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Sample records for profiling developmental neurotoxicity

  1. STATISTICAL APPROACH TO BRAIN MORPHOMETRY DATA REQUIRED IN DEVELOPMENTAL NEUROTOXICITY (DNT) TESTING GUIDELINES: PROFILE ANALYSIS.

    EPA Science Inventory

    Brain morphometry measurements are required in test guidelines proposed by the USEPA to screen chemicals for developmental neurotoxicity. Because the DNT is a screening battery, the analysis of this data should be sensitive to dose-related changes in the pattern of brain growt...

  2. Developmental Neurotoxicity of Lead.

    PubMed

    Caito, Samuel; Aschner, Michael

    2017-01-01

    Lead exposure is a major concern for the developing nervous system. Environmental exposures to lead, predominantly from contaminated water or lead paint chips, account for the majority of exposures to children. In utero and early life exposures to lead have been associated with lower IQ, antisocial and delinquent behaviors, and attention-deficit hyperactivity disorder. In this review, we will discuss sources of developmental lead exposure and mechanisms of lead neurotoxicity. We will highlight both human epidemiological studies showing associations between lead exposure and behavioral abnormalities as well as experimental data from animal studies. Finally, we will discuss the effects of lead on neurological endpoint past childhood, namely, development of Alzheimer's disease in old age.

  3. Multi-parametric profiling network based on gene expression and phenotype data: a novel approach to developmental neurotoxicity testing.

    PubMed

    Nagano, Reiko; Akanuma, Hiromi; Qin, Xian-Yang; Imanishi, Satoshi; Toyoshiba, Hiroyoshi; Yoshinaga, Jun; Ohsako, Seiichiroh; Sone, Hideko

    2012-01-01

    The establishment of more efficient approaches for developmental neurotoxicity testing (DNT) has been an emerging issue for children's environmental health. Here we describe a systematic approach for DNT using the neuronal differentiation of mouse embryonic stem cells (mESCs) as a model of fetal programming. During embryoid body (EB) formation, mESCs were exposed to 12 chemicals for 24 h and then global gene expression profiling was performed using whole genome microarray analysis. Gene expression signatures for seven kinds of gene sets related to neuronal development and neuronal diseases were selected for further analysis. At the later stages of neuronal cell differentiation from EBs, neuronal phenotypic parameters were determined using a high-content image analyzer. Bayesian network analysis was then performed based on global gene expression and neuronal phenotypic data to generate comprehensive networks with a linkage between early events and later effects. Furthermore, the probability distribution values for the strength of the linkage between parameters in each network was calculated and then used in principal component analysis. The characterization of chemicals according to their neurotoxic potential reveals that the multi-parametric analysis based on phenotype and gene expression profiling during neuronal differentiation of mESCs can provide a useful tool to monitor fetal programming and to predict developmentally neurotoxic compounds.

  4. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  5. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  6. Oxidative and excitatory mechanisms of developmental neurotoxicity: transcriptional profiles for chlorpyrifos, diazinon, dieldrin, and divalent nickel in PC12 cells.

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2009-04-01

    Oxidative stress and excitotoxicity underlie the developmental neurotoxicity of numerous chemicals. We compared the effects of organophosphates (chlorpyrifos and diazinon), an organo-chlorine (dieldrin), and a metal [divalent nickel (Ni2+)] to determine how these mechanisms contribute to similar or dissimilar neurotoxic outcomes. We used PC12 cells as a model of developing neurons and evaluated transcriptional profiles for genes for oxidative stress responses and glutamate receptors. Chlorpyrifos had a greater effect on oxidative-stress-related genes in differentiating cells compared with the undifferentiated state. Chlorpyrifos and diazinon showed significant concordance in their effects on glutathione-related genes, but they were negatively correlated for effects on catalase and superoxide dismutase isoforms and had no concordance for effects on ionotropic glutamate receptors. Surprisingly, the correlations were stronger between diazinon and dieldrin than between the two organophosphates. The effects of Ni2+ were the least similar for genes related to oxidative stress but had significant concordance with dieldrin for effects on glutamate receptors. Our results point to underlying mechanisms by which different organophosphates produce disparate neurotoxic outcomes despite their shared property as cholinesterase inhibitors. Further, apparently unrelated neurotoxicants may produce similar outcomes because of convergence on oxidative stress and excitotoxicity. The combined use of cell cultures and microarrays points to specific end points that can distinguish similarities and disparities in the effects of diverse developmental neurotoxicants.

  7. Oxidative and Excitatory Mechanisms of Developmental Neurotoxicity: Transcriptional Profiles for Chlorpyrifos, Diazinon, Dieldrin, and Divalent Nickel in PC12 Cells

    PubMed Central

    Slotkin, Theodore A.; Seidler, Frederic J.

    2009-01-01

    Background Oxidative stress and excitotoxicity underlie the developmental neurotoxicity of numerous chemicals. Objectives We compared the effects of organophosphates (chlorpyrifos and diazinon), an organo-chlorine (dieldrin), and a metal [divalent nickel (Ni2+)] to determine how these mechanisms contribute to similar or dissimilar neurotoxic outcomes. Methods We used PC12 cells as a model of developing neurons and evaluated transcriptional profiles for genes for oxidative stress responses and glutamate receptors. Results Chlorpyrifos had a greater effect on oxidative-stress–related genes in differentiating cells compared with the undifferentiated state. Chlorpyrifos and diazinon showed significant concordance in their effects on glutathione-related genes, but they were negatively correlated for effects on catalase and superoxide dismutase isoforms and had no concordance for effects on ionotropic glutamate receptors. Surprisingly, the correlations were stronger between diazinon and dieldrin than between the two organophosphates. The effects of Ni2+ were the least similar for genes related to oxidative stress but had significant concordance with dieldrin for effects on glutamate receptors. Conclusions Our results point to underlying mechanisms by which different organophosphates produce disparate neurotoxic outcomes despite their shared property as cholinesterase inhibitors. Further, apparently unrelated neurotoxicants may produce similar outcomes because of convergence on oxidative stress and excitotoxicity. The combined use of cell cultures and microarrays points to specific end points that can distinguish similarities and disparities in the effects of diverse developmental neurotoxicants. PMID:19440498

  8. Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity

    SciTech Connect

    Ho, Gideon; Zhang Chunyan; Zhuo Lang . E-mail: lzhuo@ibn.a-star.edu.sg

    2007-05-15

    Gliosis is a universal response of Brain to almost all types of neural insults, including neurotoxicity, neurodegeneration, viral infection, and stroke. A hallmark of gliotic reaction is the up-regulation of the astrocytic biomarker GFAP (glial fibrillary acidic protein), which often precedes the anatomically apparent damages in Brain. In this study, neonatal transgenic mice at postnatal day (PD) 4 expressing GFP (green fluorescent protein) under the control of a widely used 2.2-kb human GFAP promoter in Brain are treated with two model neurotoxicants, 1-methyl-4(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH{sub 3}-MPTP), and kainic acid (KA), respectively, to induce gliosis. Here we show that the neurotoxicant-induced acute gliosis can be non-invasively imaged and quantified in Brain of conscious (un-anesthetized) mice in real-time, at 0, 2, 4, 6, and 8 h post-toxicant dosing. Therefore the current methodology could be a useful tool for studying the developmental aspects of neuropathies and neurotoxicity.

  9. MicroRNA Profiling as Tool for In Vitro Developmental Neurotoxicity Testing: The Case of Sodium Valproate

    PubMed Central

    Smirnova, Lena; Block, Katharina; Sittka, Alexandra; Oelgeschläger, Michael; Seiler, Andrea E. M.; Luch, Andreas

    2014-01-01

    Studying chemical disturbances during neural differentiation of murine embryonic stem cells (mESCs) has been established as an alternative in vitro testing approach for the identification of developmental neurotoxicants. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development and ESC differentiation and specification. Thus, neural differentiation of mESCs in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed changes in miRNome and transcriptome during neural differentiation of mESCs exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neurally differentiating mESCs upon VPA treatment. Based on miRNA profiling we observed that VPA shifts the lineage specification from neural to myogenic differentiation (upregulation of muscle-abundant miRNAs, mir-206, mir-133a and mir-10a, and downregulation of neural-specific mir-124a, mir-128 and mir-137). These findings were confirmed on the mRNA level and via immunochemistry. Particularly, the expression of myogenic regulatory factors (MRFs) as well as muscle-specific genes (Actc1, calponin, myosin light chain, asporin, decorin) were found elevated, while genes involved in neurogenesis (e.g. Otx1, 2, and Zic3, 4, 5) were repressed. These results were specific for valproate treatment and―based on the following two observations―most likely due to the inhibition of histone deacetylase (HDAC) activity: (i) we did not observe any induction of muscle-specific miRNAs in neurally differentiating mESCs exposed to the unrelated developmental neurotoxicant sodium arsenite; and (ii) the expression of muscle-abundant mir-206 and mir-10a was similarly increased in cells exposed to the structurally different HDAC inhibitor trichostatin A (TSA). Based on our results we conclude that miRNA expression profiling is a suitable molecular endpoint for

  10. Phenotypic screening for developmental neurotoxicity ...

    EPA Pesticide Factsheets

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

  11. Developmental neurotoxicity of industrial chemicals.

    PubMed

    Grandjean, P; Landrigan, P J

    2006-12-16

    Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

  12. Developmental Neurotoxicology: History and Outline of Developmental Neurotoxicity Study Guidelines.

    EPA Science Inventory

    The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratoge...

  13. Developmental Neurotoxicology: History and Outline of Developmental Neurotoxicity Study Guidelines.

    EPA Science Inventory

    The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratoge...

  14. EVALUATION OF POTENTIAL DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS.

    EPA Science Inventory

    Organotins, including monomethyltin (MMT), dimethyltin (DMT), and dibutyltin (DBT), are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for developmental neurotoxic effects were raised by published findi...

  15. EVALUATION OF POTENTIAL DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS.

    EPA Science Inventory

    Organotins, including monomethyltin (MMT), dimethyltin (DMT), and dibutyltin (DBT), are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for developmental neurotoxic effects were raised by published findi...

  16. Biomarkers of adult and developmental neurotoxicity

    SciTech Connect

    Slikker, William

    2005-08-07

    Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessary for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s) (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations.

  17. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    EPA Science Inventory

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  18. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    EPA Science Inventory

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  19. Assessing the Developmental Neurotoxicity of 27 ...

    EPA Pesticide Factsheets

    Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for developmental neurotoxicity. As such, we are exploring a behavioral testing paradigm that can assess the effects of sublethal and subteratogenic concentrations of developmental neurotoxicants on zebrafish (Danio rerio). This in vivo assay quantifies the locomotor response to light stimuli under tandem light and dark conditions in a 96-well plate using a video tracking system on 6 day post fertilization zebrafish larvae. Each of twenty-seven organophosphorus pesticides was tested for their developmental neurotoxic potential by exposing zebrafish embryos/larvae to the pesticide at several concentrations (≤ 100 μM nominal concentration) during the first five days of development, followed by 24 hours of depuration and then behavioral testing. Approximately 22% of the chemicals (Acephate, Dichlorvos, Diazoxon, Bensulide,Tribufos, Tebupirimfos) did not produce any behavioral changes after developmental exposure, while many (Malaoxon Fosthiazate, Dimethoate, Dicrotophos, Ethoprop, Malathion, Naled, Diazinon, Methamidophos, Terbufos, Trichlorfon, Phorate, Pirimiphos-methyl, Profenofos, Z-Tetrachlorvinphos, Chlorpyrifos, Coumaphos, Phosmet, Omethoate) produced changes in swi

  20. Zebrafish as a systems toxicology model for developmental neurotoxicity testing.

    PubMed

    Nishimura, Yuhei; Murakami, Soichiro; Ashikawa, Yoshifumi; Sasagawa, Shota; Umemoto, Noriko; Shimada, Yasuhito; Tanaka, Toshio

    2015-02-01

    The developing brain is extremely sensitive to many chemicals. Exposure to neurotoxicants during development has been implicated in various neuropsychiatric and neurological disorders, including autism spectrum disorder, attention deficit hyperactive disorder, schizophrenia, Parkinson's disease, and Alzheimer's disease. Although rodents have been widely used for developmental neurotoxicity testing, experiments using large numbers of rodents are time-consuming, expensive, and raise ethical concerns. Using alternative non-mammalian animal models may relieve some of these pressures by allowing testing of large numbers of subjects while reducing expenses and minimizing the use of mammalian subjects. In this review, we discuss some of the advantages of using zebrafish in developmental neurotoxicity testing, focusing on central nervous system development, neurobehavior, toxicokinetics, and toxicodynamics in this species. We also describe some important examples of developmental neurotoxicity testing using zebrafish combined with gene expression profiling, neuroimaging, or neurobehavioral assessment. Zebrafish may be a systems toxicology model that has the potential to reveal the pathways of developmental neurotoxicity and to provide a sound basis for human risk assessments. © 2014 Japanese Teratology Society.

  1. Developmental neurotoxicity of polybrominated biphenyls.

    PubMed

    Henck, J W; Mattsson, J L; Rezabek, D H; Carlson, C L; Rech, R H

    1994-01-01

    Female F0 generation Sprague-Dawley rats received daily oral doses of 0, 0.2, or 2 mg/kg polybrominated biphenyls (PBB) as fireMaster BP-6 from Day 6 of gestation through Day 24 postpartum. Maternal parameters were assessed, and F1 generation offspring were evaluated for growth and survival, as well as physical and behavioral development. No adverse maternal effects were observed nor were there PBB-related effects on survival of the F1 generation or acquisition of developmental landmarks. Crown-rump length of 0.2 and 2 mg/kg male offspring was significantly less than that of controls and 2 mg/kg male and female offspring gained significantly less weight than did controls for the entire 60-day postnatal observation period. An overall evaluation of behavior by multivariate analysis of variance revealed significant PBB-related effects for acquisition of forward locomotion, cliff avoidance, cage emergence, and open-field activity of male and female offspring from dams administered 2 mg/kg. Delays in acquisition of forward locomotion and suppressed open-field activity were the most prominent effects. These indications of growth retardation and neurobehavioral toxicity occurred at concentrations of PBB in offspring body fat in the range of those which have been reported for highly exposed human subjects with neurological sequelae.

  2. Meeting Report: Alternatives for Developmental Neurotoxicity Testing

    PubMed Central

    Lein, Pamela; Locke, Paul; Goldberg, Alan

    2007-01-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13–15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children’s health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders. PMID:17520065

  3. Meeting report: alternatives for developmental neurotoxicity testing.

    PubMed

    Lein, Pamela; Locke, Paul; Goldberg, Alan

    2007-05-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13-15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children's health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders.

  4. Prospective, longitudinal assessment of developmental neurotoxicity.

    PubMed Central

    Jacobson, J L; Jacobson, S W

    1996-01-01

    Methodological issues in the design of prospective, longitudinal studies of developmental neurotoxicity in humans are reviewed. A comprehensive assessment of potential confounding influences is important in these studies because inadequate assessment of confounders can threaten the validity of causal inferences drawn from the data. Potential confounders typically include demographic background variables, alcohol and smoking during pregnancy, the quality of parental stimulation, the child's age at test, and the examiner. Exposure to other substances is assessed where significant exposure is expected in the target population. In most studies, control variables even weakly related to outcome are included in all multivariate statistical analyses, and a toxic effect is inferred only if the effect of exposure is significant after controlling for the potential confounders. Once a neurotoxic effect has been identified, suspected mediating variables may be added to the analysis to examine underlying processes or mechanisms through which the exposure may impact on developmental outcome. Individual differences in vulnerability may be examined in terms of either an additive compensatory model or a synergistic "risk and resilience" approach. Failure to detect real effects (Type II error) is of particular concern in these studies because public policy considerations make it likely that negative findings will be interpreted to mean that the exposure is safe. Important sources of Type II error include inadequate representation of highly exposed individuals, overcontrol for confounders, and inappropriate correction for multiple comparisons. Given the high cost and complexity of prospective, longitudinal investigations, cross-sectional pilot studies focusing on highly exposed individuals can be valuable for the initial identification of salient domains of impairment. PMID:9182034

  5. Recommendations for Developing Alternative Test Methods for Developmental Neurotoxicity

    EPA Science Inventory

    There is great interest in developing alternative methods for developmental neurotoxicity testing (DNT) that are cost-efficient, use fewer animals and are based on current scientific knowledge of the developing nervous system. Alternative methods will require demonstration of the...

  6. ONTOGENY OF PROTEINS FOR USE AS BIOMARKERS OF DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    The developing nervous system can be uniquely susceptible to adverse effects following exposure to environmental chemicals, and several advisory panels (e.g. ILSI, NRC, NAS) have highlighted the need for rapid and sensitive developmental neurotoxicity testing methods. Measurement...

  7. Recommendations for Developing Alternative Test Methods for Developmental Neurotoxicity

    EPA Science Inventory

    There is great interest in developing alternative methods for developmental neurotoxicity testing (DNT) that are cost-efficient, use fewer animals and are based on current scientific knowledge of the developing nervous system. Alternative methods will require demonstration of the...

  8. TESTING FOR DEVELOPMENTAL NEUROTOXICITY: CURRENT APPROACHES AND FUTURE NEEDS.

    EPA Science Inventory

    There are many adverse effects on the nervous system following exposure to environmental chemicals during development. In a number of cases (e.g., lead, methyl mercury) the developing nervous system is a highly susceptible. Developmental Neurotoxicity Testing (DNT) guidelines...

  9. TESTING FOR DEVELOPMENTAL NEUROTOXICITY: CURRENT APPROACHES AND FUTURE NEEDS.

    EPA Science Inventory

    There are many adverse effects on the nervous system following exposure to environmental chemicals during development. In a number of cases (e.g., lead, methyl mercury) the developing nervous system is a highly susceptible. Developmental Neurotoxicity Testing (DNT) guidelines...

  10. Developmental neurotoxicity test guidelines: problems and perspectives.

    PubMed

    Tohyama, Chiharu

    2016-01-01

    Epidemiologic evidence has demonstrated associations between early life exposure to industrial chemicals and the occurrence of disease states, including cognitive and behavioral abnormalities, in children. The developing brain in the fetal and infantile periods is extremely vulnerable to chemicals because the blood-brain barrier is not completely formed during these periods. The Organisation for Economic Co-operation and Development (OECD) developmental neurotoxicity (DNT) test guideline, TG426, updated in 2007, comprises in vivo behavioral observational tests and other tests intended to assess DNT induced by exposure to industrial chemicals. These chemicals may enter the market without having been subjected to DNT testing, as DNT test data is not mandated by law at the time of chemical registration. In addition, proprietary rights have led to problems concerning the non-disclosure of industrial chemical toxicity test data, including DNT test data. To overcome the disadvantages of high-cost and low time efficiency of in vivo DNT tests, in vitro or in silico tests are the proposed alternatives, but it is unlikely that the results of such tests would reflect changes in higher brain functions. Accordingly, the current DNT test guidelines need to be revised to avoid overlooking or neglecting the occurrence of DNT induced by exposure to low doses of chemicals. This review also proposes the introduction of novel in vivo DNT testing methods in light of a cost-performance analysis.

  11. Alternative Test Methods for Developmental Neurotoxicity: A ...

    EPA Pesticide Factsheets

    Exposure to environmental contaminants is well documented to adversely impact the development of the nervous system. However, the time, animal and resource intensive EPA and OECD testing guideline methods for developmental neurotoxicity (DNT) are not a viable solution to characterizing potential chemical hazards for the thousands of untested chemicals currently in commerce. Thus, research efforts over the past decade have endeavored to develop cost-effective alternative DNT testing methods. These efforts have begun to generate data that can inform regulatory decisions. Yet there are major challenges to both the acceptance and use of this data. Major scientific challenges for DNT include development of new methods and models that are “fit for purpose”, development of a decision-use framework, and regulatory acceptance of the methods. It is critical to understand that use of data from these methods will be driven mainly by the regulatory problems being addressed. Some problems may be addressed with limited datasets, while others may require data for large numbers of chemicals, or require the development and use of new biological and computational models. For example mechanistic information derived from in vitro DNT assays can be used to inform weight of evidence (WoE) or integrated approaches to testing and assessment (IATA) approaches for chemical-specific assessments. Alternatively, in vitro data can be used to prioritize (for further testing) the thousands

  12. Mental retardation and developmental disabilities influenced by environmental neurotoxic insults.

    PubMed Central

    Schroeder, S R

    2000-01-01

    This paper sets a framework for the discussion of neurotoxicity as a potentially major contributor to the etiology of many types of mental retardation and developmental disabilities. In the past the literatures on developmental neurotoxicology and on mental retardation have evolved independently, yet we know that the developing brain is a target for neurotoxicity in the developing central nervous system through many stages of pregnancy as well as during infancy and early childhood. Our definitions and theories of mental retardation and developmental disabilities affect the models of neurotoxicity we espouse. For instance, models of developmental risk in neurotoxicology have guided environmental regulation to reduce the likelihood of neurotoxic effects. On the other hand, models of developmental risk for mental retardation aim not only at primary prevention,but also at secondary and tertiary prevention through early intervention. In the future, dynamic models of neuroplasticity based on the study of gene-brain-behavior relationships are likely to guide our views of developmental neurotoxicology and prevention of mental retardation and other disabilities. PMID:10852834

  13. A screening approach using zebrafish for the detection and characterization of developmental neurotoxicity.

    EPA Science Inventory

    Thousands of chemicals have little or no data to support developmental neurotoxicity risk assessments. Current developmental neurotoxicity guideline studies mandating mammalian model systems are expensive and time consuming. Therefore a rapid, cost-effective method to assess de...

  14. Predicting developmental neurotoxicity in rodents from larval zebrafish - - and vice versa

    EPA Science Inventory

    The complexity of standard mammalian developmental neurotoxicity tests limits evaluation of large numbers of chemicals. Less complex, more rapid assays using larval zebrafish are gaining popularity for evaluating the developmental neurotoxicity of chemicals; there remains, howeve...

  15. A screening approach using zebrafish for the detection and characterization of developmental neurotoxicity.

    EPA Science Inventory

    Thousands of chemicals have little or no data to support developmental neurotoxicity risk assessments. Current developmental neurotoxicity guideline studies mandating mammalian model systems are expensive and time consuming. Therefore a rapid, cost-effective method to assess de...

  16. Predicting developmental neurotoxicity in rodents from larval zebrafish - - and vice versa

    EPA Science Inventory

    The complexity of standard mammalian developmental neurotoxicity tests limits evaluation of large numbers of chemicals. Less complex, more rapid assays using larval zebrafish are gaining popularity for evaluating the developmental neurotoxicity of chemicals; there remains, howeve...

  17. Potential developmental neurotoxicity of pesticides used in Europe.

    PubMed

    Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

    2008-10-22

    Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe--including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides--can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.

  18. Potential developmental neurotoxicity of pesticides used in Europe

    PubMed Central

    Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

    2008-01-01

    Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. PMID:18945337

  19. DEVELOPMENTAL NEUROTOXICITY OF PYRETHROID INSECTICIDES: CRITICAL REVIEW.

    EPA Science Inventory

    Pyrethroids are widely utilized insecticides whose primary action is the disruption of voltage-sensitive sodium channels (VSSC). Although these compounds have been in use for over 30 years and their acute neurotoxicity has been well characterized, there is considerably less info...

  20. DEVELOPMENTAL NEUROTOXICITY TESTING GUIDELINES: VARIABILITY IN MORPHOMETRIC ASSESSMENTS OF NEUROPATHOLOGY.

    EPA Science Inventory

    The USEPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for neuropathological and morphometric assessments of rat pups on postnatal day (PND) 11 and at study termination (after PND 60). In recent discussions about conducting these studies on pesti...

  1. Developmental neurotoxic effects of Malathion on 3D neurosphere system

    PubMed Central

    Salama, Mohamed; Lotfy, Ahmed; Fathy, Khaled; Makar, Maria; El-emam, Mona; El-gamal, Aya; El-gamal, Mohamed; Badawy, Ahmad; Mohamed, Wael M.Y.; Sobh, Mohamed

    2015-01-01

    Developmental neurotoxicity (DNT) refers to the toxic effects induced by various chemicals on brain during the early childhood period. As human brains are vulnerable during this period, various chemicals would have significant effects on brains during early childhood. Some toxicants have been confirmed to induce developmental toxic effects on CNS; however, most of agents cannot be identified with certainty. This is because available animal models do not cover the whole spectrum of CNS developmental periods. A novel alternative method that can overcome most of the limitations of the conventional techniques is the use of 3D neurosphere system. This in-vitro system can recapitulate many of the changes during the period of brain development making it an ideal model for predicting developmental neurotoxic effects. In the present study we verified the possible DNT of Malathion, which is one of organophosphate pesticides with suggested possible neurotoxic effects on nursing children. Three doses of Malathion (0.25 μM, 1 μM and 10 μM) were used in cultured neurospheres for a period of 14 days. Malathion was found to affect proliferation, differentiation and viability of neurospheres, these effects were positively correlated to doses and time progress. This study confirms the DNT effects of Malathion on 3D neurosphere model. Further epidemiological studies will be needed to link these results to human exposure and effects data. PMID:27054080

  2. Developmental Neurotoxicity Testing: A Path Forward

    EPA Science Inventory

    Great progress has been made over the past 40 years in understanding the hazards of exposure to a small number of developmental neurotoxicants. Lead, PCBs, and methylmercury are all good examples of science-based approaches to characterizing the hazard to the developing nervous s...

  3. Developmental Neurotoxicity Testing: A Path Forward

    EPA Science Inventory

    Great progress has been made over the past 40 years in understanding the hazards of exposure to a small number of developmental neurotoxicants. Lead, PCBs, and methylmercury are all good examples of science-based approaches to characterizing the hazard to the developing nervous s...

  4. Developmental neurotoxicity of methylmercury: the role of microtubules

    SciTech Connect

    Sager, P.R.

    1982-01-01

    The purpose of this research was to investigate the interaction of methylmercury with microtubules as a possible mechanism for methylmercury-caused developmental neurotoxicity. Methylmercury effects on developing cerebellar cortex, an area of rapid proliferation, were examined. This model was used to test the hypothesis that microtubules of the mitotic spindle are sensitive to methylmercury in vivo as well as in cultured cells. The effect of methylmercury on non-spindle microtubules was studied in cultured cells. Cellular levels of methylmercury were determined and were used to construct a dose-response relationship. The direct effects of methylmercury on microtubule assembly in vitro were also documented. The data from these three systems have been integrated to form a hypothesis for the role of microtubules in developmental neurotoxicity caused by methylmercury. 159 references, 23 figures, 16 tables.

  5. A critical review of neonicotinoid insecticides for developmental neurotoxicity.

    PubMed

    Sheets, Larry P; Li, Abby A; Minnema, Daniel J; Collier, Richard H; Creek, Moire R; Peffer, Richard C

    2016-02-01

    A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.

  6. A critical review of neonicotinoid insecticides for developmental neurotoxicity

    PubMed Central

    Sheets, Larry P.; Li, Abby A.; Minnema, Daniel J.; Collier, Richard H.; Creek, Moire R.; Peffer, Richard C.

    2016-01-01

    Abstract A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood–brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system. PMID:26513508

  7. A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

    PubMed Central

    Costa, Lucio G.; de Laat, Rian; Tagliaferri, Sara; Pellacani, Claudia

    2013-01-01

    Polybrominated diphenyl ethers (PBDEs), extensively used in the past few decades as flame retardants in a variety of consumer products, have become world-wide persistent environmental pollutants. Levels in North America are usually higher than those in Europe and Asia, and body burden is 3 to 9-fold higher in infants and toddlers than in adults. The latter has raised concern for potential developmental toxicity and neurotoxicity of PBDEs. Experimental studies in animals and epidemiological observations in humans suggest that PBDEs may be developmental neurotoxicants. Pre- and/or post-natal exposure to PBDEs may cause long-lasting behavioral abnormalities, particularly in the domains of motor activity and cognition. The mechanisms underlying the developmental neurotoxic effects of PBDEs are not known, though several hypotheses have been put forward. One general mode of action relates to the ability of PBDEs to impair thyroid hormone homeostasis, thus indirectly affecting the developing brain. An alternative or additional mode of action involves a direct effect of PBDEs on nervous system cells; PBDEs can cause oxidative stress-related damage (DNA damage, mitochondrial dysfunction, apoptosis), and interfere with signal transduction (particularly calcium signaling), and with neurotransmitter systems. Important issues such as bioavailability and metabolism of PBDEs, extrapolation of results to low level of exposures, and the potential effects of interactions among PBDE congeners and between PBDEs and other contaminants also need to be taken into account. PMID:24270005

  8. DEVELOPMENTAL NEUROTOXICITY OF POLYBROMINATED DIPHENYL ETHER (PBDE) FLAME RETARDANTS

    PubMed Central

    Costa, Lucio G.; Giordano, Gennaro

    2007-01-01

    Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexa BDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T4) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers. PMID:17904639

  9. Change in Gene Expression in Zebrafish as an Endpoint for Developmental Neurotoxicity Screening

    EPA Science Inventory

    Chemicals that adversely affect the developing nervous system may have long-term consequences on human health. Little information exists on a large number of environmental chemicals to guide the risk assessments for developmental neurotoxicity (DNT). As traditional developmental ...

  10. Change in Gene Expression in Zebrafish as an Endpoint for Developmental Neurotoxicity Screening

    EPA Science Inventory

    Chemicals that adversely affect the developing nervous system may have long-term consequences on human health. Little information exists on a large number of environmental chemicals to guide the risk assessments for developmental neurotoxicity (DNT). As traditional developmental ...

  11. In Vitro Assessment of Developmental Neurotoxicity: Use of Microelectrode Arrays to Measure Functional Changes in Neuronal Network Ontogeny*

    EPA Science Inventory

    Because the Developmental Neurotoxicity Testing Guidelines require large numbers of animals and is expensive, development of in vitro approaches to screen chemicals for potential developmental neurotoxicity is a high priority. Many proposed approaches for screening are biochemica...

  12. In Vitro Assessment of Developmental Neurotoxicity: Use of Microelectrode Arrays to Measure Functional Changes in Neuronal Network Ontogeny*

    EPA Science Inventory

    Because the Developmental Neurotoxicity Testing Guidelines require large numbers of animals and is expensive, development of in vitro approaches to screen chemicals for potential developmental neurotoxicity is a high priority. Many proposed approaches for screening are biochemica...

  13. IN VITRO ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: USE OF MICROELECTRODE ARRAYS TO MEASURE FUNCTIONAL CHANGES IN NEURONAL NETWORK ONTOGENY

    EPA Science Inventory

    Because the Developmental Neurotoxicity Testing Battery requires large numbers of animals and is expensive, development of in vitro approaches to screen chemicals for potential developmental neurotoxicity is a high priority. Many proposed approaches for screening are biochemical,...

  14. Developmental neurotoxicity of monocrotophos and lead is linked to thyroid disruption

    PubMed Central

    Kumar, B. Kala; Reddy, A. Gopala; Krishna, A. Vamsi; Quadri, S. S. Y. H.; Kumar, P. Shiva

    2016-01-01

    Aim: A role of thyroid disruption in developmental neurotoxicity of monocrotophos (MCP) and lead is studied. Materials and Methods: A total of 24 female rats after conception were randomized into four groups of six each and treated as follows: Group I - Sham was administered distilled water orally. Group II - A positive control was administered methyl methimazole at 0.02% orally in drinking water. Group III - MCP orally at 0.3 mg/kg and Group IV - Lead acetate at 0.2% orally in drinking water. The drug was administered from gestation day 3 through post-natal day 21 in all the groups. Acetylcholinesterase (AChE) inhibition, thyroid profile (thyroid stimulating hormone, T3 and T4), neurodevelopment (brain wet weights, DNA, RNA and protein), and neurobehavioral (elevated plus maze, photoactometry, and Morris water maze) parameters were assessed in pups. A histopathology of thyroid of dams and brain of progeny was conducted. Results: Inhibition of AChE was <20%. Thyroid profile decreased in the treatment groups. Neurodevelopmental and neurobehavioral parameters did not reveal any significant changes. Thyroid architecture was affected significantly with MCP and lead. Cortical layers too were affected. The three layers of cerebellum either had abnormal arrangement or decreased cellularity in all treated groups relating to thyroid disruption. Conclusion: MCP and lead might have affected the development of cerebrum and cerebellum via thyroid disruption leading to developmental neurotoxicity. PMID:27051198

  15. Current Practices and Future Trends in Neuropathology Assessment for Developmental Neurotoxicity Testing

    EPA Science Inventory

    The continuing education course on "Developmental Neurotoxicity Testing" (DNT) was designed to communicate current practices for DNT neuropathology, describe promising innovations in quantitative analysis and non-invasive imaging, and facilitate a discussion among experienced neu...

  16. Gene Expression Changes in Developing Zebrafish as Potential Markers for Rapid Developmental Neurotoxicity Screening

    EPA Science Inventory

    Sparse information exists on many chemicals to guide developmental neurotoxicity (DNT) risk assessments. As DNT testing using rodents is laborious and expensive, alternative species such as zebrafish are being adapted for toxicity screening. Assessing the DNT potential of chem...

  17. Webinar Presentation: Using in Vitro and in Vivo Models to Inform Understanding of Developmental Neurotoxicity

    EPA Pesticide Factsheets

    This presentation, Using in Vitro and in Vivo Models to Inform Understanding of Developmental Neurotoxicity, was given at the NIEHS/EPA Children's Centers 2015 Webinar Series: Interdisciplinary Approaches to Neurodevelopment held on Sept. 9, 2015.

  18. A QUALITATIVE RETROSPECTIVE ANALYSIS OF POSITIVE CONTROL DATA IN DEVELOPMENTAL NEUROTOXICITY STUDIES.

    EPA Science Inventory

    A manuscript reviews positive control data submitted by registrants in support of Developmental Neurotoxicity (DNT) guideline studies. Adequate positive control data are needed to evaluate laboratory proficiency in detecting changes in the structure and function of the developin...

  19. International STakeholder NETwork (ISTNET): Creating a Developmental Neurotoxicity Testing (DNT) Roadmap for Regulatory Purposes

    EPA Science Inventory

    A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a m...

  20. A QUALITATIVE RETROSPECTIVE ANALYSIS OF POSITIVE CONTROL DATA IN DEVELOPMENTAL NEUROTOXICITY STUDIES.

    EPA Science Inventory

    A manuscript reviews positive control data submitted by registrants in support of Developmental Neurotoxicity (DNT) guideline studies. Adequate positive control data are needed to evaluate laboratory proficiency in detecting changes in the structure and function of the developin...

  1. Current Practices and Future Trends in Neuropathology Assessment for Developmental Neurotoxicity Testing

    EPA Science Inventory

    The continuing education course on "Developmental Neurotoxicity Testing" (DNT) was designed to communicate current practices for DNT neuropathology, describe promising innovations in quantitative analysis and non-invasive imaging, and facilitate a discussion among experienced neu...

  2. Phenotypic screening for developmental neurotoxicity: mechanistic data at the level of the cell

    EPA Science Inventory

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemi...

  3. Phenotypic screening for developmental neurotoxicity: mechanistic data at the level of the cell

    EPA Science Inventory

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemi...

  4. The Potential Contribution of Advanced Imaging Techniques to Developmental Neurotoxicity Risk Assessment

    EPA Science Inventory

    Neuropathologic assessment provides critical data essential to developmental neurotoxicity risk assessment. There are a number of objectives in conducting a neuropathologic assessment to effectively support risk assessment. These include a comprehensive assessment of the adult an...

  5. Gene Expression Changes in Developing Zebrafish as Potential Markers for Rapid Developmental Neurotoxicity Screening

    EPA Science Inventory

    Sparse information exists on many chemicals to guide developmental neurotoxicity (DNT) risk assessments. As DNT testing using rodents is laborious and expensive, alternative species such as zebrafish are being adapted for toxicity screening. Assessing the DNT potential of chem...

  6. International STakeholder NETwork (ISTNET): Creating a Developmental Neurotoxicity Testing (DNT) Roadmap for Regulatory Purposes

    EPA Science Inventory

    A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a m...

  7. DEVELOPMENTAL NEUROTOXICITY TESTING GUIDELINES: A QUALIFICATIVE RETROSPECTIVE ANALYSIS OF POSITIVE CONTROL DATA.

    EPA Science Inventory

    The USEPA Developmental Neurotoxicity (DNT) Study Test Guideline calls for both functional and neuropathological assessments in offspring during and following maternal exposure. This guideline also requires data from positive control (PC) agents. Submission of these data permit e...

  8. The Potential Contribution of Advanced Imaging Techniques to Developmental Neurotoxicity Risk Assessment

    EPA Science Inventory

    Neuropathologic assessment provides critical data essential to developmental neurotoxicity risk assessment. There are a number of objectives in conducting a neuropathologic assessment to effectively support risk assessment. These include a comprehensive assessment of the adult an...

  9. Alternative Test Methods for Developmental Neurotoxicity: A History and Path Forward (OECD EFSA workshop)

    EPA Science Inventory

    Exposure to environmental contaminants is well documented to adversely impact the development of the nervous system. However, the time, animal and resource intensive EPA and OECD testing guideline methods for developmental neurotoxicity (DNT) are not a viable solution to characte...

  10. Novel Methods at Molecular Level for Developmental Neurotoxicity Testing in 21st Century-Utility of Structure-Activity Relationship

    EPA Science Inventory

    Current neurotoxicity and developmental neurotoxicity testing methods for hazard identification rely on in vivo neurobehavior, neurophysiological, and gross pathology of the nervous system. These measures may not be sensitive enough to detect small changes caused by realistic ex...

  11. Novel Methods at Molecular Level for Developmental Neurotoxicity Testing in 21st Century-Utility of Structure-Activity Relationship

    EPA Science Inventory

    Current neurotoxicity and developmental neurotoxicity testing methods for hazard identification rely on in vivo neurobehavior, neurophysiological, and gross pathology of the nervous system. These measures may not be sensitive enough to detect small changes caused by realistic ex...

  12. Modeling anesthetic developmental neurotoxicity using human stem cells

    PubMed Central

    Bai, Xiaowen; Twaroski, Danielle; Bosnjak, Zeljko J.

    2013-01-01

    Mounting pre-clinical evidence in rodents and non-human primates has demonstrated that prolonged exposure of developing animals to general anesthetics can induce widespread neuronal cell death followed by long-term memory and learning disabilities. In vitro experimental evidence from cultured neonatal animal neurons confirmed the in vivo findings. However, there is no direct clinical evidence of the detrimental effects of anesthetics in human fetuses, infants, or children. Development of an in vitro neurogenesis system using human stem cells has opened up avenues of research for advancing our understanding of human brain development and the issues relevant to anesthetic-induced developmental toxicity in human neuronal lineages. Recent studies from our group, as well as other groups, showed that isoflurane influences human neural stem cell proliferation and neurogenesis, while ketamine induces neuroapoptosis. Application of this high throughput in vitro stem cell neurogenesis approach is a major stride toward assuring the safety of anesthetic agents in young children. This in vitro human model allows us to (1) screen the toxic effects of various anesthetics under controlled conditions during intense neuronal growth, (2) find the trigger for the anesthetic-induced catastrophic chain of toxic events, and (3) develop prevention strategies to avoid this toxic effect. In this paper, we reviewed the current findings in anesthetic-induced neurotoxicity studies, specifically focusing on the in vitro human stem cell model. PMID:23859832

  13. The need for developmental neurotoxicity studies in risk assessment for developmental toxicity.

    PubMed

    Hass, Ulla

    2006-08-01

    The estimated frequencies of neurodevelopmental disorders in children are relatively high, i.e. around 12%. The developing central nervous system appears to be especially susceptible to toxic insults and several developmental neurotoxicants, some with widespread occupational or consumer exposure, have been identified in humans and experimental animals. Cross-species comparability between human and experimental animals supports the assumption that developmental neurotoxicity (DNT) effects in animals indicate a potential to affect development in humans. The proposed Organization for Economic Cooperation and Development (OECD) developmental neurotoxicity study (TG 426) provides an outline of behavioural and morphological endpoints that are relevant to human neurodevelopment, and the guideline is expectedly adopted during 2006. Hopefully, this may contribute to inclusion of sufficient regulatory testing for DNT in the new EU chemical regulation REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals). At present, DNT testing is not included in REACH and that gives rise to concern, as there is a recognized need for DNT testing in order to protect the susceptible developing brain.

  14. Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies.

    PubMed

    Bosnjak, Zeljko J; Logan, Sarah; Liu, Yanan; Bai, Xiaowen

    2016-11-01

    Mounting evidence has demonstrated that general anesthetics could induce developmental neurotoxicity, including acute widespread neuronal cell death, followed by long-term memory and learning abnormalities. Propofol is a commonly used intravenous anesthetic agent for the induction and maintenance of anesthesia and procedural and critical care sedation in children. Compared with other anesthetic drugs, little information is available on its potential contributions to neurotoxicity. Growing evidence from multiple experimental models showed a similar neurotoxic effect of propofol as observed in other anesthetic drugs, raising serious concerns regarding pediatric propofol anesthesia. The aim of this review is to summarize the current findings of propofol-induced developmental neurotoxicity. We first present the evidence of neurotoxicity from animal models, animal cell culture, and human stem cell-derived neuron culture studies. We then discuss the mechanism of propofol-induced developmental neurotoxicity, such as increased cell death in neurons and oligodendrocytes, dysregulation of neurogenesis, abnormal dendritic development, and decreases in neurotrophic factor expression. Recent findings of complex mechanisms of propofol action, including alterations in microRNAs and mitochondrial fission, are discussed as well. An understanding of the toxic effect of propofol and the underlying mechanisms may help to develop effective novel protective or therapeutic strategies for avoiding the neurotoxicity in the developing human brain.

  15. Studies of the Variables Affecting Behavior of Larval Zebrafish for Developmental Neurotoxicity Testing

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to detect developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral paradig...

  16. Studies on the Behavior of Larval Zebrafish for Developmental Neurotoxicity Screening

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to detect developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral paradig...

  17. Studies of the Variables Affecting Behavior of Larval Zebrafish for Developmental Neurotoxicity Testing*

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to screen for developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral par...

  18. Studies on the Behavior of Larval Zebrafish for Developmental Neurotoxicity Screening

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to detect developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral paradig...

  19. Studies of the Variables Affecting Behavior of Larval Zebrafish for Developmental Neurotoxicity Testing*

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to screen for developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral par...

  20. Studies of the Variables Affecting Behavior of Larval Zebrafish for Developmental Neurotoxicity Testing

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. We are exploring methods to detect developmentally neurotoxic chemicals using zebrafish behavior at 6 days of age. The behavioral paradig...

  1. Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity.

    PubMed

    Ryan, Kristen R; Sirenko, Oksana; Parham, Fred; Hsieh, Jui-Hua; Cromwell, Evan F; Tice, Raymond R; Behl, Mamta

    2016-03-01

    Due to the increasing prevalence of neurological disorders and the large number of untested compounds in the environment, there is a need to develop reliable and efficient screening tools to identify environmental chemicals that could potentially affect neurological development. Herein, we report on a library of 80 compounds screened for their ability to inhibit neurite outgrowth, a process by which compounds may elicit developmental neurotoxicity, in a high-throughput, high-content assay using human neurons derived from induced pluripotent stem cells (iPSC). The library contains a diverse set of compounds including those that have been known to be associated with developmental neurotoxicity (DNT) and/or neurotoxicity (NT), environmental compounds with unknown neurotoxic potential (e.g., polycyclic aromatic hydrocarbons (PAHs) and flame retardants (FRs)), as well as compounds with no documented neurotoxic potential. Neurons were treated for 72h across a 6-point concentration range (∼0.3-100μM) in 384-well plates. Effects on neurite outgrowth were assessed by quantifying total outgrowth, branches, and processes. We also assessed the number ofviable cells per well. Concentration-response profiles were evaluated using a Hill model to derive benchmark concentration (BMC) values. Assay performance was evaluated using positive and negative controls and test replicates. Compounds were ranked by activity and selectivity (i.e., specific effects on neurite outgrowth in the absence of concomitant cytotoxicity) and repeat studies were conducted to confirm selectivity. Among the 80 compounds tested, 38 compounds were active, of which 16 selectively inhibited neurite outgrowth. Of these 16 compounds, 12 were known to cause DNT/NT and the remaining 4 compounds included 3 PAHs and 1 FR. In independent repeat studies, 14/16 selective compounds were reproducibly active in the assay, of which only 6 were selective for inhibition of neurite outgrowth. These 6 compounds were

  2. MicroRNAs: New Players in Anesthetic-Induced Developmental Neurotoxicity

    PubMed Central

    Twaroski, Danielle; Bosnjak, Zeljko J.; Bai, Xiaowen

    2015-01-01

    Growing evidence demonstrates that prolonged exposure to general anesthetics during brain development induces widespread neuronal cell death followed by long-term memory and learning disabilities in animal models. These studies have raised serious concerns about the safety of anesthetic use in pregnant women and young children. However, the underlying mechanisms of anesthetic-induced neurotoxicity are complex and are not well understood. MicroRNAs are endogenous, small, non-coding RNAs that have been implicated to play important roles in many different disease processes by negatively regulating target gene expression. A possible role for microRNAs in anesthetic-induced developmental neurotoxicity has recently been identified, suggesting that microRNA-based signaling might be a novel target for preventing the neurotoxicity. Here we provide an overview of anesthetic-induced developmental neurotoxicity and focus on the role of microRNAs in the neurotoxicity observed in both human stem cell-derived neuron and animal models. Aberrant expression of some microRNAs has been shown to be involved in anesthetic-induced developmental neurotoxicity, revealing the potential of microRNAs as therapeutic or preventive targets against the toxicity. PMID:26146587

  3. Developmental neurotoxicity of chlorpyrifos: what is the vulnerable period?

    PubMed Central

    Qiao, Dan; Seidler, Frederic J; Padilla, Stephanie; Slotkin, Theodore A

    2002-01-01

    Previously, we found that exposure of neonatal rats to chlorpyrifos (CPF) produced brain cell damage and loss, with resultant abnormalities of synaptic development. We used the same biomarkers to examine prenatal CPF treatment so as to define the critical period of vulnerability. One group of pregnant rats received CPF (subcutaneous injections in dimethyl sulfoxide vehicle) on gestational days (GD) 17-20, a peak period of neurogenesis; a second group was treated on GD9-12, the period of neural tube formation. In the GD17-20 group, the threshold for a reduction in maternal weight gain was 5 mg/kg/day; at or below that dose, there was no evidence (GD21) of general fetotoxicity as assessed by the number of fetuses or fetal body and tissue weights. Above the threshold, there was brain sparing (reduced body weight with an increase in brain/body weight ratio) and a targeting of the liver (reduced liver/body weight). Indices of cell packing density (DNA per gram of tissue) and cell number (DNA content) similarly showed effects only on the liver; however, there were significant changes in the protein/DNA ratio, an index of cell size, in fetal brain regions at doses as low as 1 mg/kg, below the threshold for inhibition of fetal brain cholinesterase (2 mg/kg). Indices of cholinergic synaptic development showed significant CPF-induced defects but only at doses above the threshold for cholinesterase inhibition. With earlier CPF treatment (GD9-12), there was no evidence of general fetotoxicity or alterations of brain cell development at doses up to the threshold for maternal toxicity (5 mg/kg), assessed on GD17 and GD21; however, augmentation of cholinergic synaptic markers was detected at doses as low as 1 mg/kg. Compared with previous work on postnatal CPF exposure, the effects seen here required doses closer to the threshold for fetal weight loss; this implies a lower vulnerability in the fetal compared with the neonatal brain. Although delayed neurotoxic effects of prenatal

  4. Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts.

    PubMed

    van Thriel, Christoph; Westerink, Remco H S; Beste, Christian; Bale, Ambuja S; Lein, Pamela J; Leist, Marcel

    2012-08-01

    The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can result in neurobehavioural alterations, and these have been used as sensitive readouts to assess neurotoxicity in animals and man. Deconstructing neurobehaviour into relevant cellular and molecular components may allow for detection of specific neurotoxic effects in cell-based systems, which in turn may allow an easier examination of neurotoxic pathways and modes of actions and eventually inform the regulatory assessment of chemicals with potential developmental neurotoxicity. Here, current developments towards these goals are reviewed. Imaging genetics (CB) provides new insights into the neurobiological correlates of cognitive function that are being used to delineate neurotoxic mechanisms. The gaps between in vivo neurobehaviour and real-time in vitro measurements of neuronal function are being bridged by ex vivo measurements of synaptic plasticity (RW). An example of solvent neurotoxicity demonstrates how an in vivo neurological defect can be linked via the N-methyl-d-aspartate (NMDA)-glutamate receptor as a common target to in vitro readouts (AB). Axonal and dendritic morphology in vitro proved to be good correlates of neuronal connectivity and neurobehaviour in animals exposed to polychlorinated biphenyls and organophosphorus pesticides (PJL). Similarly, chemically induced changes in neuronal morphology affected the formation of neuronal networks on structured surfaces. Such network formation may become an important readout for developmental neurotoxicity in vitro (CvT), especially when combined with human neurons derived from embryonic stem cells (ML). We envision that future in vitro test systems for developmental neurotoxicity will combine the above approaches with exposure information, and we suggest a strategy for test system development and cell-based risk assessment. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts

    PubMed Central

    van Thriel, Christoph; Westerink, Remco; Beste, Christian; Bale, Ambuja S.; Lein, Pamela J.; Leist, Marcel

    2011-01-01

    The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can results in neurobehavioural alterations, and these have been be used as sensitive readouts to assess neurotoxicity in animals and man. Deconstructing neurobehaviour into relevant cellular and molecular components may allow for detection of specific neurotoxic effects in cell-based systems, which in turn may allow an easier examination of neurotoxic pathways and modes of actions and eventually inform the regulatory assessment of chemicals with potential developmental neurotoxicity. Here, current developments towards these goals are reviewed. Imaging genetics (CB) provides new insights into the neurobiological correlates of cognitive function that are being used to delineate neurotoxic mechanisms. The gaps between in vivo neurobehaviour and real-time in vitro measurements of neuronal function are being bridged by ex vivo measurements of synaptic plasticity (RW). An example of solvent neurotoxicity demonstrates how an in vivo neurological defect can be linked via the N-methyl-D-aspartate (NMDA)-glutamate receptor as a common target to in vitro readouts (AB). Axonal and dendritic morphology in vitro proved to be good correlates of neuronal connectivity and neurobehaviour in animals exposed to polychlorinated biphenyls and organophosphorus pesticides (PJL). Similarly, chemically-induced changes in neuronal morphology affected the formation of neuronal networks on structured surfaces. Such network formation may become an important readout for developmental neurotoxicity in vitro (CvT), especially when combined with human neurons derived from embryonic stem cells (ML). We envision that future in vitro test systems for developmental neurotoxicity will combine the above approaches with exposure information, and we suggest a strategy for test system development and cell-based risk assessment. PMID:22008243

  6. UNDERTAKING POSITIVE CONTROL STUDIES AS PART OF DEVELOPMENTAL NEUROTOXICITY TESTING: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

    EPA Science Inventory

    Developmental neurotoxicity testing involves functional and neurohistological assessments in offspring during and following maternal and/or neonatal exposure. Data from positive control studies are an integral component in developmental neurotoxicity risk assessments. Positive ...

  7. UNDERTAKING POSITIVE CONTROL STUDIES AS PART OF DEVELOPMENTAL NEUROTOXICITY TESTING: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

    EPA Science Inventory

    Developmental neurotoxicity testing involves functional and neurohistological assessments in offspring during and following maternal and/or neonatal exposure. Data from positive control studies are an integral component in developmental neurotoxicity risk assessments. Positive ...

  8. Developmental origins of adult diseases and neurotoxicity: epidemiological and experimental studies.

    PubMed

    Fox, Donald A; Grandjean, Philippe; de Groot, Didima; Paule, Merle G

    2012-08-01

    To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers at this symposium presented their research results on different neurotoxic chemicals relating to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to inorganic mercury and methylmercury, and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-dose human equivalent gestational lead exposure produces late-onset obesity only in male mice that is associated with neurodegeneration. Didima de Groot presented results on prenatal exposure of rats to methylazoxymethanol and discussed the results in light of the etiology of western Pacific amyotrophic lateral sclerosis and Parkinson-dementia complex. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following acute 24 h exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment. The results indicate that developmental neurotoxicity results in permanent changes, thus emphasizing the need to prevent such toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Developmental Origins of Adult Diseases and Neurotoxicity: Epidemiological and Experimental Studies

    PubMed Central

    Fox, Donald A.; Grandjean, Philippe; de Groot, Didima; Paule, Merle

    2013-01-01

    To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers in this symposium presented their research results on different neurotoxic chemicals as they relate to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to methylmercury and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-to-moderate dose human equivalent gestational lead exposure produced late-onset obesity, and motor and coordination dysfunction only in male mice. Didima de Groot discussed the role of caloric restriction and/or high fat diets during gestation and/or postnatal development in mediating the metabolic and neurotoxic effects of developmental methylmercury exposure in rats. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following 24 hour exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment. PMID:22245043

  10. Characterization of Human Neural Progenitor Cell Models for Developmental Neurotoxicity Screening

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating two different human neural progenitor cell (hNPC) models for their utility in screens for...

  11. Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation

    EPA Science Inventory

    1. Introduction The 3rd International Conference on Alternatives for Developmental Neurotoxicity Testing (DNT3), organized by the European Centre for the Validation of Alternative Methods (ECVAM), the Joint Research Centre of the European Commission, was held from May 10 -13, 20...

  12. MOTOR ACTIVITY IN DEVELOPMENTAL NEUROTOXICITY TESTING: A CROSS-LABORATORY COMPARISON OF CONTROL DATA.

    EPA Science Inventory

    The USEPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for a battery of functional and neuropathological assessments in offspring during and following maternal exposure. The battery includes measurement of motor activity on post-natal days (PND) ...

  13. LEARNING AND MEMORY TESTS IN DEVELOPMENTAL NEUROTOXICITY TESTING: A CROSS-LABORATORY COMPARISON OF CONTROL DATA.

    EPA Science Inventory

    The US EPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for functional tests to assess the impact of chemicals on cognitive function in offspring following maternal exposure. A test of associative learning and memory is to be conducted around th...

  14. Characterization of Human Neural Progenitor Cell Models for Developmental Neurotoxicity Screening

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating two different human neural progenitor cell (hNPC) models for their utility in screens for...

  15. Screening for Developmental Neurotoxicity in Zebrafish Larvae: Assessment of Behavior and Malformations.

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. As part of this approach, it is important to be able to separate overt toxicity (Le., malformed larvae) from the more specific neurotoxic...

  16. Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay

    EPA Science Inventory

    Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphor...

  17. Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay

    EPA Science Inventory

    Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphor...

  18. A MULTIFACETED, MEDIUM-THROUGHPUT APPROACH FOR DETECTING AND CHARACTERIZING DEVELOPMENTAL NEUROTOXICITY USING ZEBRAFISH.

    EPA Science Inventory

    To address the EPA's need to prioritize hundreds to thousands of chemicals for testing, we are developing a rapid, cost-effective in vivo screen for developmental neurotoxicity using zebrafish (Danio rerio), a small freshwater fish with external fertilization. Zebrafish embryos d...

  19. Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation

    EPA Science Inventory

    1. Introduction The 3rd International Conference on Alternatives for Developmental Neurotoxicity Testing (DNT3), organized by the European Centre for the Validation of Alternative Methods (ECVAM), the Joint Research Centre of the European Commission, was held from May 10 -13, 20...

  20. A MULTIFACETED, MEDIUM-THROUGHPUT APPROACH FOR DETECTING AND CHARACTERIZING DEVELOPMENTAL NEUROTOXICITY USING ZEBRAFISH.

    EPA Science Inventory

    To address the EPA's need to prioritize hundreds to thousands of chemicals for testing, we are developing a rapid, cost-effective in vivo screen for developmental neurotoxicity using zebrafish (Danio rerio), a small freshwater fish with external fertilization. Zebrafish embryos d...

  1. Screening for Developmental Neurotoxicity in Zebrafish Larvae: Assessment of Behavior and Malformations.

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. As part of this approach, it is important to be able to separate overt toxicity (Le., malformed larvae) from the more specific neurotoxic...

  2. LEARNING AND MEMORY TESTS IN DEVELOPMENTAL NEUROTOXICITY TESTING: A CROSS-LABORATORY COMPARISON OF CONTROL DATA.

    EPA Science Inventory

    The US EPA Developmental Neurotoxicity (DNT) Study Test Guideline (OPPTS 870.6300) calls for functional tests to assess the impact of chemicals on cognitive function in offspring following maternal exposure. A test of associative learning and memory is to be conducted around th...

  3. Recommendations for Developing Alternative Test Methods for Screening and Prioritization of Chemicals for Developmental Neurotoxicity

    EPA Science Inventory

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternative methods to current animal testing protocols and gUidelines. An immediate goal is to develop test methods that are capable of screening large numbers of chemic...

  4. Developmental fluoride neurotoxicity: a systematic review and meta-analysis.

    PubMed

    Choi, Anna L; Sun, Guifan; Zhang, Ying; Grandjean, Philippe

    2012-10-01

    Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children's neurodevelopment. We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development. We searched the MEDLINE, EMBASE, Water Resources Abstracts, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, because many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, end points of IQ scores, or related cognitive function measures with means and variances for the two exposure groups. Using random-effects models, we estimated the standardized mean difference between exposed and reference groups across all studies. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking-water fluoride as the only exposure. We performed the Cochran test for heterogeneity between studies, Begg's funnel plot, and Egger test to assess publication bias, and conducted meta-regressions to explore sources of variation in mean differences among the studies. The standardized weighted mean difference in IQ score between exposed and reference populations was -0.45 (95% confidence interval: -0.56, -0.35) using a random-effects model. Thus, children in high-fluoride areas had significantly lower IQ scores than those who lived in low-fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease. The results support the possibility of an adverse effect of high fluoride exposure on children's neurodevelopment. Future research should include detailed individual-level information on prenatal

  5. Developmental Fluoride Neurotoxicity: A Systematic Review and Meta-Analysis

    PubMed Central

    Sun, Guifan; Zhang, Ying; Grandjean, Philippe

    2012-01-01

    Background: Although fluoride may cause neurotoxicity in animal models and acute fluoride poisoning causes neurotoxicity in adults, very little is known of its effects on children’s neurodevelopment. Objective: We performed a systematic review and meta-analysis of published studies to investigate the effects of increased fluoride exposure and delayed neurobehavioral development. Methods: We searched the MEDLINE, EMBASE, Water Resources Abstracts, and TOXNET databases through 2011 for eligible studies. We also searched the China National Knowledge Infrastructure (CNKI) database, because many studies on fluoride neurotoxicity have been published in Chinese journals only. In total, we identified 27 eligible epidemiological studies with high and reference exposures, end points of IQ scores, or related cognitive function measures with means and variances for the two exposure groups. Using random-effects models, we estimated the standardized mean difference between exposed and reference groups across all studies. We conducted sensitivity analyses restricted to studies using the same outcome assessment and having drinking-water fluoride as the only exposure. We performed the Cochran test for heterogeneity between studies, Begg’s funnel plot, and Egger test to assess publication bias, and conducted meta-regressions to explore sources of variation in mean differences among the studies. Results: The standardized weighted mean difference in IQ score between exposed and reference populations was –0.45 (95% confidence interval: –0.56, –0.35) using a random-effects model. Thus, children in high-fluoride areas had significantly lower IQ scores than those who lived in low-fluoride areas. Subgroup and sensitivity analyses also indicated inverse associations, although the substantial heterogeneity did not appear to decrease. Conclusions: The results support the possibility of an adverse effect of high fluoride exposure on children’s neurodevelopment. Future research

  6. Elevation of protective autophagy as a potential way for preventing developmental neurotoxicity of general anesthetics.

    PubMed

    Li, Guohui; Yu, Buwei

    2014-02-01

    Numerous animal studies have demonstrated that commonly used general anesthetics could cause cognitive impairment in the developing brain. However, the underlying mechanism remains unclear. Recently it is reported that autophagy activation can ameliorate developmental neurotoxicity of ethanol, which is the same GABAA agonist and NMDA antagonist as general anesthetics. We thus intend to propose the possible role of autophagy in the developmental neurotoxicity of general anesthetics. Oxidative stress and neuronal apoptosis can activate autophagy, while autophagy conversely alleviates their levels in the neuron. Crosstalk among neuronal apoptosis, oxidative stress and autophagy resembles the Yin-Yang relationship in Chinese philosophy. Neuronal apoptosis and oxidative stress represent destroyable Yin, while autophagy symbols protective Yang. The destroyable Yin and protective Yang promote and counteract each other. We hypothesize that the destroyable Yin (neuronal apoptosis and oxidative stress injury) prevails over protective Yang (autophagy) when developing brain exposes to general anesthetics. Elevating protective Yang autophagy potentially reverses the neurotoxicity of general anesthetics. Once this hypothesis is proved, it will provide a new perspective to understand the developmental neurotoxicity of general anesthetics and a new way to prevent it.

  7. Interpreting epidemiologic studies of developmental neurotoxicity: conceptual and analytic issues.

    PubMed

    Bellinger, David C

    2009-01-01

    This paper discusses issues pertaining to the validity, precision, and interpretation of epidemiologic studies of neurotoxicity. With regard to validity, the critical issues pertain to the appropriate strategy for confounder adjustment, particularly when confounders are complex, multi-faceted constructs, and to the need for greater clarity and transparency in articulating the causal relationships implicit in the analytic approach applied. With regard to precision, the critical issue is a need to identify the contributors to the substantial variability observed in the effect estimates that describe dose-response and dose-effect relationships. In addition to methodological sources, such as imprecision in estimating dose at the critical organ site(s), true inter-individual differences in susceptibility to a neurotoxicant could also contribute to the variability. Variability might be reduced by taking full account of factors such as co-exposures or health co-morbidities, genetic polymorphisms, and the social ecology of exposure. With regard to interpretation, we need to do a better job as a field conveying to risk assessors and others the ecological significance of the types of performance deficits observed following neurotoxicant exposure, emphasizing the distinction between individual and population risk. A final issue discussed is the need to define standards for the conduct, analysis, and reporting of epidemiologic studies of neurotoxicity, similar to those developed for other fields.

  8. Selenium as a potential protective factor against mercury developmental neurotoxicity.

    PubMed

    Choi, Anna L; Budtz-Jørgensen, Esben; Jørgensen, Poul J; Steuerwald, Ulrike; Debes, Frodi; Weihe, Pál; Grandjean, Philippe

    2008-05-01

    Experimental studies suggest that selenium (Se) may decrease methylmercury (MeHg) toxicity under certain exposure regimens. In epidemiological studies, the exposure to MeHg occurs from fish and seafood, which are also a source of beneficial nutrients such as selenium. However, little is known about the potential protective effects of dietary Se against MeHg neurotoxicity in humans. The possible interaction was assessed in two birth cohorts in the Faroe Islands, consisting of singleton term births from 1986 to 1987 (N=1,022), and 1994 to 1995 (N=182), respectively. Dietary habits in this fishing population included frequent consumption of seafood, including whale meat high in mercury. Both Hg and Se were measured in cord whole blood. Neurodevelopmental outcomes were evaluated at age 7 years in both cohorts, and the smaller cohort also included neurological assessment on several prior occasions. Each outcome was modeled as a function of Hg and Se interactions (with adjustments for potential risk factors) by expressing the effects of log10(Hg) within the lowest 25%, the middle 50%, and the highest 25% of the Se distribution. Surplus Se was present in cord blood, the average being a 10-fold molar excess above MeHg. Regression analyses failed to show consistent effects of Se, or statistically significant interaction terms between Se and MeHg. Overall, no evidence was found that Se was an important protective factor against MeHg neurotoxicity. Prevention, therefore, needs to address MeHg exposures rather than Se intakes. Because of the benefits associated with fish intake during pregnancy, consumers should be advised to maintain a high fish and seafood intake that is low in Hg contamination. Additional research is needed to determine the identity of the nutrients responsible for the beneficial effects.

  9. Single-Neuron Axonal Pathfinding under Geometric Guidance: Low-Dose-Methylmercury Developmental Neurotoxicity Test

    PubMed Central

    Wei, Lina; Sweeney, Andrew J.; Sheng, Liyuan; Fang, Yu; Kindy, Mark S.; Xi, Tingfei; Gao, Bruce Z.

    2014-01-01

    Because the nervous system is most vulnerable to toxicants during development, there is a crucial need for a highly sensitive developmental-neurotoxicity-test model to detect potential toxicants at low doses. We developed a lab-on-chip wherein single-neuron axonal pathfinding under geometric guidance was created using soft lithography and laser cell-micropatterning techniques. After coating the surface with L1, an axon-specific member of the Ig family of cell adhesion molecules (CAMs), and optimizing microunit geometric parameters, we introduced low-dose methylmercury, a well-known, environmentally significant neurotoxicant, in the shared medium. Its developmental neurotoxicity was evaluated using a novel axonal pathfinding assay including axonal turning and branching rates at turning points in this model. Compared to the conventional neurite-outgrowth assay, this model's detection threshold for low-dose methylmercury was 10-fold more sensitive at comparable exposure durations. These preliminary results support study of developmental effects of known and potential neurotoxicants on axon pathfinding. This novel assay model would be useful to study neuronal disease mechanisms at the single-cell level. To our knowledge, the potential of methylmercury chloride to cause acute in vitro developmental neurotoxicity (DNT) at such a low dosage has not been reported. This is the first DNT test model with high reproducibility to use single-neuron axonal pathfinding under precise geometric guidance. PMID:25041816

  10. Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl.

    PubMed

    Lee, Iwa; Eriksson, Per; Fredriksson, Anders; Buratovic, Sonja; Viberg, Henrik

    2015-11-01

    In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8-12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.

  11. Developmental neurotoxicity and anticonvulsant drugs: a possible link.

    PubMed

    Verrotti, A; Scaparrotta, A; Cofini, M; Chiarelli, F; Tiboni, G M

    2014-09-01

    In utero exposure to antiepileptic drugs (AEDs) may affect neurodevelopment causing postnatal cognitive and behavioral alterations. Phenytoin and phenobarbital may lead to motor and learning dysfunctions in the pre-exposed children. These disorders may reflect the interference of these AEDs with the development of hippocampal and cerebellar neurons, as suggested by animal studies. Exposure to valproic acid may result in inhibition of neural stem cell proliferation and/or immature neuron migration in the cerebral cortex with consequent increased risk of neurodevelopmental impairment, such as autistic spectrum disorders. A central issue in the prevention of AED-mediated developmental effects is the identification of drugs that should be avoided in women of child-bearing potential and during pregnancy. The aim of this review is to explore the possible link between AEDs and neurodevelopmental dysfunctions both in human and in animal studies. The possible mechanisms underlying this association are also discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Developmental neurotoxicity of different pesticides in PC-12 cells in vitro.

    PubMed

    Christen, Verena; Rusconi, Manuel; Crettaz, Pierre; Fent, Karl

    2017-06-15

    The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many pesticides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used pesticides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, as well as quaternary ammonium compounds, the organic compound used in pesticides, piperonyl butoxide, as well as the insect repellent diethyltoluamide (DEET). We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose- dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, and dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, the pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonyl butoxide and DEET. Our study confirms potential developmental neurotoxicity of some pesticides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals

  13. A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles.

    PubMed

    Hoelting, Lisa; Scheinhardt, Benjamin; Bondarenko, Olesja; Schildknecht, Stefan; Kapitza, Marion; Tanavde, Vivek; Tan, Betty; Lee, Qian Yi; Mecking, Stefan; Leist, Marcel; Kadereit, Suzanne

    2013-04-01

    Nanoparticles (NPs) have been shown to accumulate in organs, cross the blood-brain barrier and placenta, and have the potential to elicit developmental neurotoxicity (DNT). Here, we developed a human embryonic stem cell (hESC)-derived 3-dimensional (3-D) in vitro model that allows for testing of potential developmental neurotoxicants. Early central nervous system PAX6(+) precursor cells were generated from hESCs and differentiated further within 3-D structures. The 3-D model was characterized for neural marker expression revealing robust differentiation toward neuronal precursor cells, and gene expression profiling suggested a predominantly forebrain-like development. Altered neural gene expression due to exposure to non-cytotoxic concentrations of the known developmental neurotoxicant, methylmercury, indicated that the 3-D model could detect DNT. To test for specific toxicity of NPs, chemically inert polyethylene NPs (PE-NPs) were chosen. They penetrated deep into the 3-D structures and impacted gene expression at non-cytotoxic concentrations. NOTCH pathway genes such as HES5 and NOTCH1 were reduced in expression, as well as downstream neuronal precursor genes such as NEUROD1 and ASCL1. FOXG1, a patterning marker, was also reduced. As loss of function of these genes results in severe nervous system impairments in mice, our data suggest that the 3-D hESC-derived model could be used to test for Nano-DNT.

  14. Evaluation of developmental neurotoxicity of organotins via drinking water in rats: dimethyl tin.

    PubMed

    Ehman, K D; Phillips, P M; McDaniel, K L; Barone, S; Moser, V C

    2007-01-01

    Dimethyltin (DMT) is one of several organotins that are detected in domestic water supplies due to their use as plastic stabilizers for polyvinyl chloride (PVC) and chlorinated PVC (CPVC) products. A limited number of in vitro and in vivo studies suggest that DMT may produce developmental neurotoxicity; therefore, we initiated studies to evaluate long-term neurobehavioral changes in offspring following perinatal exposure. In the first study, female Sprague-Dawley rats were exposed via drinking water to DMT (0, 3, 15, 74 ppm) before mating and throughout gestation and lactation. Male offspring were tested for changes in: 1) preweaning learning in an associative runway task, 2) motor activity ontogeny, 3) spatial learning and retention in the Morris water maze as adults, 4) brain weight, 5) biochemical evidence of apoptosis, and 6) neuropathology. DMT toxicity was expressed as depressed maternal weight gain (74 ppm), and in the offspring, decreased brain weight (3, 74 ppm), decreased apoptosis (all concentrations), mild vacuolation in adult offspring (all concentrations), and slower learning in the water maze (15 ppm) due to altered spatial search patterns. In a second study, DMT exposure (same concentrations) occurred from gestational day 6 to weaning. Male and female offspring were tested. The high concentration again depressed maternal weight gain, decreased offspring birth weight and preweaning growth, and decreased brain weight. Increased and decreased apoptotic markers were measured, depending on age. Learning deficits were observed in the runway at postnatal day 11 (15, 74 ppm) and again in the adult offspring in the water maze (15 ppm). The results of both studies demonstrate a reproducible effect of 15 ppm perinatal DMT exposure on spatial learning. Changes in expression of apoptosis, brain weight, and the occurrence of neuropathological lesions also indicate potential neurotoxicity of DMT. These results were in contrast to earlier findings with monomethyl

  15. Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism.

    PubMed

    Costa, Lucio G; Chang, Yu-Chi; Cole, Toby B

    2017-06-01

    Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted.

  16. Ameliorating the Developmental Neurotoxicity of Chlorpyrifos: A Mechanisms-Based Approach in PC12 Cells

    PubMed Central

    Slotkin, Theodore A.; MacKillop, Emiko A.; Ryde, Ian T.; Seidler, Frederic J.

    2007-01-01

    Background Organophosphate developmental neurotoxicity involves multiple mechanisms converging on neural cell replication and differentiation. Objectives We evaluated mechanisms contributing to the adverse effects of chlorpyrifos (CPF) on DNA synthesis, cell number and size, and cell signaling mediated by adenylyl cyclase (AC) in PC12 cells, a neuronotypic cell line that recapitulates the essential features of developing mammalian neurons. Results In undifferentiated cells, cholinergic receptor antagonists had little or no protective effect against the antimitotic actions of CPF; however, when nerve growth factor was used to evoke differentiation, the antagonists showed partial protection against deficits in cell loss and alteration in cell size elicited by CPF, but were ineffective in preventing the deterioration of AC signaling. Nicotine, which stimulates nicotinic acetylcholine receptors but also possesses a mixture of prooxidant/antioxidant activity, had adverse effects by itself but also protected undifferentiated cells from the actions of CPF and had mixed additive/protective effects on cell number in differentiating cells. The antioxidant vitamin E also protected both undifferentiated and differentiating cells from many of the adverse effects of CPF but worsened the impact on AC signaling. Theophylline, which prevents the breakdown of cyclic AMP, was the only agent that restored AC signaling to normal or supranormal levels but did so at further cost to cell replication. Conclusions Our results show definitive contributions of cholinergic hyperstimulation, oxidative stress, and interference with AC signaling in the developmental neurotoxicity of CPF and point to the potential use of this information to design treatments to ameliorate these adverse effects. PMID:17805420

  17. Developmental neurotoxicity of organophosphate flame retardants in early life stages of Japanese medaka (Oryzias latipes).

    PubMed

    Sun, Liwei; Tan, Hana; Peng, Tao; Wang, Sisi; Xu, Wenbin; Qian, Haifeng; Jin, Yuanxiang; Fu, Zhengwei

    2016-12-01

    Because brominated flame retardants are being banned or phased out worldwide, organophosphate flame retardants have been used as alternatives on a large scale and have thus become ubiquitous environmental contaminants; this raises great concerns about their environmental health risk and toxicity. Considering that previous research has identified the nervous system as a sensitive target, Japanese medaka were used as an aquatic organism model to evaluate the developmental neurotoxicity of 4 organophosphate flame retardants: triphenyl phosphate, tri-n-butyl phosphate, tris(2-butoxyethyl) phosphate, and tris(2-chloroethyl) phosphate (TCEP). The embryo toxicity test showed that organophosphate flame retardant exposure could decrease hatchability, delay time to hatching, increase the occurrence of malformations, reduce body length, and slow heart rate. Regarding locomotor behavior, exposure to the tested organophosphate flame retardants (except TCEP) for 96 h resulted in hypoactivity for medaka larvae in both the free-swimming and the dark-to-light photoperiod stimulation test. Changes of acetylcholinesterase activity and transcriptional responses of genes related to the nervous system likely provide a reasonable explanation for the neurobehavioral disruption. Overall, the present study clearly demonstrates the developmental neurotoxicity of various organophosphate flame retardants with very different potency and contribute to the determination of which organophosphate flame retardants are appropriate substitutes, as well as the consideration of whether regulations are reasonable and required. Environ Toxicol Chem 2016;35:2931-2940. © 2016 SETAC. © 2016 SETAC.

  18. Developmental Neurotoxicity of Methamidophos in the Embryo-Larval Stages of Zebrafish

    PubMed Central

    He, Xiaowei; Gao, Jiawei; Dong, Tianyu; Chen, Minjian; Zhou, Kun; Chang, Chunxin; Luo, Jia; Wang, Chao; Wang, Shoulin; Chen, Daozhen; Zhou, Zuomin; Tian, Ying; Xia, Yankai; Wang, Xinru

    2016-01-01

    Methamidophos is a representative organophosphate insecticide. The knowledge of its developmental neurotoxicity is limited, especially for zebrafish in the early stages of their life. Four hour post-fertilization (hpf) zebrafish embryos were exposed to several environmentally relevant concentrations of methamidophos (0, 25, and 500 μg/L) for up to 72 hpf. Locomotor behavior was then studied in the zebrafish larvae at this timepoint. Acridine orange (AO) staining was carried out in the zebrafish larvae, and the mRNA levels of genes associated with neural development (mbp and syn2a) were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The number of escape responders for mechanical stimulation was significantly decreased in exposed groups. AO staining showed noticeable signs of apoptosis mainly in the brain. In addition, the mRNA levels of mbp and syn2a were both significantly down-regulated in exposed groups. Our study provides the first evidence that methamidophos exposure can cause developmental neurotoxicity in the early stages of zebrafish life, which may be caused by the effect of methamidophos on neurodevelopmental genes and the activation of cell apoptosis in the brain. PMID:28036051

  19. Editor's Highlight: Congener-Specific Disposition of Chiral Polychlorinated Biphenyls in Lactating Mice and Their Offspring: Implications for PCB Developmental Neurotoxicity.

    PubMed

    Kania-Korwel, Izabela; Lukasiewicz, Tracy; Barnhart, Christopher D; Stamou, Marianna; Chung, Haeun; Kelly, Kevin M; Bandiera, Stelvio; Lein, Pamela J; Lehmler, Hans-Joachim

    2017-07-01

    Chiral polychlorinated biphenyl (PCB) congeners have been implicated by laboratory and epidemiological studies in PCB developmental neurotoxicity. These congeners are metabolized by cytochrome P450 (P450) enzymes to potentially neurotoxic hydroxylated metabolites (OH-PCBs). The present study explores the enantioselective disposition and toxicity of 2 environmentally relevant, neurotoxic PCB congeners and their OH-PCB metabolites in lactating mice and their offspring following dietary exposure of the dam. Female C57BL/6N mice (8-weeks old) were fed daily, beginning 2 weeks prior to conception and continuing throughout gestation and lactation, with 3.1 µmol/kg bw/d of racemic 2,2',3,5',6-pentachlorobiphenyl (PCB 95) or 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in peanut butter; controls received vehicle (peanut oil) in peanut butter. PCB 95 levels were higher than PCB 136 levels in both dams and pups, consistent with the more rapid metabolism of PCB 136 compared with PCB 95. In pups and dams, both congeners were enriched for the enantiomer eluting second on enantioselective gas chromatography columns. OH-PCB profiles in lactating mice and their offspring were complex and varied according to congener, tissue and age. Developmental exposure to PCB 95 versus PCB 136 differentially affected the expression of P450 enzymes as well as neural plasticity (arc and ppp1r9b) and thyroid hormone-responsive genes (nrgn and mbp). The results suggest that the enantioselective metabolism of PCBs to OH-PCBs may influence neurotoxic outcomes following developmental exposures, a hypothesis that warrants further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Anticonvulsant activity and acute neurotoxic profile of Achyranthes aspera Linn.

    PubMed

    Gawande, Dinesh Y; Druzhilovsky, Dmitry; Gupta, Raghbir Chand; Poroikov, Vladimir; Goel, Rajesh Kumar

    2017-04-18

    Root powder of Achyranthes aspera Linn. (A. aspera) belongs to family Amaranthaceae is used in Indian traditional medicine for the management of epilepsy and its efficacy is widely acclaimed among the different rural communities. The present study was aimed to establish the possible anticonvulsant effect of A. aspera methanolic root extract using acute anticonvulsant models and to evaluate the acute toxicity and neurotoxic potential A. aspera extract. A. aspera methanolic extract was standardized with respect to betaine using HPTLC. The maximal electroshock (MES), pentylenetetrazol (PTZ), picrotoxin and bicuculline induced seizure models were used to evaluate the anticonvulsant potential of standardized A. aspera root extract. The GABA content in cortex and hippocampus of extract treated mice was evaluated using HPLC. Moreover, the animals were also evaluated for acute toxicity study and neurotoxicity test. A significant enhancement in the seizure threshold was observed by A. aspera extract (5 and 10mg/kg) treated mice in PTZ, picrotoxin and bicuculline models as compared to saline treated mice respectively, whereas the extract failed to show protection in MES induced seizures. Moreover, A. aspera treatment (5 and 10mg/kg) significantly enhances the GABA levels in hippocampus and cortex as compared to saline treated group. A. aspera root extract was devoid of any sign of acute toxicity as well as neurotoxicity. A. aspera root extract exhibits significant anticonvulsant effect by facilitation of GABAergic neurotransmission in the brain. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  1. Assessment of learning, memory, and attention in developmental neurotoxicity regulatory studies: synthesis, commentary, and recommendations.

    PubMed

    Vorhees, Charles V; Makris, Susan L

    2015-01-01

    Cognitive tests of learning and memory (L&M) have been required by U.S. Environmental Protection Agency (EPA) developmental neurotoxicity test (DNT) guidelines for more than two decades. To evaluate the utility of these guidelines, the EPA reviewed 69 pesticide DNT studies. This review found that the DNT provided or could provide the point-of-departure for risk assessment by showing the Lowest Observable Adverse Effect Level (LOAEL) in 28 of these studies in relation to other reported end points. Among the behavioral tests, locomotor activity and auditory/acoustic startle provided the most LOAELs, and tests of cognitive function and the Functional Observational Battery (FOB) the fewest. Two issues arose from the review: (1) what is the relative utility of cognitive tests versus tests of unconditioned behavior, and (2) how might cognitive tests be improved? The EPA sponsored a symposium to address this. Bushnell reviewed studies in which both screening (locomotor activity, FOB, reflex ontogeny, etc.) and complex tests (those requiring training) were used within the same study; he found relatively little evidence that complex tests provided a LOAEL lower than screening tests (with exceptions). Levin reviewed reasons for including cognitive tests in regulatory studies and methods and evidence for the radial arm maze and its place in developmental neurotoxicity assessments. Driscoll and Strupp reviewed the value of serial reaction time operant methods for assessing executive function in developmental neurotoxicity studies. Vorhees and Williams reviewed the value of allocentric (spatial) and egocentric cognitive tests and presented methods for using the Morris water maze for spatial and the Cincinnati water maze for egocentric cognitive assessment. They also reviewed the possible use of water radial mazes. The relatively lower impact of cognitive tests in previous DNT studies in the face of the frequency of human complaints of chemical-induced cognitive dysfunction

  2. EVALUATION OF HUMAN NEURAL PROGENITOR CELLS FOR DEVELOPMENTAL NEUROTOXICITY SCREENING: TIME COURSE OF EFFECTS ON CELL PROLIFERATION AND VIABILITY.

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating human neural progenitor cells (NPCs) as a screen for DNT. ReNcell CX (ReN CX) cells are a...

  3. Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

    EPA Science Inventory

    Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

  4. Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

    EPA Science Inventory

    Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

  5. Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing

    EPA Science Inventory

    Developmental neurotoxicity (DNT) is a significant concern for environmental chemicals, as well as for food and drug constituents. The sensitivity of animal-based DNT models is unclear, and they are expensive and time consuming. Murine embryonic stem cells (mESC) recapitulate sev...

  6. Neural Progenitor Cells as Models for High-Throughput Screens of Developmental Neurotoxicity: State of the Science

    EPA Science Inventory

    In vitro, high-throughput approaches have been widely recommended as an approach to screen chemicals for the potential to cause developmental neurotoxicity and prioritize them for additional testing. The choice of cellular models for such an approach will have important ramificat...

  7. Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing

    EPA Science Inventory

    Developmental neurotoxicity (DNT) is a significant concern for environmental chemicals, as well as for food and drug constituents. The sensitivity of animal-based DNT models is unclear, and they are expensive and time consuming. Murine embryonic stem cells (mESC) recapitulate sev...

  8. EVALUATION OF HUMAN NEURAL PROGENITOR CELLS FOR DEVELOPMENTAL NEUROTOXICITY SCREENING: TIME COURSE OF EFFECTS ON CELL PROLIFERATION AND VIABILITY.

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating human neural progenitor cells (NPCs) as a screen for DNT. ReNcell CX (ReN CX) cells are a...

  9. Neural Progenitor Cells as Models for High-Throughput Screens of Developmental Neurotoxicity: State of the Science

    EPA Science Inventory

    In vitro, high-throughput approaches have been widely recommended as an approach to screen chemicals for the potential to cause developmental neurotoxicity and prioritize them for additional testing. The choice of cellular models for such an approach will have important ramificat...

  10. Developmental neurotoxicity: methylmercury and prenatal exposure protection in the context of the Minamata Convention.

    PubMed

    Boischio, Ana

    2015-09-01

    Mercury is a global pollutant of public environmental health concern due to its long-range atmospheric distribution, environmental distribution, and neurotoxic effects. Following biological methylation, methylmercury (MeHg) can be un-evenly bioaccumulated within aquatic food chains. Fish consumption can be a significant route of human exposure to MeHg. MeHg exposure in the prenatal stage, at relatively low levels, has recently been established as harmful during neurological development, potentially leading to intellectual disability. The Minamata Convention on Mercury is a global agreement, currently under ratification, to protect human health and the environment from anthropogenic emissions and releases of mercury and mercury compounds. The resolution regarding the role of the World Health Organization and ministries of health in the implementation of the Convention includes protection of human health from critical exposures to MeHg. Riverside populations living in areas with artisanal small-scale gold mining, and relying heavily on fish consumption, have been identified as the most vulnerable population in terms of MeHg exposure and developmental neurotoxicity. This article focuses on the proper design and dissemination of fish advisories within the context of implementation of the Convention.

  11. Human Neurospheres as Three-Dimensional Cellular Systems for Developmental Neurotoxicity Testing

    PubMed Central

    Moors, Michaela; Rockel, Thomas Dino; Abel, Josef; Cline, Jason E.; Gassmann, Kathrin; Schreiber, Timm; Schuwald, Janette; Weinmann, Nicole; Fritsche, Ellen

    2009-01-01

    Background Developmental neurotoxicity (DNT) of environmental chemicals is a serious threat to human health. Current DNT testing guidelines propose investigations in rodents, which require large numbers of animals. With regard to the “3 Rs” (reduction, replacement, and refinement) of animal testing and the European regulation of chemicals [Registration, Evaluation, and Authorisation of Chemicals (REACH)], alternative testing strategies are needed in order to refine and reduce animal experiments and allow faster and less expensive screening. Objectives The goal of this study was to establish a three-dimensional test system for DNT screening based on human fetal brain cells. Methods We established assays suitable for detecting disturbances in basic processes of brain development by employing human neural progenitor cells (hNPCs), which grow as neurospheres. Furthermore, we assessed effects of mercury and oxidative stress on these cells. Results We found that human neurospheres imitate proliferation, differentiation, and migration in vitro. Exposure to the proapoptotic agent staurosporine further suggests that human neurospheres possess functioning apoptosis machinery. The developmental neurotoxicants methylmercury chloride and mercury chloride decreased migration distance and number of neuronal-like cells in differentiated hNPCs. Furthermore, hNPCs undergo caspase-independent apoptosis when exposed toward high amounts of oxidative stress. Conclusions Human neurospheres are likely to imitate basic processes of brain development, and these processes can be modulated by developmental neurotoxicants. Thus, this three-dimensional cell system is a promising approach for DNT testing. PMID:19654924

  12. Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals.

    PubMed

    Crofton, Kevin M; Mundy, William R; Lein, Pamela J; Bal-Price, Anna; Coecke, Sandra; Seiler, Andrea E M; Knaut, Holger; Buzanska, Leonora; Goldberg, Alan

    2011-01-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternative methods to current animal testing protocols and guidelines. An immediate goal is to develop test methods that are capable of screening large numbers of chemicals. This document provides recommendations for developing alternative DNT approaches that will generate the type of data required for evaluating and comparing predictive capacity and efficiency across test methods and laboratories. These recommendations were originally drafted to stimulate and focus discussions of alternative testing methods and models for DNT at the TestSmart DNT II meeting (http://caat.jhsph.edu/programs/workshops/dnt2.html) and this document reflects critical feedback from all stakeholders that participated in this meeting. The intent of this document is to serve as a catalyst for engaging the research community in the development of DNT alternatives and it is expected that these recommendations will continue to evolve with the science.

  13. A qualitative retrospective analysis of positive control data in developmental neurotoxicity studies.

    PubMed

    Crofton, K M; Makris, S L; Sette, W F; Mendez, E; Raffaele, K C

    2004-01-01

    Testing for neurodevelopmental effects commonly involves both functional and neuropathological assessments in offspring during and following maternal exposure. The use of positive controls in neurotoxicity screening has been advocated by numerous expert groups. Evaluation of positive control data allows evaluation of laboratory proficiency in detecting changes in the structure and function of the developing nervous system and comparison of the sensitivity of assessments in different studies and laboratories. This project surveyed approaches taken in contract and industrial laboratories in generating and providing these data. Positive control data submitted in support of 34 developmental neurotoxicity (DNT) studies from 16 different laboratories were summarized by test method for information on the following: age relevance of test subjects, the presence of a dose-response relationship, gender, group size, statistics, report quality, quality assurance, and the year the study was conducted. Endpoints included the following: developmental landmarks, clinical observations (CO), motor activity, startle response, learning and memory, qualitative neuropathology, and quantitative brain morphometry (linear measurements of selected brain regions). Results ranged from no positive control data for three laboratories, to one laboratory that submitted 17 separate positive control reports. The qualitative range was similarly broad, from excellent to poor. Various problems were identified, including the following: inappropriate report structure (e.g., copies of poster presentations), lack of individual data, inadequate methodological details, submission of very old data (>10 years) or data from completely different laboratories, use of inappropriate positive control chemicals or doses that were without effect, lack of statistical analysis, use of only one sex, and use of incompatibly aged animals. Analyses revealed that there were only 3 out of 16 laboratories that had submitted

  14. MicroRNA and messenger RNA profiling reveals new biomarkers and mechanisms for RDX induced neurotoxicity.

    PubMed

    Deng, Youping; Ai, Junmei; Guan, Xin; Wang, Zhaohui; Yan, Bin; Zhang, Daqin; Liu, Chang; Wilbanks, Mitch S; Escalon, Barbara Lynn; Meyers, Sharon A; Yang, Mary Qu; Perkins, Edward J

    2014-01-01

    RDX is a well-known pollutant to induce neurotoxicity. MicroRNAs (miRNA) and messenger RNA (mRNA) profiles are useful tools for toxicogenomics studies. It is worthy to integrate MiRNA and mRNA expression data to understand RDX-induced neurotoxicity. Rats were treated with or without RDX for 48 h. Both miRNA and mRNA profiles were conducted using brain tissues. Nine miRNAs were significantly regulated by RDX. Of these, 6 and 3 miRNAs were up- and down-regulated respectively. The putative target genes of RDX-regulated miRNAs were highly nervous system function genes and pathways enriched. Fifteen differentially genes altered by RDX from mRNA profiles were the putative targets of regulated miRNAs. The induction of miR-71, miR-27ab, miR-98, and miR-135a expression by RDX, could reduce the expression of the genes POLE4, C5ORF13, SULF1 and ROCK2, and eventually induce neurotoxicity. Over-expression of miR-27ab, or reduction of the expression of unknown miRNAs by RDX, could up-regulate HMGCR expression and contribute to neurotoxicity. RDX regulated immune and inflammation response miRNAs and genes could contribute to RDX- induced neurotoxicity and other toxicities as well as animal defending reaction response to RDX exposure. Our results demonstrate that integrating miRNA and mRNA profiles is valuable to indentify novel biomarkers and molecular mechanisms for RDX-induced neurological disorder and neurotoxicity.

  15. MicroRNA and messenger RNA profiling reveals new biomarkers and mechanisms for RDX induced neurotoxicity

    PubMed Central

    2014-01-01

    Background RDX is a well-known pollutant to induce neurotoxicity. MicroRNAs (miRNA) and messenger RNA (mRNA) profiles are useful tools for toxicogenomics studies. It is worthy to integrate MiRNA and mRNA expression data to understand RDX-induced neurotoxicity. Results Rats were treated with or without RDX for 48 h. Both miRNA and mRNA profiles were conducted using brain tissues. Nine miRNAs were significantly regulated by RDX. Of these, 6 and 3 miRNAs were up- and down-regulated respectively. The putative target genes of RDX-regulated miRNAs were highly nervous system function genes and pathways enriched. Fifteen differentially genes altered by RDX from mRNA profiles were the putative targets of regulated miRNAs. The induction of miR-71, miR-27ab, miR-98, and miR-135a expression by RDX, could reduce the expression of the genes POLE4, C5ORF13, SULF1 and ROCK2, and eventually induce neurotoxicity. Over-expression of miR-27ab, or reduction of the expression of unknown miRNAs by RDX, could up-regulate HMGCR expression and contribute to neurotoxicity. RDX regulated immune and inflammation response miRNAs and genes could contribute to RDX- induced neurotoxicity and other toxicities as well as animal defending reaction response to RDX exposure. Conclusions Our results demonstrate that integrating miRNA and mRNA profiles is valuable to indentify novel biomarkers and molecular mechanisms for RDX-induced neurological disorder and neurotoxicity. PMID:25559034

  16. An overview of butanol-induced developmental neurotoxicity and the potential mechanisms related to these observed effects.

    PubMed

    Bale, Ambuja S; Lee, Janice S

    2016-01-01

    The purpose of this article is to briefly review the published literature on the developmental neurotoxic effects, including potential mechanisms, of four butanols: n-butanol, sec-butanol, tert-butanol, isobutanol, and identify data gaps and research needs for evaluation of human health risks in this area. Exposure potential to these four butanols is considerable given the high production volume (>1 billion lb) of n- and tert-butanol and moderate production volumes (100-500 million lb) of sec- and isobutanol. With the impetus to derive cleaner gasoline blends, butanols are being considered for use as fuel oxygenates. Notable signs of neurotoxicity and developmental neurotoxicity have been observed in some studies where laboratory animals (rodents) were gestationally exposed to n- or tert-butanol. Mechanistic data relevant to the observed developmental neurotoxicity endpoints were also reviewed to hypothesize potential mechanisms associated with the developmental neurotoxicity outcome. Data from the related and highly characterized alcohol, ethanol, were included to examine consistencies between this compound and the four butanols. It is widely known that alcohols, including butanols, interact with several ion channels and modulate the function of these targets following both acute and chronic exposures. In addition, n- and sec-butanol have been demonstrated to inhibit fetal rat brain astroglial cell proliferation. Further, rat pups exposed to n-butanol in utero were also reported to have significant increases in brain levels of dopamine and serotonin, but decreases in serotonin levels were noted with gestational exposure to tert-butanol. tert-Butanol was reported to inhibit muscarinic receptor-stimulated phosphoinositide metabolism which has been hypothesized to be a possible target for the neurotoxic effects of ethanol during brain development. The mechanistic data for the butanols support developmental neurotoxicity that has been observed in some of the rodent

  17. Global methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a systematic review

    PubMed Central

    Burke, Thomas A; Navas-Acien, Ana; Breysse, Patrick N; McGready, John; Fox, Mary A

    2014-01-01

    Abstract Objective To examine biomarkers of methylmercury (MeHg) intake in women and infants from seafood-consuming populations globally and characterize the comparative risk of fetal developmental neurotoxicity. Methods A search was conducted of the published literature reporting total mercury (Hg) in hair and blood in women and infants. These biomarkers are validated proxy measures of MeHg, a neurotoxin found primarily in seafood. Average and high-end biomarkers were extracted, stratified by seafood consumption context, and pooled by category. Medians for average and high-end pooled distributions were compared with the reference level established by a joint expert committee of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). Findings Selection criteria were met by 164 studies of women and infants from 43 countries. Pooled average biomarkers suggest an intake of MeHg several times over the FAO/WHO reference in fish-consuming riparians living near small-scale gold mining and well over the reference in consumers of marine mammals in Arctic regions. In coastal regions of south-eastern Asia, the western Pacific and the Mediterranean, average biomarkers approach the reference. Although the two former groups have a higher risk of neurotoxicity than the latter, coastal regions are home to the largest number at risk. High-end biomarkers across all categories indicate MeHg intake is in excess of the reference value. Conclusion There is a need for policies to reduce Hg exposure among women and infants and for surveillance in high-risk populations, the majority of which live in low-and middle-income countries. PMID:24700993

  18. Global methylmercury exposure from seafood consumption and risk of developmental neurotoxicity: a systematic review.

    PubMed

    Sheehan, Mary C; Burke, Thomas A; Navas-Acien, Ana; Breysse, Patrick N; McGready, John; Fox, Mary A

    2014-04-01

    To examine biomarkers of methylmercury (MeHg) intake in women and infants from seafood-consuming populations globally and characterize the comparative risk of fetal developmental neurotoxicity. A search was conducted of the published literature reporting total mercury (Hg) in hair and blood in women and infants. These biomarkers are validated proxy measures of MeHg, a neurotoxin found primarily in seafood. Average and high-end biomarkers were extracted, stratified by seafood consumption context, and pooled by category. Medians for average and high-end pooled distributions were compared with the reference level established by a joint expert committee of the Food and Agriculture Organization (FAO) and the World Health Organization (WHO). Selection criteria were met by 164 studies of women and infants from 43 countries. Pooled average biomarkers suggest an intake of MeHg several times over the FAO/WHO reference in fish-consuming riparians living near small-scale gold mining and well over the reference in consumers of marine mammals in Arctic regions. In coastal regions of south-eastern Asia, the western Pacific and the Mediterranean, average biomarkers approach the reference. Although the two former groups have a higher risk of neurotoxicity than the latter, coastal regions are home to the largest number at risk. High-end biomarkers across all categories indicate MeHg intake is in excess of the reference value. There is a need for policies to reduce Hg exposure among women and infants and for surveillance in high-risk populations, the majority of which live in low-and middle-income countries.

  19. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

    PubMed Central

    Dorman, D C; Allen, S L; Byczkowski, J Z; Claudio, L; Fisher, J E; Fisher, J W; Harry, G J; Li, A A; Makris, S L; Padilla, S; Sultatos, L G; Mileson, B E

    2001-01-01

    We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic. PMID:11250810

  20. Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling.

    PubMed

    Wang, Wen-Yuan; Jia, Li-Jie; Luo, Yan; Zhang, Hong-Hai; Cai, Fang; Mao, Hui; Xu, Wei-Cai; Fang, Jun-Biao; Peng, Zhi-You; Ma, Zheng-Wen; Chen, Yan-Hong; Zhang, Juan; Wei, Zhen; Yu, Bu-Wei; Hu, Shuang-Fei

    2016-01-01

    It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors

  1. IDENTIFICATION AND INTERPRETATION OF DEVELOPMENTAL NEUROTOXICITY EFFECTS: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

    EPA Science Inventory

    The reliable detection, measurement, and interpretation of treatment-related developmental neurotoxicity (DNT) effects depend on appropriate study design and execution, using scientifically established methodologies, with appropriate controls to minimize confounding factors. App...

  2. IDENTIFICATION AND INTERPRETATION OF DEVELOPMENTAL NEUROTOXICITY EFFECTS: A REPORT FROM THE ILSI RESEARCH FOUNDATION/RISK SCIENCE INSTITUTE EXPERT WORKING GROUP ON NEURODEVELOPMENTAL ENDPOINTS

    EPA Science Inventory

    The reliable detection, measurement, and interpretation of treatment-related developmental neurotoxicity (DNT) effects depend on appropriate study design and execution, using scientifically established methodologies, with appropriate controls to minimize confounding factors. App...

  3. Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway

    SciTech Connect

    Wang, Yi; Wei, Wei; Wang, Yuan; Dong, Jing; Song, Binbin; Min, Hui; Teng, Weiping; Chen, Jie

    2013-09-01

    Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway – a pathway closely associated with synaptic plasticity and learning and memory – was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and

  4. Developmental neurotoxicity evaluation of the avermectin pesticide, emamectin benzoate, in Sprague-Dawley rats.

    PubMed

    Wise, L D; Allen, H L; Hoe, C M; Verbeke, D R; Gerson, R J

    1997-01-01

    The potential of emamectin benzoate (EB) to cause developmental neurotoxicity in Sprague-Dawley rats was assessed using a study design by the US EPA. Dosages of 0 (deionized water), 0.1, 0.6, or 3.6 mg/kg/day were administered at 5 ml/kg by oral gavage from gestational day (GD) 6 to lactational day (LD) 20 to groups of 25 mated females each. Between GD 17 and 20 the high dose was reduced to 2.5 mg/kg/day because of pup tremors observed at this dose level in a concurrent two-generation study. Females were allowed to deliver and the young were evaluated for survival, growth, development, behavior, and histological changes to brain, spinal cord, peripheral nerve, and skeletal muscle. Behavioral assessment of the offspring consisted of open field motor activity, auditory startle habituation, and passive avoidance tests; each was conducted on weanling and adult animals (one animal/sex/litter). Histopathological examination of the CNS and PNS was conducted on one animal/sex/litter on postnatal days (PND) 11 and 60. There were significant increases in average F0 maternal body weight gains during gestation in the 0.6 and 3.6/2.5 mg/kg/day groups, but no other effects were observed in pregnant females of these or the low-dose groups during the study. Beginning on PND 6, tremors were observed in high-dose pups, and this was followed by hindlimb splay in all high-dose pups by PND 15-26. Both of these physical signs disappeared by PND 34 (i.e., 10-11 days after weaning). There were no compound-related deaths in F1 offspring. Beginning on PND 11, progressive decreases in preweaning average weights were observed in the high-dose group (to 42% below control in females on PND 21). Average weight gain during the postweaning period was significantly decreased in the 3.6/2.5 mg/kg/day group. There were EB-related effects in behavioral tests only in the high-dose group. A significant increase in PND 13 average horizontal motor activity was due to stereotypical movements. Average

  5. Recommended Methods for Brain Processing and Quantitative Analysis in Rodent Developmental Neurotoxicity Studies.

    PubMed

    Garman, Robert H; Li, Abby A; Kaufmann, Wolfgang; Auer, Roland N; Bolon, Brad

    2016-01-01

    Neuropathology methods in rodent developmental neurotoxicity (DNT) studies have evolved with experience and changing regulatory guidance. This article emphasizes principles and methods to promote more standardized DNT neuropathology evaluation, particularly procurement of highly homologous brain sections and collection of the most reproducible morphometric measurements. To minimize bias, brains from all animals at all dose levels should be processed from brain weighing through paraffin embedding at one time using a counterbalanced design. Morphometric measurements should be anchored by distinct neuroanatomic landmarks that can be identified reliably on the faced block or in unstained sections and which address the region-specific circuitry of the measured area. Common test article-related qualitative changes in the developing brain include abnormal cell numbers (yielding altered regional size), displaced cells (ectopia and heterotopia), and/or aberrant differentiation (indicated by defective myelination or synaptogenesis), but rarely glial or inflammatory reactions. Inclusion of digital images in the DNT pathology raw data provides confidence that the quantitative analysis was done on anatomically matched (i.e., highly homologous) sections. Interpreting DNT neuropathology data and their presumptive correlation with neurobehavioral data requires an integrative weight-of-evidence approach including consideration of maternal toxicity, body weight, brain weight, and the pattern of findings across brain regions, doses, sexes, and ages.

  6. Developmental neurotoxic effects of graphene oxide exposure in zebrafish larvae (Danio rerio).

    PubMed

    Soares, J C; Pereira, Tcb; Costa, K M; Maraschin, T; Basso, N R; Bogo, M R

    2017-09-01

    Although graphene oxide (GO), a nanomaterial with hexagonal planar layer, has been widely studied due to its applications in neurobiology that include drug delivery and tissue engineering, additional studies to assess its potential toxic effects are still needed. Thus, this study evaluated the effects of GO exposure (at 5, 10, 50 or 100mg/L) during six consecutive days on mortality, hatching, spontaneous movement, heart rate, morphology, locomotion behavior, acetylcholinesterase (AChE) activity, dopamine levels and relative gene expression of developmental neurology-related genes using zebrafish larvae. In the 5mg/L dose, synapsin IIa expression up-regulation was seen concomitantly with down-regulation of dat expression, showing a potential compensatory mechanism. Moreover, the 10mg/L exposure caused an increase in heart rate, in absolute turn angle, brain cell damage and a decrease in dopamine levels. These alterations may be associated with autophagosome formation found in GO-exposed larval brain. No changes were observed on higher doses of GO exposure, probably due to nanomaterial agglomeration. Taken together, these results show that toxic effects of GO exposure are not dose-dependent, and are preeminent in lower concentrations. Additional studies are needed to deepen the specific mechanisms of GO neurotoxicity and are required to elucidate its potential biomedical use. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae.

    PubMed

    Chen, Lianguo; Huang, Changjiang; Hu, Chenyan; Yu, Ke; Yang, Lihua; Zhou, Bingsheng

    2012-10-01

    The aim of the present study was to investigate the acute developmental neurotoxicity of polybrominated diphenyl ethers (PBDEs) in zebrafish larvae. From 2 to 120 h postfertilization zebrafish embryos were exposed to DE-71 (0, 31.0, 68.7, and 227.6 µg/L). The authors studied the locomotor behavior of larvae, involvement of the cholinergic system, and selected gene and protein expressions in the central nervous system. The results showed that low DE-71 concentration caused hyperactivity, whereas higher concentrations decreased activity during the dark period. During the light period, larval activity was significantly reduced in a concentration-dependent manner. In the cholinergic system, acetylcholinesterase activity significantly increased (10.7 and 12.4%) in the 68.7 and 227.6 µg/L exposure groups, respectively, and acetylcholine concentration accordingly decreased (60.5%) in the 227.6 µg/L exposure group. The mRNA expressions of genes encoding myelin basic protein, neuron microtubule protein (α1-tubulin), and sonic hedgehog a were significantly downregulated. Western blotting assay demonstrated that the protein concentration of α1-tubulin was also decreased. Overall, the present study demonstrated that acute exposure to PBDEs can disrupt the neurobehavior of zebrafish larvae and affect cholinergic neurotransmission and neuron development.

  8. Polybrominated Diphenyl Ethers Induce Developmental Neurotoxicity in a Human in Vitro Model: Evidence for Endocrine Disruption

    PubMed Central

    Schreiber, Timm; Gassmann, Kathrin; Götz, Christine; Hübenthal, Ulrike; Moors, Michaela; Krause, Guido; Merk, Hans F.; Nguyen, Ngoc-Ha; Scanlan, Thomas S.; Abel, Josef; Rose, Christine R.; Fritsche, Ellen

    2010-01-01

    Background Polybrominated diphenyl ethers (PBDEs) are persistent and bioaccumulative flame retardants, which are found in rising concentrations in human tissues. They are of concern for human health because animal studies have shown that they possess the potential to be developmentally neurotoxic. Objective Because there is little knowledge of the effects of PBDEs on human brain cells, we investigated their toxic potential for human neural development in vitro. Moreover, we studied the involvement of thyroid hormone (TH) disruption in the effects caused by PBDEs. Methods We used the two PBDE congeners BDE-47 and BDE-99 (0.1–10 μM), which are most prominent in human tissues. As a model of neural development, we employed primary fetal human neural progenitor cells (hNPCs), which are cultured as neurospheres and mimic basic processes of brain development in vitro: proliferation, migration, and differentiation. Results PBDEs do not disturb hNPC proliferation but decrease migration distance of hNPCs. Moreover, they cause a reduction of differentiation into neurons and oligodendrocytes. Simultaneous exposure with the TH receptor (THR) agonist triiodothyronine rescues these effects on migration and differentiation, whereas the THR antagonist NH-3 does not exert an additive effect. Conclusion PBDEs disturb development of hNPCs in vitro via endocrine disruption of cellular TH signaling at concentrations that might be of relevance for human exposure. PMID:20368126

  9. Continuing education course #3: current practices and future trends in neuropathology assessment for developmental neurotoxicity testing.

    PubMed

    Bolon, Brad; Garman, Robert H; Gundersen, Hans Jørgen G; Allan Johnson, G; Kaufmann, Wolfgang; Krinke, Georg; Little, Peter B; Makris, Susan L; Mellon, R Daniel; Sulik, Kathleen K; Jensen, Karl

    2011-01-01

    The continuing education course on Developmental Neurotoxicity Testing (DNT) was designed to communicate current practices for DNT neuropathology, describe promising innovations in quantitative analysis and noninvasive imaging, and facilitate a discussion among experienced neuropathologists and regulatory scientists regarding suitable DNT practices. Conventional DNT neuropathology endpoints are qualitative histopathology and morphometric endpoints of particularly vulnerable sites (e.g., cerebral, cerebellar, or hippocampal thickness). Novel imaging and stereology measurements hold promise for automated analysis of factors that cannot be effectively examined in routinely processed specimens (e.g., cell numbers, fiber tract integrity). The panel recommended that dedicated DNT neuropathology data sets be acquired on a minimum of 8 sections (for qualitative assessment) or 3 sections (for quantitative linear and stereological analyses) using a small battery of stains to examine neurons and myelin. Where guidelines permit discretion, immersion fixation is acceptable for younger animals (postnatal day 22 or earlier), and peripheral nerves may be embedded in paraffin. Frequent concerns regarding DNT data sets include false-negative outcomes due to processing difficulties (e.g., lack of concordance among sections from different animals) and insensitive analytical endpoints (e.g., qualitative evaluation) as well as false-positive results arising from overinterpretation or misreading by inexperienced pathologists.

  10. Developmental Neurotoxicity of Tobacco Smoke Directed Toward Cholinergic and Serotonergic Systems: More Than Just Nicotine.

    PubMed

    Slotkin, Theodore A; Skavicus, Samantha; Card, Jennifer; Stadler, Ashley; Levin, Edward D; Seidler, Frederic J

    2015-09-01

    Tobacco smoke contains thousands of compounds in addition to nicotine, a known neuroteratogen. We evaluated the developmental neurotoxicity of tobacco smoke extract (TSE) administered to pregnant rats starting preconception and continued through the second postnatal week. We simulated nicotine concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers, and compared TSE with an equivalent dose of nicotine alone, and to a 10-fold higher nicotine dose. We conducted longitudinal evaluations in multiple brain regions, starting in adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although both nicotine doses produced presynaptic cholinergic deficits, these were partially compensated by hyperinnervation and receptor upregulation, effects that were absent with TSE. TSE also produced deficits in serotonin receptors in females that were not seen with nicotine. Regression analysis showed a profound sex difference in the degree to which nicotine could account for overall TSE effects: whereas the 2 nicotine doses accounted for 36%-46% of TSE effects in males, it accounted for only 7%-13% in females. Our results show that the adverse effects of TSE on neurodevelopment exceed those that can be attributed to just the nicotine present in the mixture, and further, that the sensitivity extends down to levels commensurate with second-hand smoke exposure. Because nicotine itself evoked deficits at low exposures, "harm reduction" nicotine products do not eliminate the potential for neurodevelopmental damage.

  11. A Retrospective Performance Assessment of the Developmental Neurotoxicity Study in Support of OECD Test Guideline 426

    PubMed Central

    Makris, Susan L.; Raffaele, Kathleen; Allen, Sandra; Bowers, Wayne J.; Hass, Ulla; Alleva, Enrico; Calamandrei, Gemma; Sheets, Larry; Amcoff, Patric; Delrue, Nathalie; Crofton, Kevin M.

    2009-01-01

    Objective We conducted a review of the history and performance of developmental neurotoxicity (DNT) testing in support of the finalization and implementation of Organisation of Economic Co-operation and Development (OECD) DNT test guideline 426 (TG 426). Information sources and analysis In this review we summarize extensive scientific efforts that form the foundation for this testing paradigm, including basic neurotoxicology research, interlaboratory collaborative studies, expert workshops, and validation studies, and we address the relevance, applicability, and use of the DNT study in risk assessment. Conclusions The OECD DNT guideline represents the best available science for assessing the potential for DNT in human health risk assessment, and data generated with this protocol are relevant and reliable for the assessment of these end points. The test methods used have been subjected to an extensive history of international validation, peer review, and evaluation, which is contained in the public record. The reproducibility, reliability, and sensitivity of these methods have been demonstrated, using a wide variety of test substances, in accordance with OECD guidance on the validation and international acceptance of new or updated test methods for hazard characterization. Multiple independent, expert scientific peer reviews affirm these conclusions. PMID:19165382

  12. Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat.

    PubMed

    Gill, M W; Swanson, M S; Murphy, S R; Bailey, G P

    2000-01-01

    The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no

  13. Assessment of learning, memory and attention in developmental neurotoxicity regulatory studies: Introduction.

    PubMed

    Makris, Susan L; Vorhees, Charles V

    2015-01-01

    There are a variety of chemicals, including pharmaceuticals, that alter neurobehavior following developmental exposure and guidelines for the conduct of studies to detect such effects by statute in the United States and Europe. Guidelines for Developmental Neurotoxicity Testing (DNT) studies issued by the U.S. Environmental Protection Agency (EPA) under prevailing law and European Organization for Economic Cooperation and Development (OECD) recommendations to member countries provide that such studies include a series of neurobehavioral and neuropathological assessments. Among these are assessment of cognitive function, specifically learning and memory. After reviewing 69 DNT studies submitted to the EPA, tests of learning and memory were noted to have detected the lowest observed adverse effect level (LOAELs) less frequently than behavioral tests of locomotor activity and acoustic/auditory startle, but slightly more than for the developmental Functional Observational Battery (devFOB; which is less extensive than the full FOB), but the reasons for the lower LOAEL detection rate for learning and memory assessment could not be determined. A major concern identified in the review, however, was the adequacy of the methods employed in these studies rather than on the importance of learning and memory to the proper assessment of brain function. Accordingly, a symposium was conducted to consider how the guidelines for tests of learning and memory might be improved. Four laboratories with established histories investigating the effects of chemical exposures during development on learning, memory, and attention, were invited to review the topic and offer recommendations, both theoretical and practical, on approaches to improve the assessment of these vital CNS functions. Reviewers were asked to recommend methods that are grounded in functional importance to CNS integrity, well-validated, reliable, and amenable to the context of regulatory studies as well as to basic

  14. Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing.

    PubMed

    Kuegler, Philipp B; Zimmer, Bastian; Waldmann, Tanja; Baudis, Birte; Ilmjärv, Sten; Hescheler, Jürgen; Gaughwin, Phil; Brundin, Patrik; Mundy, William; Bal-Price, Anna K; Schrattenholz, André; Krause, Karl-Heinz; van Thriel, Christoph; Rao, Mahendra S; Kadereit, Suzanne; Leist, Marcel

    2010-01-01

    Developmental neurotoxicity (DNT) is a serious concern for environmental chemicals, as well as for food and drug constituents. Animal-based DNT models have relatively low sensitivity, and they are burdened by high work-load, cost and animal ethics. Murine embryonic stem cells (mESC) recapitulate several critical processes involved in the development of the nervous system if they are induced to differentiate into neural cells. They therefore represent an alternative toxicological model to predict human hazard. In this review, we discuss how mESC can be used for DNT assays. We have compiled a list of mRNA markers that define undifferentiated mESC (n = 42), neural stem cells (n = 73), astrocytes (n = 25) and the pattern of different neuronal and non-neuronal cell types generated (n = 57). We propose that transcriptional profiling can be used as a sensitive endpoint in toxicity assays to distinguish neural differentiation states during normal and disturbed development. Importantly, we believe that it can be scaled up to relatively high throughput whilst still providing rich information on disturbances affecting small cell subpopulations. Moreover, this approach can provide insight into underlying mechanisms and pathways of toxicity. We broadly discuss the methodological basis of marker lists and DNT assay design. The discussion is put in the context of a new generation of alternative assays (embryonic stem cell based DNT testing = ESDNT V2.0), that may later include human induced pluripotent stem cells, and that are not designed for 1:1 replacement of animal experiments, but are rather intended to improve human risk assessment by using independent scientific principles.

  15. Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity.

    PubMed

    Behl, Mamta; Hsieh, Jui-Hua; Shafer, Timothy J; Mundy, William R; Rice, Julie R; Boyd, Windy A; Freedman, Jonathan H; Hunter, E Sidney; Jarema, Kimberly A; Padilla, Stephanie; Tice, Raymond R

    2015-01-01

    Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPFRs). There is, however, limited information on the potential health effects of OPFRs. Due to the structural similarity of the OPFRs to organophosphorus insecticides, there is concern regarding developmental toxicity and neurotoxicity. In response, we evaluated a set of OPFRs (triphenyl phosphate [TPHP]), isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], (tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl)phosphate [TCEP]) in a battery of cell-based in vitro assays and alternative model organisms and compared the results to those obtained for two classical BFRs (3,3',5,5'-tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). The assays used evaluated the effects of chemicals on the differentiation of mouse embryonic stem cells, the proliferation and growth of human neural stem cells, rat neuronal growth and network activity, and development of nematode (Caenorhabditis elegans) and zebrafish (Danio rerio). All assays were performed in a concentration-response format, allowing for the determination of the point of departure (POD: the lowest concentration where a chemically-induced response exceeds background noise). The majority of OPFRs (8/9) were active in multiple assays in the range of 1-10 μM, most of which had comparable activity to the BFRs TBBPA and BDE-47. TCEP was negative in all assays. The results indicate that the replacement OPFRs, with the exception of TCEP, showed comparable activity to the two BFRs in the assays tested. Based on these results, more comprehensive studies are warranted to further characterize the potential hazard

  16. Developmental neurotoxicity of methanol exposure by inhalation in rats. Research report, June 1990-June 1994

    SciTech Connect

    Weiss, B.; Stern, S.; Soderholm, S.C.; Cox, C.; Sharma, A.

    1996-04-01

    The possibility of widespread methanol exposure via inhalation stemming from its adoption as an automotive fuel or fuel component arouses concern about the potential vulnerability of the fetal brain. This project was designed to help address such concerns by studying the behavior of neonate and adult Long-Evans hooded rats following perinatal exposure to methanol vapor at 4,500 ppm for six hours daily beginning on gestation day 6 with both dams and pups then being exposed through postnatal day (PND) 21. Blood methanol concentrations of the dams, measured immediately following a six-hour exposure, were approximately 500 to 800 micrograms/milliliter. Average blood methanol concentrations in the pups were about twice those of the dams. Neurotoxicity was assessed by behavioral tests used previously to reveal adverse effects following developmental exposures to ethanol, cocaine, heavy metals, and other agents. Exposure of neonates to methanol did not affect suckling latency and attachment on PND 5, or performance on the conditioned olfactory aversion test on PND 10. Exposure to methanol did alter performances in the motor activity tests. Methanol-exposed neonates were less active on PND 18, but more active on PND 25 than the equivalent control-group pups. Schedule-controlled running in adults displayed a complex interaction with treatment. Changes in performance over the course of training differed between males and females depending on exposure to methanol. The results of the complex stochastic reinforcement schedule revealed behavioral differences due to methanol exposure in adults that were relatively subtle in nature and appeared after a new pattern of contingencies was introduced.

  17. Workshop report on developmental neurotoxic effects associated with exposure to PCBs. Held in Research Triangle Park, North Carolina on September 14-15, 1992

    SciTech Connect

    Not Available

    1993-05-01

    The report summarizes the outcome of the PCB Developmental Neurotoxicity Workshop in relation to the stated goals of the workshop. The first goal was to address the question of whether currently available data are sufficient for risk assessment. Based on an evaluation of the strengths and weaknesses in the data and on the consistency of effects seen in all species tested, including humans, there is sufficient information to indicate that PCBs cause developmental neurotoxicity. The second goal of the workshop was to identify any additional information that might be used to support the developmental neurotoxicity data in risk assessment. The third goal of the workshop was to recommend research needed to address risk assessment issues. The overwhelming sense of the meeting was that there is a need for more research on the developmental effects of PCBs.

  18. Transformation of Developmental Neurotoxicity Data into a Structure-Searchable Relational Database

    EPA Science Inventory

    A database of neurotoxicants is critical to support the development and validation of animal alternatives for neurotoxicity. Validation of in vitro test methods can only be done using known animal and human neurotoxicants producing defined responses for neurochemical, neuropatho...

  19. Transformation of Developmental Neurotoxicity Data into a Structure-Searchable Relational Database

    EPA Science Inventory

    A database of neurotoxicants is critical to support the development and validation of animal alternatives for neurotoxicity. Validation of in vitro test methods can only be done using known animal and human neurotoxicants producing defined responses for neurochemical, neuropatho...

  20. The classification of motor neuron defects in the zebrafish embryo toxicity test (ZFET) as an animal alternative approach to assess developmental neurotoxicity.

    PubMed

    Muth-Köhne, Elke; Wichmann, Arne; Delov, Vera; Fenske, Martina

    2012-07-01

    Rodents are widely used to test the developmental neurotoxicity potential of chemical substances. The regulatory test procedures are elaborate and the requirement of numerous animals is ethically disputable. Therefore, non-animal alternatives are highly desirable, but appropriate test systems that meet regulatory demands are not yet available. Hence, we have developed a new developmental neurotoxicity assay based on specific whole-mount immunostainings of primary and secondary motor neurons (using the monoclonal antibodies znp1 and zn8) in zebrafish embryos. By classifying the motor neuron defects, we evaluated the severity of the neurotoxic damage to individual primary and secondary motor neurons caused by chemical exposure and determined the corresponding effect concentration values (EC₅₀). In a proof-of-principle study, we investigated the effects of three model compounds thiocyclam, cartap and disulfiram, which show some neurotoxicity-indicating effects in vertebrates, and the positive controls ethanol and nicotine and the negative controls 3,4-dichloroaniline (3,4-DCA) and triclosan. As a quantitative measure of the neurotoxic potential of the test compounds, we calculated the ratios of the EC₅₀ values for motor neuron defects and the cumulative malformations, as determined in a zebrafish embryo toxicity test (zFET). Based on this index, disulfiram was classified as the most potent and thiocyclam as the least potent developmental neurotoxin. The index also confirmed the control compounds as positive and negative neurotoxicants. Our findings demonstrate that this index can be used to reliably distinguish between neurotoxic and non-neurotoxic chemicals and provide a sound estimate for the neurodevelopmental hazard potential of a chemical. The demonstrated method can be a feasible approach to reduce the number of animals used in developmental neurotoxicity evaluation procedures.

  1. Assessment of attention and inhibitory control in rodent developmental neurotoxicity studies.

    PubMed

    Driscoll, Lori L; Strupp, Barbara J

    2015-01-01

    In designing screens to assess potential neurotoxicants, the paramount goal is that the selected assessment tools detect dysfunction if it exists. This goal is particularly challenging in the case of cognitive assessments. Cognition is not a unitary phenomenon, and indeed there is growing evidence that different aspects of cognitive functioning are subserved by distinct neural systems. As a result, if a particular neurotoxicant selectively damages certain neural systems but not others, it can impair some cognitive, sensory, or affective functions, but leave many others intact. Accordingly, studies with human subjects use batteries of cognitive tests, cognizant of the fact that no one test is capable of detecting all forms of cognitive dysfunction. In contrast, assessment of cognitive functioning in non-human animal developmental neurotoxicity (DNT) studies typically consists of a single, presumably representative, "learning and memory" task that is expected to detect all potential effects on cognitive functioning. Streamlining the cognitive assessment in these studies saves time and money, but these shortcuts can have serious consequences if the aspect of cognitive functioning that is impaired is not tapped by the single selected task. In particular, executive functioning - a constellation of cognitive functions which enables the organism to focus on multiple streams of information simultaneously, and revise plans as necessary - is poorly assessed in most animal DNT studies. The failure to adequately assess these functions - which include attention, working memory, inhibitory control, and planning - is particularly worrisome in light of evidence that the neural systems that subserve these functions may be uniquely vulnerable to early developmental insults. We illustrate the importance of tapping these areas of functioning in DNT studies by describing the pattern of effects produced by early developmental Pb exposure. Rats exposed to lead (Pb) early in development

  2. Distinct developmental profiles in typical speech acquisition

    PubMed Central

    Campbell, Thomas F.; Shriberg, Lawrence D.; Green, Jordan R.; Abdi, Hervé; Rusiewicz, Heather Leavy; Venkatesh, Lakshmi; Moore, Christopher A.

    2012-01-01

    Three- to five-year-old children produce speech that is characterized by a high level of variability within and across individuals. This variability, which is manifest in speech movements, acoustics, and overt behaviors, can be input to subgroup discovery methods to identify cohesive subgroups of speakers or to reveal distinct developmental pathways or profiles. This investigation characterized three distinct groups of typically developing children and provided normative benchmarks for speech development. These speech development profiles, identified among 63 typically developing preschool-aged speakers (ages 36–59 mo), were derived from the children's performance on multiple measures. These profiles were obtained by submitting to a k-means cluster analysis of 72 measures that composed three levels of speech analysis: behavioral (e.g., task accuracy, percentage of consonants correct), acoustic (e.g., syllable duration, syllable stress), and kinematic (e.g., variability of movements of the upper lip, lower lip, and jaw). Two of the discovered group profiles were distinguished by measures of variability but not by phonemic accuracy; the third group of children was characterized by their relatively low phonemic accuracy but not by an increase in measures of variability. Analyses revealed that of the original 72 measures, 8 key measures were sufficient to best distinguish the 3 profile groups. PMID:22357794

  3. Distinct developmental profiles in typical speech acquisition.

    PubMed

    Vick, Jennell C; Campbell, Thomas F; Shriberg, Lawrence D; Green, Jordan R; Abdi, Hervé; Rusiewicz, Heather Leavy; Venkatesh, Lakshmi; Moore, Christopher A

    2012-05-01

    Three- to five-year-old children produce speech that is characterized by a high level of variability within and across individuals. This variability, which is manifest in speech movements, acoustics, and overt behaviors, can be input to subgroup discovery methods to identify cohesive subgroups of speakers or to reveal distinct developmental pathways or profiles. This investigation characterized three distinct groups of typically developing children and provided normative benchmarks for speech development. These speech development profiles, identified among 63 typically developing preschool-aged speakers (ages 36-59 mo), were derived from the children's performance on multiple measures. These profiles were obtained by submitting to a k-means cluster analysis of 72 measures that composed three levels of speech analysis: behavioral (e.g., task accuracy, percentage of consonants correct), acoustic (e.g., syllable duration, syllable stress), and kinematic (e.g., variability of movements of the upper lip, lower lip, and jaw). Two of the discovered group profiles were distinguished by measures of variability but not by phonemic accuracy; the third group of children was characterized by their relatively low phonemic accuracy but not by an increase in measures of variability. Analyses revealed that of the original 72 measures, 8 key measures were sufficient to best distinguish the 3 profile groups.

  4. Coordinated waves of gene expression during neuronal differentiation of embryonic stem cells as basis for novel approaches to developmental neurotoxicity testing

    PubMed Central

    Zimmer, B; Kuegler, P B; Baudis, B; Genewsky, A; Tanavde, V; Koh, W; Tan, B; Waldmann, T; Kadereit, S; Leist, M

    2011-01-01

    As neuronal differentiation of embryonic stem cells (ESCs) recapitulates embryonic neurogenesis, disturbances of this process may model developmental neurotoxicity (DNT). To identify the relevant steps of in vitro neurodevelopment, we implemented a differentiation protocol yielding neurons with desired electrophysiological properties. Results from focussed transcriptional profiling suggested that detection of non-cytotoxic developmental disturbances triggered by toxicants such as retinoic acid (RA) or cyclopamine was possible. Therefore, a broad transcriptional profile of the 20-day differentiation process was obtained. Cluster analysis of expression kinetics, and bioinformatic identification of overrepresented gene ontologies revealed waves of regulation relevant for DNT testing. We further explored the concept of superimposed waves as descriptor of ordered, but overlapping biological processes. The initial wave of transcripts indicated reorganization of chromatin and epigenetic changes. Then, a transient upregulation of genes involved in the formation and patterning of neuronal precursors followed. Simultaneously, a long wave of ongoing neuronal differentiation started. This was again superseded towards the end of the process by shorter waves of neuronal maturation that yielded information on specification, extracellular matrix formation, disease-associated genes and the generation of glia. Short exposure to lead during the final differentiation phase, disturbed neuronal maturation. Thus, the wave kinetics and the patterns of neuronal specification define the time windows and end points for examination of DNT. PMID:20865013

  5. Proteomic profiling of proteins associated with methamphetamine-induced neurotoxicity in different regions of rat brain.

    PubMed

    Li, Xuefeng; Wang, Huijun; Qiu, Pingming; Luo, Hong

    2008-01-01

    It is well documented that methamphetamine (MA) can cause obvious damage to the brain, but the exact mechanism is still unknown. In the present study, proteomic methods of two-dimensional gel electrophoresis in combination with mass spectrometry analysis were used to identify global protein profiles associated with MA-induced neurotoxicity. For the first time, 30 protein spots have been found differentially expressed in different regions of rat brain, including 14 in striatum, 12 in hippocampus and 4 in frontal cortex. The proteins identified by tandem mass spectrometry were Cu, Zn superoxide dismutase, dimethylarginine dimethylaminohydrolase 1, alpha synuclein, ubiquitin-conjugating enzyme E2N, stathmin 1, calcineurin B, cystatin B, subunit of mitochondrial H-ATP synthase, ATP synthase D chain, mitochondrial, NADH dehydrogenase(ubiquinone) Fe-S protein 8, glia maturation factor, beta, Ash-m, neurocalcin delta, myotrophin, profiling IIa, D-dopachrome tautomerase, and brain lipid binding protein. The known functions of these proteins were related to the pathogenesis of MA-induced neurotoxicity, including oxidative stress, degeneration/apoptosis, mitochontrial/energy metabolism and others. Of these proteins, alpha-synuclein was up-regulated, and ATP synthase D chain, mitochondrial was down-regulated in all brain regions. Two proteins, Cu, Zn superoxide dismutase, subunit of mitochondrial H-ATPsynthase were down-regulated and Ubiquitin-conjugating enzyme E2N, NADH dehydrogenase (ubiquinone) Fe-S protein 8 were up-regulated simultaneously in striatum and hippocaltum. The expression of dimethylarginine dimethylaminohydrolase 1 (DDAH 1) increased both in striatum and frontal cortex. The parallel expression patterns of these proteins suggest that the pathogenesis of MA neurotoxicity in different brain regions may share some same pathways.

  6. Neurotoxicity of developmental hypothyroxinemia and hypothyroidism in rats: Impairments of long-term potentiation are mediated by phosphatidylinositol 3-kinase signaling pathway.

    PubMed

    Wang, Yi; Wei, Wei; Wang, Yuan; Dong, Jing; Song, Binbin; Min, Hui; Teng, Weiping; Chen, Jie

    2013-09-01

    Neurotoxicity of iodine deficiency-induced hypothyroidism during developmental period results in serious impairments of brain function, such as learning and memory. These impairments are largely irreversible, and the underlying mechanisms remain unclear. In addition to hypothyroidism, iodine deficiency may cause hypothyroxinemia, a relatively subtle form of thyroid hormone deficiency. Neurotoxicity of developmental hypothyroxinemia also potentially impairs learning and memory. However, more direct evidence of the associations between developmental hypothyroxinemia and impairments of learning and memory should be provided, and the underlying mechanisms remain to be elucidated. Thus, in the present study, we investigated the effects of developmental hypothyroxinemia and hypothyroidism on long-term potentiation (LTP), a widely accepted cellular model of learning and memory, in the hippocampal CA1 region. The activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway - a pathway closely associated with synaptic plasticity and learning and memory - was also investigated. Wistar rats were treated with iodine deficient diet or methimazole (MMZ) to induce developmental hypothyroxinemia or hypothyroidism. The results showed that developmental hypothyroxinemia caused by mild iodine deficiency and developmental hypothyroidism caused by severe iodine deficiency or MMZ significantly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Decreased activation of the PI3K signaling pathway was also observed in rats subjected to developmental hypothyroxinemia or hypothyroidism. Our results may support the hypothesis that neurotoxicity of both developmental hypothyroxinemia and hypothyroidism causes damages to learning and memory. Our results also suggest that decreased activation of the PI3K signaling pathway may contribute to impairments of LTP caused by neurotoxicity of both developmental hypothyroxinemia and

  7. Evaluating alterations in Zebrafish retino-tectal projections as an indication of developmental neurotoxicity

    EPA Science Inventory

    The U.S. EPA is developing alternative screening methods to identify putative developmental neurotoxicants and prioritize chemicals for additional testing. One method developmentally exposes zebrafish embryos and assesses nervous system structure at 2 days post-fertilization (dpf...

  8. Evaluating alterations in Zebrafish retino-tectal projections as an indication of developmental neurotoxicity

    EPA Science Inventory

    The U.S. EPA is developing alternative screening methods to identify putative developmental neurotoxicants and prioritize chemicals for additional testing. One method developmentally exposes zebrafish embryos and assesses nervous system structure at 2 days post-fertilization (dpf...

  9. Synergistic interactions between commonly used food additives in a developmental neurotoxicity test.

    PubMed

    Lau, Karen; McLean, W Graham; Williams, Dominic P; Howard, C Vyvyan

    2006-03-01

    Exposure to non-nutritional food additives during the critical development window has been implicated in the induction and severity of behavioral disorders such as attention deficit hyperactivity disorder (ADHD). Although the use of single food additives at their regulated concentrations is believed to be relatively safe in terms of neuronal development, their combined effects remain unclear. We therefore examined the neurotoxic effects of four common food additives in combinations of two (Brilliant Blue and L-glutamic acid, Quinoline Yellow and aspartame) to assess potential interactions. Mouse NB2a neuroblastoma cells were induced to differentiate and grow neurites in the presence of additives. After 24 h, cells were fixed and stained and neurite length measured by light microscopy with computerized image analysis. Neurotoxicity was measured as an inhibition of neurite outgrowth. Two independent models were used to analyze combination effects: effect additivity and dose additivity. Significant synergy was observed between combinations of Brilliant Blue with L-glutamic acid, and Quinoline Yellow with aspartame, in both models. Involvement of N-methyl-D-aspartate (NMDA) receptors in food additive-induced neurite inhibition was assessed with a NMDA antagonist, CNS-1102. L-glutamic acid- and aspartame-induced neurotoxicity was reduced in the presence of CNS-1102; however, the antagonist did not prevent food color-induced neurotoxicity. Theoretical exposure to additives was calculated based on analysis of content in foodstuff, and estimated percentage absorption from the gut. Inhibition of neurite outgrowth was found at concentrations of additives theoretically achievable in plasma by ingestion of a typical snack and drink. In addition, Trypan Blue dye exclusion was used to evaluate the cellular toxicity of food additives on cell viability of NB2a cells; both combinations had a straightforward additive effect on cytotoxicity. These data have implications for the

  10. Overexpression cdc42 attenuates isoflurane-induced neurotoxicity in developmental brain of rats.

    PubMed

    Fang, Xi; Li, Shiyong; Han, Qiang; Zhao, Yilin; Gao, Jie; Yan, Jing; Luo, Ailin

    2017-08-26

    Nowadays many children receive operations with general anesthesia. Isoflurane is a commonly-used general anesthetic. Numbers of studies demonstrated that isoflurane induced neurotoxicity and neurobehavioral deficiency in young rats, however, the underlying mechanism remained unknown. Cell division cycle 42 (cdc42) played an important role in regulating synaptic vesicle trafficking and actin dynamics in neuron, which closely linked to synaptic plasticity and dendritic spine formation. Meanwhile, cdc42 also involved in many neurodegenerative diseases. However, whether cdc42 provided a protective role in isoflurane induced synaptogenesis dysfunction still unknown. As the upstream of cdc42, calcium/Calmodulin-dependent protein kinase II (CaMKII) interacts with ion channels such as VDCCs and N-methyl-d-aspartate receptors (NMDARs), which closely associated with neuroapoptosis and cognitive deficiency in developing brain. The phosphorylation of CaMKIIα at Thr 286 plays an important role in introduction and maintenance of long-term potentiation (LTP). Therefore, we investigated the effect of isoflurane on cdc42 and its upstream Calcium/Calmodulin-dependent protein kinase II (CaMKII) and its downstream p21 activated kinase 3 (PAK3), then determined whether CaMKIIα/cdc42/PAK3 signaling pathway was involved in neurotoxicity and cognitive deficiency induced by isoflurane. Our study found that isoflurane induced neurotoxicity and resulted in cognitive impairment in young rats through suppressed CaMKIIα/cdc42/PAK3 signaling pathway. Cdc42 over-expression could reverse neurotoxicity and improve cognitive impairment induced by isoflurane. