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AbstractXylene is a high production volume chemical that is widely used as a solvent and polymer precursor, and is currently undergoing substance evaluation under Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). Xylenes recently received testing decisions on one-generation reproductive toxicity (EOGRT) studies with additional developmental neurotoxicity (DNT) cohorts for each of the three isomers. Xylene presents a unique opportunity to investigate the need for additional animal DNT toxicology testing because it is a legacy industrial chemical for which a significant amount of animal and human data already exists on its toxicity profile, including central nervous system effects. Therefore, to address the need for further vertebrate testing, a comprehensive weight of evidence (WOE) review of published and previously unpublished new studies of xylene substances was performed. Evidence topics included the pharmacokinetics, narcotic effects in humans and animals, narcotic mode of action (MOA), and strength of DNT signal for xylene. Pharmacokinetic data indicate minimal distribution of the unmetabolized parent compound to the fetus relative to parental brain tissue, and rapid metabolism of xylene to methyl hippuric acid (MHA), which is also rapidly excreted in both humans and animals. Xylene exposure has also resulted in transient, nonspecific neurological effects including delays in reaction time of human volunteers and reductions in motor activity of animals. This narcotic MOA for xylene occurs by the nonspecific perturbation of nervous cell membrane phospholipids, such that membrane-bound proteins and their respective functions are impaired. Furthermore, an in-depth review of the available DNT data indicates significant methodological deficiencies in several studies in the literature purported to provide evidence of a DNT concern following xylene exposure and no DNT concern reported in one reliable study. In conclusion, based on xylene’s pharmacokinetics, narcotic effects on the central nervous system observed in animal and human studies, its narcotic MOA, and the lack of a robust signal from the published DNT studies, there is no trigger for the additional EOGRT study DNT cohort to be conducted for xylene. Further, the findings on narcotic effects and MOA underscore the difficulty in separating transient, acute intoxication effects via direct exposure of the offspring from investigating DNT effects (as investigated in a standard guideline (426) DNT study) in the EOGRT study, therefore producing unreliable data, which is ethically at odds with REACH and 3 R principles. [ABSTRACT FROM AUTHOR]

Neonicotinoids are the most widely used class of insecticides in the United States (U.S.). and the world. Consistent with their high use and persistence, neonicotinoids are often found contaminating drinking water and food. They are also detected in human urine, breast milk, amniotic and cerebrospinal fluids, as well as the brains of treated rodents. Neonicotinoids were once thought to pose little neurotoxic risk to humans, but a growing body of research challenges that assumption. In this study we provide the first comprehensive assessment of unpublished rodent developmental neurotoxicity (DNT) studies on five neonicotinoids that were submitted to the U.S. Environmental Protection Agency (EPA) by neonicotinoid manufacturers. Groups of female rats were administered three different doses of a neonicotinoid during pregnancy and lactation, and their offspring subjected to various neurological tests and brain measurements. We identified nicotine-like effects such as reduced brain size, indicative of neuronal cell loss. Statistically significant shrinkage of brain tissue was observed in high-dose offspring for five neonicotinoids: acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam. Two brain regions reduced in the rodent studies-the corpus callosum and caudateputa mentend to be smaller in people diagnosed with attention-deficit hyperactivity disorder (ADHD), and in children of mothers who smoked during pregnancy, suggesting a possible link between perinatal neonicotinoid exposure and ADHD. A decreased auditory startle reflex was reported for acetamiprid at all doses and was statistically significant in the mid- and high-dose offspring, and for clothianidin in juvenile high-dose females. No mid- or low-dose brain morphometric data were submitted for acetamiprid, imidacloprid, or thiacloprid. Thiamethoxam mid- and low-dose brain morphometric data were provided to EPA upon request. Only partial mid-dose brain morphometry data were submitted for clothianidin, but no low-dose data. Yet despite this lack of data, EPA concluded that only the high-dose brain morphometric effects were treatment-related-setting the mid-dose as the study's No Observed Adverse Effect Level (NOAEL) or failing to find a definitive NOAEL for acetamiprid, clothianidin, imidacloprid, thiacloprid and thiamethoxam. We found numerous deficiencies in EPA's regulatory oversight and data analyses. EPA dismissed statistically significant adverse effects, accepted substandard DNT studies despite lack of valid positive control data, and allowed neonicotinoid registrants to unduly influence agency decision-making. We conclude that perinatal exposure to neonicotinoids and their metabolites induces adverse, nicotine-like neurotoxic effects in rodent bioassays, and that the exposure limits set by EPA for human exposure are either not protective or not supported by available neurotoxicity data. We propose regulatory changes to empower EPA to better protect public health from developmental neurotoxins like neonicotinoids. [ABSTRACT FROM AUTHOR]

Background/Objectives: Many pregnant women globally suffer from depression and are routinely prescribed selective serotonin reuptake inhibitors (SSRIs). These drugs function by blocking the re-uptake of serotonin by the serotonin transporter (SERT) into neurons, resulting in its accumulation in the presynaptic cleft. Despite a large amount of research suggesting a potential link to neurodevelopmental disorders in children whose mothers took these drugs during pregnancy, their possible adverse effects are still debated, and results are contradictory. On the other hand, there is an immediate need for improved cell-based models for developmental neurotoxicity studies (DNT) to minimize the use of animals in research. Methods: In this study, we aimed to assess the effects of clinically relevant concentrations of paroxetine (PAR), fluoxetine (FLX), and citalopram (CIT)—on maturing neurons derived from human neural stem cells using multiple endpoints. Results: Although none of the tested concentrations of FLX, CIT, or PAR significantly affected cell viability, FLX (10 µM) exhibited the highest reduction in viability compared to the other drugs. Regarding neurite outgrowth, CIT did not have a significant effect. However, FLX (10 µM) significantly reduced both mean neurite outgrowth and mean processes, PAR significantly reduced mean processes, and showed a trend of dysregulation of multiple genes associated with neuronal development at therapeutic-relevant serum concentrations. Conclusions: Transcriptomic data and uptake experiments found no SERT activity in the system, suggesting that the adverse effects of FLX and PAR are independent of SERT. [ABSTRACT FROM AUTHOR]

