OXODG) LEVELS IN 2'-DEOXYGUANOSINE (DG) AND ISOLATED DNA HAS DEMONSTRATED THAT LINOLEIC AND ARACHIDONIC ACID ARE CAPABLE OF INDUCING THIS SPECIFIC GENOTOXIC DAMAGE. THIS EFFECT APPEARS TO BE RELATED TO THE DEGREE OF FATTY ACID UNSATURATION, SINCE IT WAS NOT INDUCED BY MONOUNSATURATED OLEIC ACID. ENZYMATIC PEROXIDATION OF LINOLEIC AND ARACHIDONIC ACID RESULTED IN A SIGNIFICANT INCREASE IN OXIDATIVE DNA DAMAGE. STUDIES ON THE INTERFERENCE OF RADICAL SCAVENGERS WITH THE INDUCTION OF 8-OXODG IN COMBINATION WITH ELECTRON SPIN RESONANCE SPECTROSCOPY DEMONSTRATED THAT THE SUPEROXIDE ANION WAS GENERATED DURING PEROXIDATION OF THESE FATTY ACIDS AND THAT SINGLET OXYGEN IS MOST LIKELY INVOLVED IN THE FORMATION OF OXIDATIVE DNA DAMAGE. THE LEVEL OF OXIDATIVE DAMAGE IN DG AND SINGLE-STRANDED DNA WAS HIGHER AS COMPARED TO THAT IN NATIVE DNA AFTER EQUIMOLAR TREATMENT. EXPOSURE OF HUMAN LYMPHOCYTES TO LINOLEIC OR ARACHIDONIC ACID DID NOT RESULT IN A SIGNIFICANT INCREASE IN LEVELS OF 8-OXODG. THIS MAY INDICATE THAT THE RATE OF INTRACELLULAR PEROXIDATION IS RELATIVELY LOW AND/OR THAT NUCLEAR DNA IN INTACT CELLS IS EFFECTIVELY PROTECTED AGAINST GENETIC DAMAGE INDUCED BY REACTIVE OXYGEN SPECIES. IT IS THEREFORE CONCLUDED THAT RELATIVELY SHORT PERIODS OF LINOLEIC OR ARACHIDONIC ACID ADMINISTRATION ARE NOT LIKELY TO IMPOSE A DIRECT GENOTOXIC RISK. IT CAN, HOWEVER, NOT BE EXCLUDED THAT CHRONIC EXPOSURE TO POLYUNSATURATED FATTY ACIDS INDUCES OXIDATIVE DNA DAMAGE OR IS RELATED TO CANCER RISK BY EPIGENETIC MECHANISMS, AS IS ALSO INDICATED BY THE OBSERVED CYTOTOXIC EFFECTS OF LINOLEIC AND ARACHIDONIC ACID. 1994 6 3661 25 INDUCTION OF INNATE IMMUNE MEMORY BY ENGINEERED NANOPARTICLES IN MONOCYTES/MACROPHAGES: FROM HYPOTHESIS TO REALITY. THE CAPACITY OF ENGINEERED NANOPARTICLES TO ACTIVATE CELLS OF THE INNATE IMMUNE SYSTEM, IN PARTICULAR MONOCYTES AND MACROPHAGES, IS CONSIDERED AT THE BASIS OF THEIR TOXIC/INFLAMMATORY EFFECTS. IT IS, HOWEVER, EVIDENT THAT EVEN NANOPARTICLES THAT DO NOT DIRECTLY INDUCE INFLAMMATORY ACTIVATION, AND ARE THEREFORE CONSIDERED AS SAFE, CAN NEVERTHELESS INDUCE EPIGENETIC MODIFICATIONS AND AFFECT METABOLIC PATHWAYS IN MONOCYTES AND MACROPHAGES. SINCE EPIGENETIC AND METABOLIC CHANGES ARE THE MAIN MECHANISMS OF INNATE MEMORY, WE HAD PREVIOUSLY PROPOSED THAT NANOPARTICLES CAN INDUCE/MODULATE INNATE MEMORY, THAT IS, HAVE THE ABILITY OF SHAPING THE SECONDARY RESPONSE TO INFLAMMATORY CHALLENGES. IN LIGHT OF NEW DATA, IT IS NOW POSSIBLE TO SUPPORT THE ORIGINAL HYPOTHESIS AND SHOW THAT DIFFERENT TYPES OF NANOPARTICLES CAN BOTH DIRECTLY INDUCE INNATE MEMORY, PRIMING MACROPHAGES FOR A MORE POTENT RESPONSE TO SUBSEQUENT STIMULI, AND MODULATE BACTERIA-INDUCED MEMORY BY ATTENUATING THE PRIMING-INDUCED ENHANCEMENT. THIS EVIDENCE RAISES TWO IMPORTANT ISSUES. FIRST, IN ADDITION TO OVERT TOXIC/INFLAMMATORY EFFECTS, WE SHOULD CONSIDER EVALUATING THE CAPACITY TO INDUCE INNATE MEMORY AND THE RELATED EPIGENETIC AND METABOLIC CHANGES IN THE IMMUNOSAFETY ASSESSMENT OF NANOMATERIALS, SINCE MODULATION OF INNATE MEMORY MAY BE AT THE BASIS OF LONG-TERM UNWANTED IMMUNOLOGICAL EFFECTS. THE OTHER IMPORTANT CONSIDERATION IS THAT THIS CAPACITY OF NANOMATERIALS COULD OPEN A NEW AVENUE IN IMMUNOMODULATION AND THE POSSIBILITY OF USING ENGINEERED NANOMATERIALS FOR IMPROVING IMMUNE RESPONSES TO VACCINES AND RESISTANCE TO INFECTIONS, AND MODULATE ANOMALOUS IMMUNE/INFLAMMATORY REACTIONS IN CHRONIC INFLAMMATORY DISEASES, AUTOIMMUNITY, AND A RANGE OF OTHER IMMUNE-RELATED PATHOLOGIES. 2020 7 5113 24 POPULATION-LEVEL IMPACTS OF PESTICIDE-INDUCED CHRONIC EFFECTS ON INDIVIDUALS DEPEND MORE ON ECOLOGY THAN TOXICOLOGY. THE CURRENT METHOD FOR ASSESSING LONG-TERM RISK OF PESTICIDES TO MAMMALS IN THE EU IS BASED ON THE INDIVIDUAL RATHER THAN THE POPULATION-LEVEL AND LACKS ECOLOGICAL REALISM. HENCE THERE IS LITTLE POSSIBILITY FOR REGULATORY AUTHORITIES TO INCREASE ECOLOGICAL REALISM AND UNDERSTANDING OF RISKS AT THE POPULATION-LEVEL. HERE WE DEMONSTRATE HOW, USING ABM MODELLING, ASSESSMENTS AT THE POPULATION-LEVEL CAN BE OBTAINED EVEN FOR A PESTICIDE WITH COMPLEX LONG-TERM EFFECTS SUCH AS EPIGENETIC TRANSMISSION OF REPRODUCTIVE DEPRESSION. BY OBJECTIVELY FITTING NONLINEAR MODELS TO THE SIMULATION OUTPUTS IT WAS POSSIBLE TO COMPARE POPULATION DEPRESSION AND RECOVERY RATES FOR A RANGE OF SCENARIOS IN WHICH TOXICITY AND EXPOSURE FACTORS WERE VARIED. THE SYSTEM WAS DIFFERENTIALLY SENSITIVE TO THE VARIOUS FACTORS, BUT VOLE ECOLOGY AND BEHAVIOUR WERE AT LEAST AS IMPORTANT PREDICTORS OF POPULATION-LEVEL EFFECTS AS TOXICOLOGY. THIS EMPHASISES THE NEED FOR GREATER FOCUS ON ANIMAL ECOLOGY IN RISK ASSESSMENTS. 2009 8 4588 42 NANOPARTICLE EXPOSURES FROM NANO-ENABLED TONER-BASED PRINTING EQUIPMENT AND HUMAN HEALTH: STATE OF SCIENCE AND FUTURE RESEARCH NEEDS. TONER FORMULATIONS USED BY LASER PRINTERS (LP) AND PHOTOCOPIERS (PC), COLLECTIVELY CALLED "TONER-BASED PRINTING EQUIPMENT" (TPE), ARE NANO-ENABLED PRODUCTS (NEP) BECAUSE THEY CONTAIN SEVERAL ENGINEERED NANOMATERIALS (ENM) THAT IMPROVE TONER PERFORMANCE. IT HAS BEEN SHOWN THAT DURING CONSUMER USE (PRINTING), THESE ENM ARE RELEASED IN THE AIR, TOGETHER WITH OTHER SEMI-VOLATILE ORGANIC NANOPARTICLES, AND NEWLY FORMED GASEOUS CO-POLLUTANTS SUCH AS VOLATILE ORGANIC COMPOUNDS (VOC). THE AIM OF THIS REVIEW IS TO DETAIL AND ANALYZE PHYSICO-CHEMICAL AND MORPHOLOGICAL (PCM), AS WELL AS THE TOXICOLOGICAL PROPERTIES OF PARTICULATE MATTER (PM) EMISSIONS FROM TPE. THE REVIEW COVERS EVOLUTION OF SCIENCE SINCE THE EARLY 2000, WHEN THIS PRINTING TECHNOLOGY FIRST BECAME A SUBJECT OF PUBLIC INTEREST, AS WELL AS THE LAGGING REGULATORY FRAMEWORK AROUND IT. IMPORTANT STUDIES THAT HAVE SIGNIFICANTLY CHANGED OUR UNDERSTANDING OF THESE EXPOSURES ARE ALSO HIGHLIGHTED. THE REVIEW CONTINUES WITH A CRITICAL APPRAISAL OF THE MOST UP-TO-DATE CELLULAR, ANIMAL AND HUMAN TOXICOLOGICAL EVIDENCE ON THE POTENTIAL ADVERSE HUMAN HEALTH EFFECTS OF PM EMITTED FROM TPE. WE HIGHLIGHT SEVERAL LIMITATIONS OF EXISTING STUDIES, INCLUDING (I) USE OF HIGH AND OFTEN UNREALISTIC DOSES IN VITRO OR IN VIVO; (II) UNREALISTICALLY HIGH-DOSE RATES IN INTRATRACHEAL INSTILLATION STUDIES; (III) IMPROPER USE OF TONERS AS SURROGATE FOR EMITTED NANOPARTICLES; (IV) LACK OF OR INADEQUATE PCM CHARACTERIZATION OF EXPOSURES; AND (V) LACK OF DOSIMETRY CONSIDERATIONS IN IN VITRO STUDIES. PRESENTLY, THERE IS COMPELLING EVIDENCE THAT THE PM(0.1) FROM TPE ARE BIOLOGICALLY ACTIVE AND CAPABLE OF INDUCING OXIDATIVE STRESS IN VITRO AND IN VIVO, RESPIRATORY TRACT INFLAMMATION IN VIVO (IN RATS) AND IN HUMANS, SEVERAL ENDPOINTS OF CELLULAR INJURY IN MONOCULTURES AND CO-CULTURES, INCLUDING MODERATE EPIGENETIC MODIFICATIONS IN VITRO. IN HUMANS, LIMITED EPIDEMIOLOGICAL STUDIES REPORT TYPICALLY 2-3 TIMES HIGHER PREVALENCE OF CHRONIC COUGH, WHEEZING, NASAL BLOCKAGE, EXCESSIVE SPUTUM PRODUCTION, BREATHING DIFFICULTIES, AND SHORTNESS OF BREATH, IN COPIER OPERATORS RELATIVE TO CONTROLS. SUCH SYMPTOMS CAN BE EXACERBATED DURING CHRONIC EXPOSURES, AND IN INDIVIDUALS SUSCEPTIBLE TO INHALED POLLUTANTS. THUS RESPIRATORY, IMMUNOLOGICAL, CARDIOVASCULAR, AND OTHER DISORDERS MAY BE DEVELOPED FOLLOWING SUCH EXPOSURES; HOWEVER, FURTHER TOXICOLOGICAL AND LARGER SCALE MOLECULAR EPIDEMIOLOGICAL STUDIES MUST BE DONE TO FULLY UNDERSTAND THE MECHANISM OF ACTION OF THESE TPE EMITTED NANOPARTICLES. MAJOR RESEARCH GAPS HAVE ALSO BEEN IDENTIFIED. AMONG THEM, A METHODICAL RISK ASSESSMENT BASED ON "REAL WORLD" EXPOSURES RATHER THAN ON THE TONER PARTICLES ALONE NEEDS TO BE PERFORMED TO PROVIDE THE MUCH-NEEDED DATA TO ESTABLISH REGULATORY GUIDELINES PROTECTIVE OF INDIVIDUALS EXPOSED TO TPE EMISSIONS AT BOTH THE OCCUPATIONAL AND CONSUMER LEVEL. INDUSTRY-WIDE MOLECULAR EPIDEMIOLOGY AS WELL AS MECHANISTIC ANIMAL AND HUMAN STUDIES ARE ALSO URGENTLY NEEDED. 2017 9 5051 21 PHARMACOLOGICAL RESCUE OF NOCICEPTIVE HYPERSENSITIVITY AND OXYTOCIN ANALGESIA IMPAIRMENT IN A RAT MODEL OF NEONATAL MATERNAL SEPARATION. OXYTOCIN (OT), KNOWN FOR ITS NEUROHORMONAL EFFECTS AROUND BIRTH, HAS RECENTLY BEEN SUGGESTED FOR BEING A CRITICAL DETERMINANT IN NEURODEVELOPMENTAL DISORDERS. THIS HYPOTHALAMIC NEUROPEPTIDE EXERTS A POTENT ANALGESIC EFFECT THROUGH AN ACTION ON THE NOCICEPTIVE SYSTEM. THIS ENDOGENOUS CONTROL OF PAIN HAS AN IMPORTANT ADAPTIVE VALUE BUT MIGHT BE ALTERED BY EARLY LIFE STRESS, POSSIBLY CONTRIBUTING TO ITS LONG-TERM CONSEQUENCES ON PAIN RESPONSES AND ASSOCIATED COMORBIDITIES. WE TESTED THIS HYPOTHESIS USING A RAT MODEL OF NEONATAL MATERNAL SEPARATION (NMS) KNOWN TO INDUCE LONG-TERM CONSEQUENCES ON SEVERAL BRAIN FUNCTIONS INCLUDING CHRONIC STRESS, ANXIETY, ALTERED SOCIAL BEHAVIOR, AND VISCERAL HYPERSENSITIVITY. WE FOUND THAT ADULT RATS WITH A HISTORY OF NMS WERE HYPERSENSITIVE TO NOXIOUS MECHANICAL/THERMAL HOT STIMULI AND TO INFLAMMATORY PAIN. WE FAILED TO OBSERVE OT RECEPTOR-MEDIATED STRESS-INDUCED ANALGESIA AND OT ANTIHYPERALGESIA AFTER CARRAGEENAN INFLAMMATION. THESE ALTERATIONS WERE PARTIALLY RESCUED IF NMS PUPS WERE TREATED BY INTRAPERITONEAL DAILY INJECTION DURING NMS WITH OT OR ITS DOWNSTREAM SECOND MESSENGER ALLOPREGNANOLONE. THE INVOLVEMENT OF EPIGENETIC CHANGES IN THESE ALTERATIONS WAS CONFIRMED SINCE NEONATAL TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR SAHA, NOT ONLY NORMALIZED NOCICEPTIVE SENSITIVITIES BUT ALSO RESTORED OT RECEPTOR-MEDIATED STRESS-INDUCED ANALGESIA AND THE ENDOGENOUS ANTIHYPERALGESIA IN INFLAMED NMS RATS. THERE IS GROWING EVIDENCE IN THE LITERATURE THAT EARLY LIFE STRESS MIGHT IMPAIR THE NOCICEPTIVE SYSTEM ONTOGENY AND FUNCTION. THIS STUDY SUGGESTS THAT THESE ALTERATIONS MIGHT BE RESTORED WHILE STIMULATING OT RECEPTOR SIGNALING OR HISTONE DEACETYLASE INHIBITORS, USING MOLECULES THAT ARE CURRENTLY AVAILABLE OR PART OF CLINICAL TRIALS FOR OTHER PATHOLOGIES. 2018 10 108 23 A REVIEW OF THE PROTECTIVE EFFECT OF MELATONIN IN PESTICIDE-INDUCED TOXICITY. PESTICIDES ARE AMONG THE MOST IMPORTANT CHEMICALS USED IN AGRICULTURE SECTOR. HOWEVER, THEIR EXTENSIVE USE HAS POLLUTED THE ENVIRONMENT AND INCREASED HUMAN VULNERABILITY TO VARIOUS CHRONIC DISEASES. PESTICIDE EXPOSURE CAUSES GENETIC AND EPIGENETIC MODIFICATIONS, ENDOCRINE DISRUPTION, MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS. AREAS COVERED: THIS REVIEW IS BASED ON THE LITERATURE STUDIES CURRENTLY REPORTED ON PESTICIDE-INDUCED TOXICITY AND THE PROTECTIVE ROLE OF MELATONIN. SCIENTIFIC DATABASES SUCH AS PUBMED, SCOPUS AND WEB OF SCIENCE WERE SEARCHED USING KEYWORDS 'PESTICIDE' AND 'MELATONIN' UP TO JANUARY 2016. FULL LENGTH ARTICLES RELATED TO ANIMAL AND HUMAN EXPOSURE WERE RETRIEVED. A TOTAL NUMBER OF 181 RECORDS WERE OBTAINED, AND AFTER EXCLUDING THE DUPLICATES, 97 PAPERS WERE FURTHER SCREENED ON THE BASIS OF RELEVANCE TO THE TOPIC. EXPERT OPINION: MELATONIN AS A BROAD-SPECTRUM ANTIOXIDANT IS ABLE TO PENETRATE CELLULAR COMPARTMENTS SPECIFICALLY THE MITOCHONDRIA. IT IS A POTENT FREE RADICAL SCAVENGER WITH LOW TOXICITY AND DESIRABLE SOLUBILITY IN ORGANIC AND AQUEOUS PHASES. WE ARE OF THE OPINION THAT MELATONIN IS A PROMISING AGENT IN MINIMIZING ORGAN INJURIES INDUCED BY PESTICIDES. 2017 11 5493 21 REVIEW OF IN VITRO TEST SYSTEMS USING DNA DAMAGE AND REPAIR FOR SCREENING OF CHEMICAL CARCINOGENS. CHEMICAL CARCINOGENS ARE MECHANISTICALLY CLASSIFIED AS GENOTOXIC WHICH INTERACT DIRECTLY WITH DNA, AND EPIGENETIC WHICH CAUSE CHRONIC TISSUE INJURY, HORMONAL IMBALANCE, AND PROMOTIONAL EFFECTS. THIS REVIEW EVALUATES IN VITRO TESTS FOR THEIR CONTRIBUTION TO A BATTERY FOR IDENTIFYING GENOTOXIC CHEMICAL CARCINOGENS. IN ADDITION TO BACTERIAL MUTAGENIC ASSAYS, NONSPECIFIC DNA DAMAGE/REPAIR TESTS ARE RECOMMENDED FOR SCREENING CHEMICALS, IN PARTICULAR THE HEPATOCYTE PRIMARY CULTURE/DNA REPAIR TEST. 1979 12 3712 23 INHALED POLLUTANTS: THE MOLECULAR SCENE BEHIND RESPIRATORY AND SYSTEMIC DISEASES ASSOCIATED WITH ULTRAFINE PARTICULATE MATTER. AIR POLLUTION OF ANTHROPOGENIC ORIGIN IS LARGELY FROM THE COMBUSTION OF BIOMASS (E.G., WOOD), FOSSIL FUELS (E.G., CARS AND TRUCKS), INCINERATORS, LANDFILLS, AGRICULTURAL ACTIVITIES AND TOBACCO SMOKE. AIR POLLUTION IS A COMPLEX MIXTURE THAT VARIES IN SPACE AND TIME, AND CONTAINS HUNDREDS OF COMPOUNDS INCLUDING VOLATILE ORGANIC COMPOUNDS (E.G., BENZENE), METALS, SULPHUR AND NITROGEN OXIDES, OZONE AND PARTICULATE MATTER (PM). PM(0.1) (ULTRAFINE PARTICLES (UFP)), THOSE PARTICLES WITH A DIAMETER LESS THAN 100 NM (INCLUDES NANOPARTICLES (NP)) ARE CONSIDERED ESPECIALLY DANGEROUS TO HUMAN HEALTH AND MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF NUMEROUS RESPIRATORY AND CARDIOVASCULAR DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND ATHEROSCLEROSIS. SOME OF THE PATHOGENIC MECHANISMS THROUGH WHICH PM(0.1) MAY CONTRIBUTE TO CHRONIC DISEASE IS THEIR ABILITY TO INDUCE INFLAMMATION, OXIDATIVE STRESS AND CELL DEATH BY MOLECULAR MECHANISMS THAT INCLUDE TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR KAPPAB (NF-KAPPAB) AND NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE 2 (NRF2). EPIGENETIC MECHANISMS INCLUDING NON-CODING RNA (NCRNA) MAY ALSO CONTRIBUTE TOWARDS THE DEVELOPMENT OF CHRONIC DISEASE ASSOCIATED WITH EXPOSURE TO PM(0.1). THIS PAPER HIGHLIGHTS EMERGING MOLECULAR CONCEPTS ASSOCIATED WITH INHALATIONAL EXPOSURE TO PM(0.1) AND THEIR ABILITY TO CONTRIBUTE TO CHRONIC RESPIRATORY AND SYSTEMIC DISEASE. 2017 13 6485 28 TOXICOLOGICAL MECHANISM OF INDIVIDUAL SUSCEPTIBILITY TO FORMALDEHYDE-INDUCED RESPIRATORY EFFECTS. UNDERSTANDING THE MECHANISMS OF INDIVIDUAL SUSCEPTIBILITY TO EXPOSURE TO ENVIRONMENTAL POLLUTANTS HAS BEEN A CHALLENGE IN HEALTH RISK ASSESSMENT. HERE, AN INTEGRATED APPROACH COMBINING A CRISPR SCREEN IN HUMAN CELLS AND EPIDEMIOLOGICAL ANALYSIS WAS DEVELOPED TO IDENTIFY THE INDIVIDUAL SUSCEPTIBILITY TO THE ADVERSE HEALTH EFFECTS OF AIR POLLUTANTS BY TAKING FORMALDEHYDE (FA) AND THE ASSOCIATED CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AS A CASE STUDY. AMONG THE PRIMARY HITS OF CRISPR SCREENING OF FA IN HUMAN A549 CELLS, HTR4 WAS THE ONLY GENE GENETICALLY ASSOCIATED WITH COPD SUSCEPTIBILITY IN GLOBAL POPULATIONS. HOWEVER, THE ASSOCIATION BETWEEN HTR4 AND FA-INDUCED RESPIRATORY TOXICITY IS UNKNOWN IN THE LITERATURE. ADVERSE OUTCOME PATHWAY (AOP) NETWORK ANALYSIS OF CRISPR SCREEN HITS PROVIDED A POTENTIAL MECHANISTIC LINK BETWEEN ACTIVATION OF HTR4 (MOLECULAR INITIATING EVENT) AND FA-INDUCED LUNG INJURY (ADVERSE OUTCOME). SYSTEMATIC TOXICOLOGY TESTS (IN VITRO AND ANIMAL EXPERIMENTS) WERE CONDUCTED TO REVEAL THE HTR4-INVOLVED BIOLOGICAL MECHANISMS UNDERLYING THE SUSCEPTIBILITY TO ADVERSE HEALTH EFFECTS OF FA. FUNCTIONALITY AND ENHANCED EXPRESSION OF HTR4 WERE REQUIRED FOR SUSCEPTIBILITY TO FA-INDUCED LUNG INJURY, AND FA-INDUCED EPIGENETIC CHANGES COULD RESULT IN ENHANCED EXPRESSION OF HTR4. SPECIFIC EPIGENETIC AND GENETIC CHARACTERISTICS OF HTR4 WERE ASSOCIATED WITH THE PROGRESSION AND PREVALENCE OF COPD, RESPECTIVELY, AND THESE GENETIC RISK FACTORS FOR COPD COULD BE POTENTIAL BIOMARKERS OF INDIVIDUAL SUSCEPTIBILITY TO ADVERSE RESPIRATORY EFFECTS OF FA. THESE BIOMARKERS COULD BE OF GREAT SIGNIFICANCE FOR DEFINING SUBPOPULATIONS SUSCEPTIBLE TO EXPOSURE TO FA AND REDUCING UNCERTAINTY IN THE NEXT-GENERATION HEALTH RISK ASSESSMENT OF AIR POLLUTANTS. OUR STUDY DELINEATED A NOVEL TOXICOLOGICAL PATHWAY MEDIATED BY HTR4 IN FA-INDUCED LUNG INJURY, WHICH COULD PROVIDE A MECHANISTIC UNDERSTANDING OF THE POTENTIAL BIOMARKERS OF INDIVIDUAL SUSCEPTIBILITY TO ADVERSE RESPIRATORY EFFECTS OF FA. 2022 14 3901 28 LEAD (PB) AND NEURODEVELOPMENT: A REVIEW ON EXPOSURE AND BIOMARKERS OF EFFECT (BDNF, HDL) AND SUSCEPTIBILITY. LEAD (PB) IS A UBIQUITOUS ENVIRONMENTAL POLLUTANT AND A POTENT TOXIC COMPOUND. HUMANS ARE EXPOSED TO PB THROUGH INHALATION, INGESTION, AND SKIN CONTACT VIA FOOD, WATER, TOBACCO SMOKE, AIR, DUST, AND SOIL. PB ACCUMULATES IN BONES, BRAIN, LIVER AND KIDNEY. FETAL EXPOSURE OCCURS VIA TRANSPLACENTAL TRANSMISSION. THE MOST CRITICAL HEALTH EFFECTS ARE DEVELOPMENTAL NEUROTOXICITY IN INFANTS AND CARDIOVASCULAR EFFECTS AND NEPHROTOXICITY IN ADULTS. PB EXPOSURE HAS BEEN STEADILY DECREASING OVER THE PAST DECADES, BUT THERE ARE FEW RECENT EXPOSURE DATA FROM THE GENERAL EUROPEAN POPULATION; MOREOVER, NO SAFE PB LIMIT HAS BEEN SET. SENSITIVE BIOMARKERS OF EXPOSURE, EFFECT AND SUSCEPTIBILITY, THAT RELIABLY AND TIMELY INDICATE PB-ASSOCIATED TOXICITY ARE REQUIRED TO ASSESS HUMAN EXPOSURE-HEALTH RELATIONSHIPS IN A SITUATION OF LOW TO MODERATE EXPOSURE. THEREFORE, A SYSTEMATIC LITERATURE REVIEW BASED ON PUBMED ENTRIES PUBLISHED BEFORE JULY 2019 THAT ADDRESSED PB EXPOSURE AND BIOMARKERS OF EFFECT AND SUSCEPTIBILITY, NEURODEVELOPMENTAL TOXICITY, EPIGENETIC MODIFICATIONS, AND TRANSCRIPTOMICS WAS CONDUCTED. FINALLY INCLUDED WERE 58 ORIGINAL PAPERS ON PB EXPOSURE AND 17 STUDIES ON BIOMARKERS. THE BIOMARKERS THAT ARE LINKED TO PB EXPOSURE AND NEURODEVELOPMENT WERE GROUPED INTO EFFECT BIOMARKERS (SERUM BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND SERUM/SALIVA CORTISOL), SUSCEPTIBILITY MARKERS (EPIGENETIC MARKERS AND GENE SEQUENCE VARIANTS) AND OTHER BIOMARKERS (SERUM HIGH-DENSITY LIPOPROTEIN (HDL), MATERNAL IRON (FE) AND CALCIUM (CA) STATUS). SERUM BDNF AND PLASMA HDL ARE POTENTIAL CANDIDATES TO BE FURTHER VALIDATED AS EFFECT MARKERS FOR ROUTINE USE IN HBM STUDIES OF PB, COMPLEMENTED BY MARKERS OF FE AND CA STATUS TO ALSO ADDRESS NUTRITIONAL INTERACTIONS RELATED TO NEURODEVELOPMENTAL DISORDERS. FOR SEVERAL MARKERS, A CAUSAL RELATIONSHIP WITH PB-INDUCED NEURODEVELOPMENTAL TOXICITY IS LIKELY. RESULTS ON BDNF ARE DISCUSSED IN RELATION TO ADVERSE OUTCOME PATHWAY (AOP) 13 ("CHRONIC BINDING OF ANTAGONIST TO N-METHYL-D-ASPARTATE RECEPTORS (NMDARS) DURING BRAIN DEVELOPMENT INDUCES IMPAIRMENT OF LEARNING AND MEMORY ABILITIES") OF THE AOP-WIKI. FURTHER STUDIES ARE NEEDED TO VALIDATE SENSITIVE, RELIABLE, AND TIMELY EFFECT BIOMARKERS, ESPECIALLY FOR LOW TO MODERATE PB EXPOSURE SCENARIOS. 2021 15 5174 27 PREDICTIVE AND PROGNOSTIC BIOMARKERS OF RESPIRATORY DISEASES DUE TO PARTICULATE MATTER EXPOSURE. AIR POLLUTION IS GETTING SEVERE AND CONCERNS ABOUT ITS TOXICITY EFFECTS ON AIRWAY AND LUNG DISEASE ARE ALSO INCREASING. PARTICULATE MATTER (PM) IS MAJOR COMPONENT OF AIR POLLUTANT. IT CAUSES RESPIRATORY DISEASES, SUCH AS ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, LUNG CANCER, AND SO ON. PM PARTICLES ENTER THE AIRWAY AND LUNG BY INHALATION, CAUSING DAMAGES TO THEM. ESPECIALLY, PM(2.5) CAN PENETRATE INTO THE ALVEOLUS AND PASS TO THE SYSTEMIC CIRCULATION. IT CAN AFFECT THE CARDIOPULMONARY SYSTEM AND CAUSE CARDIOPULMONARY DISORDERS. IN THIS REVIEW, WE FOCUSED ON PM-INDUCING TOXICITY MECHANISMS IN THE FRAMEWORK OF OXIDATIVE STRESS, INFLAMMATION, AND EPIGENETIC CHANGES. WE ALSO REVIEWED ITS CORRELATION WITH RESPIRATORY DISEASES. IN ADDITION, WE REVIEWED BIOMARKERS RELATED TO PM-INDUCED RESPIRATORY DISEASES. THESE BIOMARKERS MIGHT BE USED FOR DISEASE PREDICTION AND EARLY DIAGNOSIS. WITH RECENT TREND OF USING GENOMIC ANALYSIS TOOLS IN THE FIELD OF TOXICOGENOMICS, RESPIRATORY DISEASE BIOMARKERS ASSOCIATED WITH PM WILL BE CONTINUOUSLY INVESTIGATED. EFFECTIVE BIOMARKERS DERIVED FROM EARLIER STUDIES AND FURTHER STUDIES MIGHT BE UTILIZED TO REDUCE RESPIRATORY DISEASES. 2017 16 1352 35 DEVELOPMENT AND APPLICATION OF THE ADVERSE OUTCOME PATHWAY FRAMEWORK FOR UNDERSTANDING AND PREDICTING CHRONIC TOXICITY: I. CHALLENGES AND RESEARCH NEEDS IN ECOTOXICOLOGY. TO ELUCIDATE THE EFFECTS OF CHEMICALS ON POPULATIONS OF DIFFERENT SPECIES IN THE ENVIRONMENT, EFFICIENT TESTING AND MODELING APPROACHES ARE NEEDED THAT CONSIDER MULTIPLE STRESSORS AND ALLOW RELIABLE EXTRAPOLATION OF RESPONSES ACROSS SPECIES. AN ADVERSE OUTCOME PATHWAY (AOP) IS A CONCEPT THAT PROVIDES A FRAMEWORK FOR ORGANIZING KNOWLEDGE ABOUT THE PROGRESSION OF TOXICITY EVENTS ACROSS SCALES OF BIOLOGICAL ORGANIZATION THAT LEAD TO ADVERSE OUTCOMES RELEVANT FOR RISK ASSESSMENT. IN THIS PAPER, WE FOCUS ON EXPLORING HOW THE AOP CONCEPT CAN BE USED TO GUIDE RESEARCH AIMED AT IMPROVING BOTH OUR UNDERSTANDING OF CHRONIC TOXICITY, INCLUDING DELAYED TOXICITY AS WELL AS EPIGENETIC AND TRANSGENERATIONAL EFFECTS OF CHEMICALS, AND OUR ABILITY TO PREDICT ADVERSE OUTCOMES. A BETTER UNDERSTANDING OF THE INFLUENCE OF SUBTLE TOXICITY ON INDIVIDUAL AND POPULATION FITNESS WOULD SUPPORT A BROADER INTEGRATION OF SUBLETHAL ENDPOINTS INTO RISK ASSESSMENT FRAMEWORKS. DETAILED MECHANISTIC KNOWLEDGE WOULD FACILITATE THE DEVELOPMENT OF ALTERNATIVE TESTING METHODS AS WELL AS HELP PRIORITIZE HIGHER TIER TOXICITY TESTING. WE ARGUE THAT TARGETED DEVELOPMENT OF AOPS SUPPORTS BOTH OF THESE ASPECTS BY PROMOTING THE ELUCIDATION OF MOLECULAR MECHANISMS AND THEIR CONTRIBUTION TO RELEVANT TOXICITY OUTCOMES ACROSS BIOLOGICAL SCALES. WE FURTHER DISCUSS INFORMATION REQUIREMENTS AND CHALLENGES IN APPLICATION OF AOPS FOR CHEMICAL- AND SITE-SPECIFIC RISK ASSESSMENT AND FOR EXTRAPOLATION ACROSS SPECIES. WE PROVIDE RECOMMENDATIONS FOR POTENTIAL EXTENSION OF THE AOP FRAMEWORK TO INCORPORATE INFORMATION ON EXPOSURE, TOXICOKINETICS AND SITUATION-SPECIFIC ECOLOGICAL CONTEXTS, AND DISCUSS COMMON INTERFACES THAT CAN BE EMPLOYED TO COUPLE AOPS WITH COMPUTATIONAL MODELING APPROACHES AND WITH EVOLUTIONARY LIFE HISTORY THEORY. THE EXTENDED AOP FRAMEWORK CAN SERVE AS A VENUE FOR INTEGRATION OF KNOWLEDGE DERIVED FROM VARIOUS SOURCES, INCLUDING EMPIRICAL DATA AS WELL AS MOLECULAR, QUANTITATIVE AND EVOLUTIONARY-BASED MODELS DESCRIBING SPECIES RESPONSES TO TOXICANTS. THIS WILL ALLOW A MORE EFFICIENT APPLICATION OF AOP KNOWLEDGE FOR QUANTITATIVE CHEMICAL- AND SITE-SPECIFIC RISK ASSESSMENT AS WELL AS FOR EXTRAPOLATION ACROSS SPECIES IN THE FUTURE. 2015 17 5450 29 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 18 5380 28 RECENT UPDATES ON BIOMARKERS OF EXPOSURE AND SYSTEMIC TOXICITY IN E-CIGARETTE USERS AND EVALI. ELECTRONIC NICOTINE DELIVERY SYSTEMS (ENDS), OR E-CIGARETTES, ARE EMERGING TOBACCO PRODUCTS THAT PRODUCE AEROSOLS BY HEATING E-LIQUIDS, WHICH MOST OFTEN CONSIST OF PROPYLENE GLYCOL AND VEGETABLE GLYCERIN ALONG WITH VARIOUS FLAVORING COMPOUNDS, BYPASSING THE COMBUSTION THAT OCCURS IN THE USE OF TRADITIONAL TOBACCO CIGARETTES. THESE PRODUCTS HAVE SEEN A DRASTIC INCREASE IN POPULARITY IN RECENT YEARS BOTH AS SMOKING CESSATION DEVICES AS WELL AS AMONG YOUNGER GENERATIONS, DUE IN LARGE PART TO THE WIDESPREAD PERCEPTION AMONG CONSUMERS THAT E-CIGS ARE SIGNIFICANTLY LESS HARMFUL TO HEALTH THAN TRADITIONAL TOBACCO CIGARETTES. DUE TO THE NOVELTY OF ENDS AS WELL AS THEIR RAPIDLY INCREASING USE, RESEARCH INTO BIOMARKERS OF E-CIG EXPOSURE AND TOXICITY HAVE LAGGED BEHIND THEIR POPULARITY, LEAVING IMPORTANT QUESTIONS ABOUT THEIR POTENTIAL TOXICITY UNANSWERED. RESEARCH INTO POTENTIAL BIOMARKERS OF ACUTE AND CHRONIC E-CIG USE, AND E-CIGARETTE- OR VAPING-ASSOCIATED LUNG INJURY IS NECESSARY FOR INFORMING BOTH CLINICAL AND REGULATORY DECISION-MAKING. WE AIM TO PROVIDE AN UPDATED REVIEW OF RECENT RESEARCH INTO POTENTIAL CIRCULATING, GENOMIC, TRANSCRIPTOMIC, AND EPIGENETIC BIOMARKERS OF EXPOSURE TO AND TOXICITY OF E-CIGS. WE ADDITIONALLY HIGHLIGHT RESEARCH AREAS THAT WARRANT ADDITIONAL STUDY TO GAIN A BETTER UNDERSTANDING OF HEALTH RISKS ASSOCIATED WITH ENDS USE, AS WELL AS TO PROVIDE VALIDATION OF EXISTING DATA AND METHODS FOR MEASURING AND ANALYZING E-CIG-ASSOCIATED BIOMARKERS IN HUMAN AND ANIMAL BIOFLUIDS, TISSUES, AND CELLS. THIS REVIEW ALSO HIGHLIGHTS ONGOING EFFORTS WITHIN THE WNY CENTER FOR RESEARCH ON FLAVORED TOBACCO FOR RESEARCH INTO NOVEL BIOMARKERS IN EXTRACELLULAR VESICLES THAT MAY BE ASSOCIATED WITH SHORT- AND LONG-TERM ENDS USE. 2021 19 2790 40 FACTORS TO CONSIDER IN THE USE OF STEM CELLS FOR PHARMACEUTIC DRUG DEVELOPMENT AND FOR CHEMICAL SAFETY ASSESSMENT. GIVEN THE REALITY OF THE INADEQUACIES OF CURRENT CONCEPTS OF THE MECHANISMS OF CHEMICAL TOXICITIES, OF THE VARIOUS ASSAYS TO PREDICT TOXICITIES FROM CURRENT MOLECULAR, BIOCHEMICAL, IN VITRO AND ANIMAL BIOASSAYS, AND OF THE FAILURE TO GENERATE EFFICACIOUS AND SAFE CHEMICALS FOR MEDICINES, FOOD SUPPLEMENTS, INDUSTRIAL, CONSUMER AND AGRICULTURAL CHEMICALS, THE RECENT NAS REPORT, "TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY", HAS DRAWN ATTENTION TO A RENEWED EXAMINATION OF WHAT NEEDS TO BE DONE TO IMPROVE OUR CURRENT APPROACH FOR BETTER ASSESSMENT OF POTENTIAL RISK TO HUMAN HEALTH. THIS "COMMENTARY" PROVIDES A MAJOR PARADIGM CHALLENGE TO THE CURRENT CONCEPTS OF HOW CHEMICALS INDUCE TOXICITIES AND HOW THESE VARIOUS MECHANISMS OF TOXICITIES CAN CONTRIBUTE TO THE PATHOGENESIS OF SOME HUMAN DISEASES, SUCH AS BIRTH DEFECTS AND CANCER. IN CONCORDANCE WITH THE NAS REPORT TO TAKE "... ADVANTAGE OF THE ON-GOING REVOLUTION IN BIOLOGY AND BIOTECHNOLOGY", THIS "COMMENTARY" SUPPORTS THE USE OF HUMAN EMBRYONIC AND ADULT STEM CELLS, GROWN IN VITRO UNDER SIMULATED "IN VIVO NICHE CONDITIONS". THE HUMAN BEING SHOULD BE VIEWED "AS GREATER THAN THE SUM OF ITS PARTS". HOMEOSTATIC CONTROL OF THE "EMERGENT PROPERTIES" OF THE HUMAN HIERARCHY, NEEDED TO MAINTAIN HUMAN HEALTH, REQUIRES COMPLEX INTEGRATION OF ENDOGENOUS AND EXOGENOUS SIGNALING MOLECULES THAT CONTROL CELL PROLIFERATION, DIFFERENTIATION, APOPTOSIS AND SENESCENCE OF STEM, PROGENITOR AND DIFFERENTIATED CELLS. CURRENTLY, IN VITRO TOXICITY ASSAYS (MUTAGENESIS, CYTOTOXICITY, EPIGENETIC MODULATION), DONE ON 2-DIMENSIONAL PRIMARY RODENT OR HUMAN CELLS (WHICH ARE ALWAYS MIXTURES OF CELLS), ON IMMORTALIZED OR TUMORIGENIC RODENT OR HUMAN CELL LINES DO NOT REPRESENT NORMAL HUMAN CELLS IN VIVO [WHICH DO NOT GROW ON PLASTIC AND WHICH ARE IN MICRO-ENVIRONMENTS REPRESENTING 3 DIMENSIONS AND CONSTANTLY INTERACTING FACTORS]. IN ADDITION, WITH THE KNOWN GENETIC, GENDER, AND DEVELOPMENTAL STATE OF CELLS IN VIVO, ANY IN VITRO TOXICITY ASSAY WILL NEED TO MIMIC THESE CONDITIONS IN VITRO. MORE SPECIFICALLY, WHILE TISSUES CONTAIN A FEW STEM CELLS, MANY PROGENITOR/TRANSIT CELLS AND TERMINALLY DIFFERENTIATED CELLS, IT SHOULD BE OBVIOUS THAT BOTH EMBRYONIC AND ADULT STEM CELLS WOULD BE CRITICAL "TARGET" CELLS FOR TOXICITY TESTING. THE ULTIMATE POTENTIAL FOR IN VITRO TESTING OF HUMAN STEM CELLS WILL TO TRY TO MIMIC A 3-D IN VITRO MICRO-ENVIRONMENT ON MULTIPLE "ORGAN-SPECIFIC AND MULTIPLE GENOTYPIC/GENDER "ADULT STEM CELLS. THE ROLE OF STEM CELLS IN MANY CHRONIC DISEASES, SUCH AS CANCER, BIRTH DEFECTS, AND POSSIBLY ADULT DISEASES AFTER PRE-NATAL AND EARLY POST-NATAL EXPOSURES (BARKER HYPOTHESIS), DEMANDS TOXICITY STUDIES OF STEM CELLS. WHILE ALTERATION OF GENE EXPRESSION ("TOXICO-EPIGENOMICS") IS A LEGITIMATE ENDPOINT OF THESE TOXICITY STUDIES, ALTERATION OF THE QUANTITY OF STEM CELLS DURING DEVELOPMENT MUST BE SERIOUS CONSIDERED. IF THE FUTURE UTILITY OF HUMAN STEM CELLS PROVES TO BE VALID, THE ELIMINATION OF LESS RELEVANT, EXPENSIVE AND TIME-CONSUMING RODENT AND 2-D HUMAN IN VITRO ASSAYS WILL BE ELIMINATED. 2010 20 3630 27 INCLUSION OF SOCIAL AND STRUCTURAL DETERMINANTS OF HEALTH TO ADVANCE UNDERSTANDING OF THEIR INFLUENCE ON THE BIOLOGY OF CHRONIC DISEASE. SOCIAL DETERMINANTS OF HEALTH (SDOH) CONSIDER SOCIAL, POLITICAL, AND ECONOMIC FACTORS THAT CONTRIBUTE TO HEALTH DISPARITIES IN PATIENTS AND POPULATIONS. THE MOST COMMON HEALTH-RELATED SDOH EXPOSURES ARE FOOD AND HOUSING INSECURITY, FINANCIAL INSTABILITY, TRANSPORTATION NEEDS, LOW LEVELS OF EDUCATION, AND PSYCHOSOCIAL STRESS. THESE DOMAINS DESCRIBE RISKS THAT CAN IMPACT HEALTH OUTCOMES MORE THAN HEALTH CARE. EPIDEMIOLOGIC AND TRANSLATIONAL RESEARCH DEMONSTRATES THAT SDOH FACTORS REPRESENT EXPOSURES THAT PREDICT HARM AND IMPACT THE HEALTH OF INDIVIDUALS. INTERNATIONAL AND NATIONAL GUIDELINES URGE HEALTH PROFESSIONALS TO ADDRESS SDOH IN CLINICAL PRACTICE AND PUBLIC HEALTH. THE FURTHER IMPLEMENTATION OF THESE RECOMMENDATIONS INTO BASIC AND TRANSLATIONAL RESEARCH, HOWEVER, IS LAGGING. HEREIN, WE CONSIDER A PRECISION HEALTH FRAMEWORK TO DESCRIBE HOW SDOH CONTRIBUTES TO THE EXPOSOME AND EXACERBATES PHYSIOLOGIC PATHWAYS THAT LEAD TO CHRONIC DISEASE. SDOH FACTORS ARE ASSOCIATED WITH VARIOUS FORMS OF STRESSORS THAT IMPACT PHYSIOLOGICAL PROCESSES THROUGH EPIGENETIC, INFLAMMATORY, AND REDOX REGULATION. MANY SDOH EXPOSURES MAY ADD TO OR POTENTIATE THE PATHOLOGIC EFFECTS OF ADDITIONAL ENVIRONMENTAL EXPOSURES. THIS OVERVIEW AIMS TO INFORM BASIC LIFE SCIENCE AND TRANSLATIONAL RESEARCHERS ABOUT SDOH EXPOSURES THAT CAN CONFOUND ASSOCIATIONS BETWEEN CLASSIC BIOMEDICAL DETERMINANTS OF DISEASE AND HEALTH OUTCOMES. TO ADVANCE THE STUDY OF TOXICOLOGY THROUGH EITHER QUALITATIVE OR QUANTITATIVE ASSESSMENT OF EXPOSURES TO CHEMICAL AND BIOLOGICAL SUBSTANCES, A MORE COMPLETE ENVIRONMENTAL EVALUATION SHOULD INCLUDE SDOH EXPOSURES. WE DISCUSS COMMON APPROACHES TO MEASURE SDOH FACTORS AT INDIVIDUAL AND POPULATION LEVELS AND REVIEW THE ASSOCIATIONS BETWEEN SDOH RISK FACTORS AND PHYSIOLOGIC MECHANISMS THAT INFLUENCE CHRONIC DISEASE. WE PROVIDE CLINICAL AND POLICY-BASED MOTIVATION TO ENCOURAGE RESEARCHERS TO CONSIDER THE IMPACT OF SDOH EXPOSURES ON STUDY RESULTS AND DATA INTERPRETATION. WITH VALID MEASURES OF SDOH FACTORS INCORPORATED INTO STUDY DESIGN AND ANALYSES, FUTURE TOXICOLOGICAL RESEARCH MAY CONTRIBUTE TO AN EVIDENCE BASE THAT CAN BETTER INFORM PREVENTION AND TREATMENT OPTIONS, TO IMPROVE EQUITABLE CLINICAL CARE AND POPULATION HEALTH. (C) 2022 WILEY PERIODICALS LLC. 2022