The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause–effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence‐based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified. [ABSTRACT FROM AUTHOR]

Neonicotinoids are the most widely used class of insecticides in the United States (U.S.). and the world. Consistent with their high use and persistence, neonicotinoids are often found contaminating drinking water and food. They are also detected in human urine, breast milk, amniotic and cerebrospinal fluids, as well as the brains of treated rodents. Neonicotinoids were once thought to pose little neurotoxic risk to humans, but a growing body of research challenges that assumption. In this study we provide the first comprehensive assessment of unpublished rodent developmental neurotoxicity (DNT) studies on five neonicotinoids that were submitted to the U.S. Environmental Protection Agency (EPA) by neonicotinoid manufacturers. Groups of female rats were administered three different doses of a neonicotinoid during pregnancy and lactation, and their offspring subjected to various neurological tests and brain measurements. We identified nicotine-like effects such as reduced brain size, indicative of neuronal cell loss. Statistically significant shrinkage of brain tissue was observed in high-dose offspring for five neonicotinoids: acetamiprid, clothianidin, imidacloprid, thiacloprid, and thiamethoxam. Two brain regions reduced in the rodent studies–the corpus callosum and caudate-putamen–tend to be smaller in people diagnosed with attention-deficit hyperactivity disorder (ADHD), and in children of mothers who smoked during pregnancy, suggesting a possible link between perinatal neonicotinoid exposure and ADHD. A decreased auditory startle reflex was reported for acetamiprid at all doses and was statistically significant in the mid- and high-dose offspring, and for clothianidin in juvenile high-dose females. No mid- or low-dose brain morphometric data were submitted for acetamiprid, imidacloprid, or thiacloprid. Thiamethoxam mid- and low-dose brain morphometric data were provided to EPA upon request. Only partial mid-dose brain morphometry data were submitted for clothianidin, but no low-dose data. Yet despite this lack of data, EPA concluded that only the high-dose brain morphometric effects were treatment-related–setting the mid-dose as the study’s No Observed Adverse Effect Level (NOAEL) or failing to find a definitive NOAEL for acetamiprid, clothianidin, imidacloprid, thiacloprid and thiamethoxam. We found numerous deficiencies in EPA’s regulatory oversight and data analyses. EPA dismissed statistically significant adverse effects, accepted substandard DNT studies despite lack of valid positive control data, and allowed neonicotinoid registrants to unduly influence agency decision-making. We conclude that perinatal exposure to neonicotinoids and their metabolites induces adverse, nicotine-like neurotoxic effects in rodent bioassays, and that the exposure limits set by EPA for human exposure are either not protective or not supported by available neurotoxicity data. We propose regulatory changes to empower EPA to better protect public health from developmental neurotoxins like neonicotinoids.

Nanoparticles (NPs) are becoming increasingly important novel materials for many purposes, including basic research, medicine, agriculture, and engineering. Increasing human and environmental exposure to these promising compounds requires assessment of their potential health risks. While the general direct cytotoxicity of NPs is often routinely measured, more indirect possible long-term effects, such as reproductive or developmental neurotoxicity (DNT), have been studied only occasionally and, if so, mostly on non-human animal models, such as zebrafish embryos. In this present study, we employed a well-characterized human neuronal precursor cell line to test the concentration-dependent DNT of green-manufactured copper sulfide (CuS) nanoparticles on crucial early events in human brain development. CuS NPs turned out to be generally cytotoxic in the low ppm range. Using an established prediction model, we found a clear DNT potential of CuS NPs on neuronal precursor cell migration and neurite outgrowth, with IC50 values 10 times and 5 times, respectively, lower for the specific DNT endpoint than for general cytotoxicity. We conclude that, in addition to the opportunities of NPs, their risks to human health should be carefully considered. [ABSTRACT FROM AUTHOR]

Objective: The aim was to assess the effectiveness of an optimized emergency green channel in the treatment of acute ischemic stroke (AIS) patients and its effect on emergency response time, effectiveness, anxiety, and acute stress. Methods: A retrospective analysis was conducted on 349 AIS patients treated with intravenous thrombolysis from January 2019 to May 2022. The patients were divided into those who received optimized emergency green channel treatment (155) and those who did not (194). Propensity score matching (PSM) was used to balance the admission pathways, living conditions, insurance methods, and residential locations of the 2 patient groups. The key metrics comprised the times from onset to admission, admission to computed tomography (CT), CT to thrombolysis, admission to thrombolysis (door-to-needle time (DNT)), National Institute of Health Stroke Scale (NIHSS) scores at various intervals post thrombolysis, heart rate, blood pressure, and scores in Self-Rating Anxiety Scale (SAS) and the Stanford Acute Stress Reaction Questionnaire (SASRQ). Results: Post PSM, 118 patients were analyzed (54 control and 64 observation). The observation group showed significantly lower time results than the control group, which included the following: the time from onset to admission (t=31.428, P < .001), door-toimaging time (t=27.317, P < .001), imaging-to-needle time (t=20.951, P < .001, and DNT (t=25.954, P < .001). Significant differences were observed in 24 hour-post thrombolysis NIHSS scores, heart rate, blood pressure, SAS, and SASRQ scores (P < .05) but not in NIHSS scores at 7 and 30 days. Conclusion: The optimized emergency green channel process effectively reduced the treatment time for ischemic stroke patients, improved rescue efficiency, and positively influenced the psychological stress levels of patients post treatment. [ABSTRACT FROM AUTHOR]

Abstract The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause–effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence‐based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified.

Background/Objectives: Many pregnant women globally suffer from depression and are routinely prescribed selective serotonin reuptake inhibitors (SSRIs). These drugs function by blocking the re-uptake of serotonin by the serotonin transporter (SERT) into neurons, resulting in its accumulation in the presynaptic cleft. Despite a large amount of research suggesting a potential link to neurodevelopmental disorders in children whose mothers took these drugs during pregnancy, their possible adverse effects are still debated, and results are contradictory. On the other hand, there is an immediate need for improved cell-based models for developmental neurotoxicity studies (DNT) to minimize the use of animals in research. Methods: In this study, we aimed to assess the effects of clinically relevant concentrations of paroxetine (PAR), fluoxetine (FLX), and citalopram (CIT)—on maturing neurons derived from human neural stem cells using multiple endpoints. Results: Although none of the tested concentrations of FLX, CIT, or PAR significantly affected cell viability, FLX (10 µM) exhibited the highest reduction in viability compared to the other drugs. Regarding neurite outgrowth, CIT did not have a significant effect. However, FLX (10 µM) significantly reduced both mean neurite outgrowth and mean processes, PAR significantly reduced mean processes, and showed a trend of dysregulation of multiple genes associated with neuronal development at therapeutic-relevant serum concentrations. Conclusions: Transcriptomic data and uptake experiments found no SERT activity in the system, suggesting that the adverse effects of FLX and PAR are independent of SERT.

Introduction: Flame retardants (FRs) are common bodily and environmental pollutants, creating concern about their potential toxicity. We and others have found that the commercial mixture FireMaster® 550 (FM 550) or its individual brominated (BFR) and organophosphate ester (OPFR) components are potential developmental neurotoxicants. Using Wistar rats, we previously reported that developmental exposure to FM 550 or its component classes produced sex- and compound-specific effects on adult socioemotional behaviors. The underlying mechanisms driving the behavioral phenotypes are unknown. Methods: To further mechanistic understanding, here we conducted transcriptomics in parallel with a novel lipidomics approach using cortical tissues from newborn siblings of the rats in the published behavioral study. Inclusion of lipid composition is significant because it is rarely examined in developmental neurotoxicity studies. Pups were gestationally exposed via oral dosing to the dam to FM 550 or the BFR or OPFR components at environmentally relevant doses. Results: The neonatal cortex was highly sexually dimorphic in lipid and transcriptome composition, and males were more significantly impacted by FR exposure. Multiple adverse modes of action for the BFRs and OPFRs on neurodevelopment were identified, with the OPFRs being more disruptive than the BFRs via multiple mechanisms including dysregulation of mitochondrial function and disruption of cholinergic and glutamatergic systems. Disrupted mitochondrial function by environmental factors has been linked to a higher risk of autism spectrum disorders and neurodegenerative disorders. Impacted lipid classes included ceramides, sphingomyelins, and triacylglycerides. Robust ceramide upregulation in the OPFR females could suggest a heightened risk of brain metabolic disease. Conclusions: This study reveals multiple mechanisms by which the components of a common FR mixture are developmentally neurotoxic and that the OPFRs may be the compounds of greatest concern. [ABSTRACT FROM AUTHOR]

This paper describes the deuterium‐labelling of alkylnitroaromatics by base‐catalysed exchange with deuterium oxide. As the alkyl protons alpha to the aromatic ring are the most acidic sites in the molecule, regioselective hydrogen isotope exchange at this benzylic location leads to a regiospecifically deuterated product. The exchange labelling takes place in good yields and with high atom% abundance in the presence of an appropriate nitrogen base. Alkylated 2,4‐dinitrobenzenes deuterate at room temperature under catalysis by triethylamine, whilst alkylated 2‐nitro‐ or 4‐nitrobenzenes and related mono‐nitroaromatics require higher temperatures and catalysis by 1,5‐diazobicyclo[4.3.0]non‐5‐ene (DBN). The labelling reactions require an inert gas atmosphere, but otherwise are simple and high yielding with no obvious byproducts. Those compounds in which the benzylic protons are in an ortho‐orientation with respect to the nitro group label somewhat more slowly than the analogues where there is a para relationship. In addition, higher alkyl homologues undergo benzylic deuteration at slower rates than methyl. [ABSTRACT FROM AUTHOR]

BackgroundThe autoimmune lymphoproliferative syndrome (ALPS) is a rare disease characterized by defective function of the FAS death receptor, which results in chronic, non-malignant lymphoproliferation and autoimmunity accompanied by elevated numbers of double-negative (DN) T cells (T-cell receptor α/β + CD4–CD8–) and an increased risk of developing malignancies later in life.Case descriptionHere, we report a patient with a de novo FAS mutation with a severe phenotype of ALPS-FAS. The FAS gene identified as a novel spontaneous germline heterozygous missense mutation (c.857G > A, p.G286E) in exon 9, causing an amino acid exchange and difference in hydrogen bond formation. Consequently, the treatment with sirolimus was initiated. Subsequently, the patient’s clinical condition improved rapidly. Moreover, DNT ratio continuously decreased during sirolimus application.ConclusionWe described a novel germline FAS mutation (c.857G > A, p.G286E) associated with a severe clinical phenotype of ALPS-FAS. Sirolimus effectively improved the patient clinical manifestations with obvious reduction of the DNT ratio.

Human brain is undoubtedly the most complex organ in the body. Thus, it is difficult to develop adequate and at the same time human relevant test systems and models to cover the aspects of brain homeostasis and even more challenging to address brain development. Animal tests for Developmental Neurotoxicity (DNT) have been devised, but because of complex underlying mechanisms of neural development, and interspecies differences, there are many limitations of animal-based approaches. The high costs, high number of animals used per test and technical difficulties of these tests are prohibitive for routine DNT chemical screening. Therefore, many potential DNT chemicals remain unidentified. New approach methodologies (NAMs) are needed to change this. Experts in the field have recommended the use of a battery of human in vitro tests to be used for the initial prioritization of high-risk environmental chemicals for DNT testing. Microphysiological systems (MPS) of the brain mimic the in vivo counterpart in terms of cellular composition, recapitulation of regional architecture and functionality. These systems amendable to use in a DNT test battery with promising features such as (i) complexity, (ii) closer recapitulation of in vivo response and (iii) possibility to multiplex many assays in one test system, which can increase throughput and predictivity for human health. The resent progress in 3D brain MPS research, advantages, limitations and future perspectives are discussed in this review.

Dinitrotoluene (DNT) has been extensively used in manufacturing munitions, polyurethane foams and other important chemical products. However, it is highly toxic and mutagenic to most organisms. Here, we synthesized a codon‐optimized bacterial nitroreductase gene, NfsI, for plant expression. The kinetic analysis indicates that the recombinant NfsI can detoxify both 2,4‐DNT and its sulfonate (DNTS), while it has a 97.6‐fold higher catalytic efficiency for 2,4‐DNT than DNTS. Furthermore, we overexpressed NfsI in switchgrass (Panicum virgatum L.), which is a multiple‐purpose crop used for fodder and biofuel production as well as phytoremediation. The 2,4‐DNT treatment inhibited root elongation of wild‐type switchgrass plants and promoted reactive oxygen species (ROS) accumulation in roots. In contrast, overexpression of NfsI in switchgrass significantly alleviated 2,4‐DNT‐induced root growth inhibition and ROS overproduction. Thus, the NfsI overexpressing transgenic switchgrass plant removed 94.1% 2,4‐DNT after 6 days, whose efficiency was 1.7‐fold higher than control plants. Moreover, the comparative transcriptome analysis suggests that 22.9% of differentially expressed genes induced by 2,4‐DNT may participate in NfsI‐mediated 2,4‐DNT detoxification in switchgrass. Our work sheds light on the function of NfsI during DNT phytoremediation for the first time, revealing the application potential of switchgrass plants engineered with NfsI. Overexpression of NfsI significantly improved 2,4‐dinitrotoluene (DNT) uptake of switchgrass.More potential genetic targets for 2,4‐DNT detoxification were uncovered. [ABSTRACT FROM AUTHOR]

• Novel DNT Method was Built Employing Sox1-GFP cells. • Neural Differentiation Marker Sox1 Used to Evaluating Chemical Neurotoxicity. • Neuronal Differentiation of Sox1-GFP cells is Inhibited by the Neurotoxic Chemicals. Developmental toxicity tests have been generated by applying the embryonic stem cell tests at the European Centre for the Validation of Alternative Methods, or by using the embryoid body test in our laboratory. This study was undertaken to explore novel developmental neurotoxicity (DNT) assay, using a Sox1-GFP cell line (mouse embryonic stem cells with an endogenous Sox1-GFP reporter). The expression of Sox1, a marker for neuroepithelial cells, is detected by green fluorescence, and the fluorescence intensity is a critical factor for achieving neuronal differentiation. Sox1-GFP cells cultured for 24 h were exposed to eleven neurotoxicants and four non-neurotoxicants. CCK-8 assays were performed to determine IC 50 values after 48 h of chemical treatment. The fluorescence intensity of GFP was measured 4 days after treating the cells, and it was observed to decrease after exposure to neurotoxicants at higher concentrations, thereby indicating that the neuronal differentiation of Sox1-GFP cells is inhibited by the chemicals. Taken together, the results obtained in this study provide a model for DNT using embryonic stem cells, which may be applied to evaluate the toxicity of new chemicals or new drug candidates. [ABSTRACT FROM AUTHOR]

Pesticide exposure during in utero and early postnatal development can cause a wide range of neurological defects. However, relatively few insecticides have been recognized as developmental neurotoxicants, so far. Recently, discovery of the insecticide, fipronil, in chicken eggs has raised public concern. The status of fipronil as a potential developmental neurotoxicant is still under debate. Whereas several in vivo and in vitro studies suggest specific toxicity, other in vitro studies could not confirm this concern. Here, we tested fipronil and its main metabolic product, fipronil sulfone both at concentrations between 1.98 and 62.5 µM, alongside with the established developmental neurotoxicant, rotenone (0.004–10 µM) in vitro on the human neuronal precursor cell line NT2. We found that rotenone impaired all three tested DNT endpoints, neurite outgrowth, neuronal differentiation, and precursor cell migration in a dose-dependent manner and clearly separable from general cytotoxicity in the nanomolar range. Fipronil and fipronil sulfone specifically inhibited cell migration and neuronal differentiation, but not neurite outgrowth in the micromolar range. The rho-kinase inhibitor Y-27632 counteracted inhibition of migration for all three compounds (EC50 between 12 and 50 µM). The antioxidant, n-acetyl cysteine, could ameliorate the inhibitory effects of fipronil on all three tested endpoints (EC 50 between 84 and 164 µM), indicating the involvement of oxidative stress. Fipronil sulfone had a stronger effect than fipronil, confirming the importance to test metabolic products alongside original pesticides. We conclude that in vitro fipronil and fipronil sulfone display specific developmental neurotoxicity on developing human model neurons. [ABSTRACT FROM AUTHOR]

Abstract The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self‐task mandate (EFSA‐Q‐2019‐00100), two adverse outcome pathway (AOP)‐informed integrated approach to testing and assessment (IATA) case studies to answer a developmental neurotoxicity (DNT) hazard identification and characterisation problem formulation that could support the regulatory decisions for the pesticide active substances deltamethrin and flufenacet. The IATA were developed to assess the applicability of the DNT in vitro testing battery (IVB), designed to explore fundamental neurodevelopmental processes, in the regulatory risk assessment of pesticides. For this purpose, an evidence‐based‐approach methodology was applied: 1) systematic literature review and critical appraisal of all the evidence i.e. human observational studies, in vivo data from rodent models and new approach methodologies (NAMs, i.e. in vitro studies including high‐throughput testing from IVB and zebrafish studies from the literature) for both case studies; 2) a quantitative uncertainty analysis of all the evidence using expert knowledge elicitation (EKE) and a probabilistic approach; 3) integration of all the evidence using the AOP conceptual framework. This stepwise approach resulted in the postulation of an evidence‐based AOP network for one of the case studies. A probabilistic quantification of the weight of evidence (WoE) using Bayesian network analysis allowed the assessment and the quantification of the uncertainty in the postulated AOP. The approach taken allowed conclusions to be drawn with an acceptable level of certainty in DNT hazard identification and characterisation of deltamethrin and that flufenacet is not a developmental neurotoxicant, supporting the relevance of the mechanistic understanding. The case studies show the applicability of the DNT‐IVB for hazard identification and characterisation and illustrate the usefulness of an AOP‐informed IATA for regulatory decision making. The overall activity led to improved interpretation of human data by providing a plausible mechanistic link to adverse outcomes, which would support their contextualisation in the risk assessment process. This Scientific Opinion allows the PPR Panel to draft several recommendations for the implementation of the AOP‐informed IATA methodology and of the DNT‐IVB in the regulatory risk assessment of pesticides.

The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self‐task mandate (EFSA‐Q‐2019‐00100), two adverse outcome pathway (AOP)‐informed integrated approach to testing and assessment (IATA) case studies to answer a developmental neurotoxicity (DNT) hazard identification and characterisation problem formulation that could support the regulatory decisions for the pesticide active substances deltamethrin and flufenacet. The IATA were developed to assess the applicability of the DNT in vitro testing battery (IVB), designed to explore fundamental neurodevelopmental processes, in the regulatory risk assessment of pesticides. For this purpose, an evidence‐based‐approach methodology was applied: 1) systematic literature review and critical appraisal of all the evidence i.e. human observational studies, in vivo data from rodent models and new approach methodologies (NAMs, i.e. in vitro studies including high‐throughput testing from IVB and zebrafish studies from the literature) for both case studies; 2) a quantitative uncertainty analysis of all the evidence using expert knowledge elicitation (EKE) and a probabilistic approach; 3) integration of all the evidence using the AOP conceptual framework. This stepwise approach resulted in the postulation of an evidence‐based AOP network for one of the case studies. A probabilistic quantification of the weight of evidence (WoE) using Bayesian network analysis allowed the assessment and the quantification of the uncertainty in the postulated AOP. The approach taken allowed conclusions to be drawn with an acceptable level of certainty in DNT hazard identification and characterisation of deltamethrin and that flufenacet is not a developmental neurotoxicant, supporting the relevance of the mechanistic understanding. The case studies show the applicability of the DNT‐IVB for hazard identification and characterisation and illustrate the usefulness of an AOP‐informed IATA for regulatory decision making. The overall activity led to improved interpretation of human data by providing a plausible mechanistic link to adverse outcomes, which would support their contextualisation in the risk assessment process. This Scientific Opinion allows the PPR Panel to draft several recommendations for the implementation of the AOP‐informed IATA methodology and of the DNT‐IVB in the regulatory risk assessment of pesticides. [ABSTRACT FROM AUTHOR]

Exposure to environmental chemicals during in utero and early postnatal development can cause a wide range of neurological defects. Since current guidelines for identifying developmental neurotoxic chemicals depend on the use of large numbers of rodents in animal experiments, it has been proposed to design rapid and cost-efficient in vitro screening test batteries that are mainly based on mixed neuronal/glial cultures. However, cell culture tests do not assay correct wiring of neuronal circuits. The establishment of precise anatomical connectivity is a key event in the development of a functional brain. Here, we expose intact embryos of the locust (Locusta migratoria) in serum-free culture to test chemicals and visualize correct navigation of identified pioneer axons by fluorescence microscopy. We define separate toxicological endpoints for axonal elongation and navigation along a stereotyped pathway. To distinguish developmental neurotoxicity (DNT) from general toxicity, we quantify defects in axonal elongation and navigation in concentration–response curves and compare it to the biochemically determined viability of the embryo. The investigation of a panel of recognized DNT-positive and -negative test compounds supports a rather high predictability of this invertebrate embryo assay. Similar to the semaphorin-mediated guidance of neurites in mammalian cortex, correct axonal navigation of the locust pioneer axons relies on steering cues from members of this family of cell recognition molecules. Due to the evolutionary conserved mechanisms of neurite guidance, we suggest that our pioneer axon paradigm might provide mechanistically relevant information on the DNT potential of chemical agents on the processes of axon elongation, navigation, and fasciculation. [ABSTRACT FROM AUTHOR]

This paper presents flexible explosive sensors possibly manufacturable using high volume techniques. The flexible sensors were created using channel circuit electrodes (CCE) coated with hydrazinium graphene (HG) by a sprayer. The channel circuits produced using paste fill of fine traces is a simple yet largely unreported technique for creating electrodes. The CCE were prepared by molding electrode patterns into resin and filling the channels with conductive paste, producing trace widths of 100 µm and thickness of 4 µm. Its resistance was 5–10 kΩ/each electrode of 60 cm long in serpentine shape. Sensors created using HG as the resistive layer on CCE showed their ability to detect 18.1 ppb of Dinitrotoluene 2,4 (DNT), a precursor to trinitrotoluene (TNT). To form a complete package, resistive type sensors could be made into a portable detection system using simple electronics; we demonstrated the system with battery powered portable electronics. [ABSTRACT FROM AUTHOR]

Dysembryoplastic neuroepithelial tumors (DNTs) are regarded as benign glioneuronal neoplasms because of their excellent outcomes; however, rare DNTs show malignant transformation. We herein described a case of DNT showing malignant transformation. The patient had intractable epilepsy caused by a tumor at 1 year of age and partial resection was performed. After surgery, the residual tumor showed regrowth and surgery was performed again at 4 years of age. The resected tumor showed the typical histological features of DNT, such as specific glioneuronal elements and alveolar structures. Tumor regrowth was detected again at 6 years of age, and the patient underwent gross total resection. Histologically, the tumor was composed of a high-grade glial component mixed with atypical neuronal cells, and the diagnosis of an anaplastic glioneuronal tumor was made. Genetically, DNT and the anaplastic glioneuronal tumor both shared a copy number gain of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1), as demonstrated by multiplex ligation-dependent probe amplification (MLPA), corresponding to internal tandem duplication (ITD). A frequent FGFR1-ITD in DNT was previously reported. To the best of our knowledge, an identical mutation between primary and transformed DNT has not yet been demonstrated by MLPA. [ABSTRACT FROM AUTHOR]

Elevated TCRαβ+CD4−CD8− double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U). We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway–related genes could explain these cases. Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway–related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH). Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing. [ABSTRACT FROM AUTHOR]

Dysembryoplastic neuroepithelial tumour (DNT) is categorized as a benign glioneuronal neoplasm affecting children and young adults with chronic epileptic seizures. It is characterized by predominant intracortical localization and nodular architecture. Dysembryoplastic neuroepithelial tumour usually demonstrates a distinctive morphological pattern with a specific glioneuronal element but occasionally, its morphological picture is heterogeneous and unspecific. Thus, considering the morphology of DNT, three different histopathological subtypes are distinguished: simple, complex, and non-specific and diffuse. The DNT lesions are often related with focal cortical dysplasia (FCD) type IIIb, which is postulated to play a role in epileptogenicity. Moreover, the accompanying inflammation process might be implicated in DNT-related epileptogenesis. Dysembryoplastic neuroepithelial tumour is generally characterized by favourable prognosis and good results of surgical treatment. The pathogenesis and molecular mechanisms involved in DNT development remain uncertain. The main molecular findings are connected with BRAF alterations and activation of RAS/ERK, PI3K/AKT and mTOR signalling pathways. The present review summarizes the clinical, histopathological and molecular findings of DNT. The classification controversy, morphological heterogeneity and diagnostic problems are also discussed.

Objective: The aim was to assess the effectiveness of an optimized emergency green channel in the treatment of acute ischemic stroke (AIS) patients and its effect on emergency response time, effectiveness, anxiety, and acute stress., Methods: A retrospective analysis was conducted on 349 AIS patients treated with intravenous thrombolysis from January 2019 to May 2022. The patients were divided into those who received optimized emergency green channel treatment (155) and those who did not (194). Propensity score matching (PSM) was used to balance the admission pathways, living conditions, insurance methods, and residential locations of the 2 patient groups. The key metrics comprised the times from onset to admission, admission to computed tomography (CT), CT to thrombolysis, admission to thrombolysis (door-to-needle time (DNT)), National Institute of Health Stroke Scale (NIHSS) scores at various intervals post thrombolysis, heart rate, blood pressure, and scores in Self-Rating Anxiety Scale (SAS) and the Stanford Acute Stress Reaction Questionnaire (SASRQ)., Results: Post PSM, 118 patients were analyzed (54 control and 64 observation). The observation group showed significantly lower time results than the control group, which included the following: the time from onset to admission ( t  = 31.428, P < .001), door-to-imaging time ( t  = 27.317, P < .001), imaging-to-needle time ( t  = 20.951, P < .001, and DNT ( t  = 25.954, P < .001). Significant differences were observed in 24 hour-post thrombolysis NIHSS scores, heart rate, blood pressure, SAS, and SASRQ scores ( P < .05) but not in NIHSS scores at 7 and 30 days., Conclusion: The optimized emergency green channel process effectively reduced the treatment time for ischemic stroke patients, improved rescue efficiency, and positively influenced the psychological stress levels of patients post treatment., (2024 authors.)

Abstract A sensitive fibre optic fluorescence intensity meter has been designed and built as a transducer to detect quenching of conjugated polymer fluorescence with minimum adjustment between air- and waterborne analytes. Only generic, commercially available parts including optical fibres, solvents, airbrush, standard optical and electronic parts, and a digital lock-in amplifier have been used, avoiding the need for a fluorescence spectrometer. To test the instrument, optical fibres were sensitised with the generic fluorescent poly(phenylene-vinylene) derivative MDMO-PPV and exposed to a variety of vapour pressures, and concentrations in water, of the nitroaromatic explosive 2,4 dinitrotoluene (DNT). We establish dimensionless Stern-Volmer constants (K SV) and limit-of-detection (LoD) for air- and water-borne DNT as K SV (air) = 1.4 × 107 vs. K SV (water) = 5.8 × 106 and LoD(air) = 10.9 ppb and LoD(water) = 56 ppb. These LoDs compare favourably to prior reports. We consider our study of the MDMO-PPV/DNT system as a successful test of our transducer design and recommend its wider use. Graphical abstract fx1 Highlights • We describe and test a versatile fibre optic transducer for fluorescent sensors. • The transducer works in air and aqueous media with minimum adaptation. • We establish optimised operation protocols and show how to account for photophysical degradation of the fluorophore. • As application example, we detect airborne and waterborne nitroaromatics via a fluorescent PPV derivative. • We establish Stern Volmer constants and limits- of- detection (LoDs) in both media, our LoDs compare favourably to values established with other transducers using similar fluorophores. [ABSTRACT FROM AUTHOR]

• Reviewed cell-based, and organism-based alternative models for DNT. • Provided an overview of current state of the science on DNT AOPs. • Identified common key events of AOPs that could serve as endpoints for DNT testing using alternative methods. • Proposed a streamlined screening strategy. Developmental neurotoxicity (DNT) is an important endpoint for the safety assessment of chemicals. However, the current in vivo animal model for DNT assessment is resource-intensive and may not fully capture all mechanisms that may be relevant to DNT in humans. As a result, there is a growing need for more reliable, time- and cost-efficient approaches for DNT evaluation. Toward this end, many stem/progenitor cell-based in vitro models and alternative organism-based models are becoming available with the potential for high throughput screening of DNT. Meanwhile, with advances in the knowledgebase of DNT molecular mechanisms and the identification of DNT-related adverse outcome pathways (AOP) there is potential to develop a mechanism-based integrated testing strategy for DNT assessment. This review summarizes the state of science regarding currently available human stem/progenitor cell-based in vitro models and alternative organism-based models that could be used for DNT testing. In addition, the current knowledge regarding DNT AOPs is reviewed to identify common key events that could serve as critical endpoints to assess multiple AOPs that underlie DNT. Following the identification of common key events, a streamlined strategy is proposed using alternative models to assess the DNT potential of chemicals as an early screening approach for chemicals in development. [ABSTRACT FROM AUTHOR]

Purpose: Dysembryoplastic neuroepithelial tumors (DNTs) are slow-growing glioneuronal tumors, and their genetic backgrounds are getting unveiled. Recently, fibroblast growth factor receptor 1 internal tandem duplication (FGFR1-ITD) of the tyrosine kinase domain (TKD) has been demonstrated by whole-genome sequencing. Methods and Results: Here, we analyzed 22 DNTs using multiplex ligation-dependent probe amplification (MLPA) with formalin-fixed paraffin-embedded specimens and found a copy number gain in TKD of FGFR1 (13 cases, 59%), which suggested the presence of FGFR1-ITD. Another 5 DNTs harbored FGFR1 hot spot mutations including a double mutant case, and FGFR1 alterations were detected in 18 DNTs (82%). The BRAF V600E mutation, another important mutation in DNTs, was not observed. Conclusions: With recent findings of less frequent or absent FGFR1-ITD in pilocytic astrocytomas or rosette-forming glioneuronal tumors, the analysis of FGFR1 aberrations, especially FGFR1-ITD, was suggested to be helpful to discriminate DNTs from their histological mimics. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • New AIE materials applied in DNT vapor based on films: For rapid DNT vapor detection, new AIE molecules BTT and BPT were designed and synthesized. • Rapid response: Only in 5 s, the fluorescence of BTT and BPT is quenched 68% and 61%, respectively, which are remarkable compared with other reported works. • On-site test: The filter papers and spin-films of BTT and BPT were chose for simplicity and rapid on-site test of DNT. Abstract New aggregation-induced emission (AIE) materials 4 - (3, 5- bis (4′-(1, 2, 2-triphenylvinyl)-[1, 1′-biphenyl]-4-yl)-4 H -1, 2, 4-triazol-4-yl)- N , N -diphenylaniline (BTT) and 9-(4-(3, 5-bis(4′-(1, 2, 2-triphenylvinyl)-[1, 1′-biphenyl]-4-yl)- 4 H -1, 2, 4-triazol-4-yl) phenyl)-9H-carbazole (BPT) are designed and synthesized, which contain triazole, tetraphenylethylene and electron donating units. Further, their spin-coated films are used as fluorescent probes to detect 2, 4-dinitrotoluene (DNT) vapor with rapid fluorescence response, high sensitivity, high selectivity and reutilization. Moreover, by comparing BTT and BPT with other similar molecules without AIE properties, the extrusive sensing performances of BTT and BPT can be attributed to the introduction of AIE units. [ABSTRACT FROM AUTHOR]

Preventing unexpected explosive attacks and tracing explosion-related molecules require the development of highly sensitive gas-vapor detection systems. For that purpose, a micromechanical cantilever-based olfactory sensing system including a sample preconcentrator was developed to detect 2,4-dinitrotoluene (2,4-DNT), which is a well-known by-product of the explosive molecule trinitrotoluene (TNT) and exists in concentrations on the order of parts per billion in the atmosphere at room temperature. A peptide receptor (His-Pro-Asn-Phe-Ser-Lys-Tyr-Ile-Leu-His-Gln-Arg) that has high binding affinity for 2,4-DNT was immobilized on the surface of the cantilever sensors to detect 2,4-DNT vapor for highly selective detection. A micro-preconcentrator (µPC) was developed using Tenax-TA adsorbent to produce higher concentrations of 2,4-DNT molecules. The preconcentration was achieved via adsorption and thermal desorption phenomena occurring between target molecules and the adsorbent. The µPC directly integrated with a cantilever sensor and enhanced the sensitivity of the cantilever sensor as a pretreatment tool for the target vapor. The response was rapidly saturated within 5 min and sustained for more than 10 min when the concentrated vapor was introduced. By calculating preconcentration factor values, we verified that the cantilever sensor provides up to an eightfold improvement in sensing performance.

There is evidence that chemical exposure during development can cause irreversible impairments of the human developing nervous system. Therefore, testing compounds for their developmentally neurotoxic potential has high priority for different stakeholders: academia, industry, and regulatory bodies. Due to the resource-intensity of current developmental neurotoxicity (DNT) in vivo guidelines, alternative methods that are scientifically valid and have a high predictivity for humans are especially desired by regulators. Here, we review availability of stem−/progenitor cell-based in vitro methods for DNT evaluation that is based on the concept of neurodevelopmental process assessment. These test methods are assembled into a DNT in vitro testing battery. Gaps in this testing battery addressing research needs are also pointed out. [ABSTRACT FROM AUTHOR]

Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and NT assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predict and study human toxicity. By combining these technologies, we generated multicellular brain spheroids (BrainSpheres) from human iPSC. The model has previously shown to be reproducible and recapitulates several neurodevelopmental features. Our results indicate, rotenone's toxic potency varies depending on the differentiation status of the cells, showing higher reactive oxygen species (ROS) and higher mitochondrial dysfunction during early than later differentiation stages. Immuno-fluorescence morphology analysis after rotenone exposure indicated dopaminergic-neuron selective toxicity at non-cytotoxic concentrations (1 μM), while astrocytes and other neuronal cell types were affected at (general) cytotoxic concentrations (25 μM). Omics analysis showed changes in key pathways necessary for brain development, indicating rotenone as a developmental neurotoxicant and show a possible link between previously shown effects on neurite outgrowth and presently observed effects on Ca2+ reabsorption, synaptogenesis and PPAR pathway disruption. In conclusion, our BrainSpheres model has shown to be a reproducible and novel tool to study neurotoxicity and developmental neurotoxicity. Results presented here support the idea that rotenone can potentially be a developmental neurotoxicant. [ABSTRACT FROM AUTHOR]

There is a need for a more effective Developmental Neurotoxicity (DNT) screening which is scientifically driven by the fact that the developing nervous system might be more sensitive to exposures to some hazardous chemical. Additional concern comes from the recent societal concerns that toxic chemicals can contribute to the prevalence of neurodevelopment disabilities. Consequently, hazard identification and actions to reduce exposure to these chemicals is a priority in chemical risk assessment. To reach this goal a cost-efficient testing strategy based on a reliable in-vitro testing battery should be developed. Although this goal is representing a huge challenge in risk assessment, available data and methodologies are supporting the ultimate aim of developing a predictive model able to respond to different regulatory based problem formulations. [ABSTRACT FROM AUTHOR]

It is widely accepted that human brain development has unique features that cannot be represented by rodents. Obvious reasons are the evolutionary distance and divergent physiology. This might lead to false predictions when rodents are used for safety or pharmacological efficacy studies. For a better translation of animal-based research to the human situation, human in vitro systems might be useful. In this study, we characterize developing neural progenitor cells from prenatal human and time-matched rat and mouse brains by analyzing the changes in their transcriptome profile during neural differentiation. Moreover, we identify hub molecules that regulate neurodevelopmental processes like migration and differentiation. Consequences of modulation of three of those hubs on these processes were studied in a species-specific context. We found that although the gene expression profiles of the three species largely differ qualitatively and quantitatively, they cluster in similar GO terms like cell migration, gliogenesis, neurogenesis or development of multicellular organism. Pharmacological modulation of the identified hub molecules triggered species-specific cellular responses. This study underlines the importance of understanding species differences on the molecular level and advocates the use of human based in vitro models for pharmacological and toxicological research. [ABSTRACT FROM AUTHOR]

Routine coagulation test before intravenous tissue plasminogen activator (tPA) use increases the door to needle time (DNT). We sought to evaluate the safety of tPA use without coagulation results and its impact on prognosis. In our stroke registry, tPA was delivered with coagulation results from December 2015 to April 2016 and without coagulation results from May 2016 to December 2016. Differences of demographics, clinical characteristic, and prognosis between these two groups were analyzed. In addition, logistic regression analysis was conducted to identify predictors for DNT of over 60 min. A total of 201 stroke patients were included in the final analysis. Of these, 81 patients received tPA with coagulation results and 120 patients without coagulation results. Only one (0.8%) patient with abnormal coagulation results met the exclusion criteria of tPA use in patients without coagulation results. The difference of DNT between groups with (mean, 61.7 min) and without (mean, 41.9 min) coagulation results was significant (P = 0.00). The group without coagulation results had a higher rate of favorable 90-day outcome (74.2 vs 70.4%) and lower rates of symptomatic intracranial hemorrhage/nonintracranial hemorrhage (4.9 and 22.2% vs 1.7 and 19.2%) than the group with coagulation results did; these differences were not statistically significant. In multivariate analysis, only tPA use with coagulation results was the predictor for DNT of over 60 min (P = 0.0030, OR = 2.44, 95% CI 1.28-4.65). The present study suggests that tPA could be delivered safely without coagulation results in patients without suspected coagulopathy, and avoiding coagulation tests reduces significantly the DNT interval. [ABSTRACT FROM AUTHOR]

In Mobile Ad Hoc Network (MANET), the existing routing protocol may result in overhead and increased collisions during data transmission. In order to overcome this issue, in this paper, we propose to design a cooperation based directional routing protocol in MANET. Initially the source nodes discover neighbors by constructing the Directional Neighbour Table (DNT). Then the node with minimum transfer time is selected as best relay node. The transfer time is estimated using bio-inspired algorithm. Once the relay nodes are selected, the source node follows the Adaptive Directional Monitoring MAC (ADMMAC) protocol to transmit the data to the destination. In this technique, the nodes use the co-operative transmission mode when it requires transmitting the data packet faster. By simulation results, we show that the proposed technique minimizes the overhead and enhances the efficiency. [ABSTRACT FROM AUTHOR]

Developmental exposure to neurotoxic chemicals presents significant health concerns because of the vulnerability of the developing central nervous system (CNS) and the immature brain barrier. To date, a short list of chemicals including some metals have been identified as known developmental neurotoxicants; however, there are still numerous chemicals that remain to be evaluated for their potential developmental neurotoxicity (DNT). To facilitate evaluation of chemicals for DNT, the zebrafish vertebrate model system has emerged as a promising tool. The zebrafish possesses a number of strengths as a test species in DNT studies including an abundance of embryos developing ex utero presenting ease in chemical dosing and microscopic assessment at all early developmental stages. Additionally, rapid neurodevelopment via conserved molecular pathways supports the likelihood of recapitulating neurotoxic effects observed in other vertebrates. In this review, we describe the biological relevance of zebrafish as a complementary model for assessment of DNT. We then focus on a metalloid and two metals that are known developmental neurotoxicants (arsenic, methylmercury, and lead). We summarize studies in humans and traditional vertebrate models and then detail studies defining the toxicity of these substances using the zebrafish to support application of this model system in DNT studies.

In this study, we designed and synthesized two small fluorescent molecules, TCAC and TCA. Their spin-coated films were used as fluorescent sensors for 2, 4-dinitrotoluene (DNT) vapor. Compared with TCAC, which has carbazole units at the end of the hexyl side chains, TCA films exhibited better sensitivity and selectivity to DNT vapor with good reutilization in 30 s. Furthermore, TCA was performed to detect trace DNT by contact mode approach for real-time field and visualized detection with good performances. [ABSTRACT FROM AUTHOR]

Food supplements based on herbal products are widely used during pregnancy as part of a self-care approach. The idea that such supplements are safe and healthy is deeply seated in the general population, although they do not underlie the same strict safety regulations than medical drugs. We aimed to characterize the neurodevelopmental effects of the green tea catechin epigallocatechin gallate (EGCG), which is now commercialized as high-dose food supplement. We used the 'Neurosphere Assay' to study the effects and unravel underlying molecular mechanisms of EGCG treatment on human and rat neural progenitor cells (NPCs) development in vitro. EGCG alters human and rat NPC development in vitro. It disturbs migration distance, migration pattern, and nuclear density of NPCs growing as neurospheres. These functional impairments are initiated by EGCG binding to the extracellular matrix glycoprotein laminin, preventing its binding to β1-integrin subunits, thereby prohibiting cell adhesion and resulting in altered glia alignment and decreased number of migrating young neurons. Our data raise a concern on the intake of high-dose EGCG food supplements during pregnancy and highlight the need of an in vivo characterization of the effects of high-dose EGCG exposure during neurodevelopment. [ABSTRACT FROM AUTHOR]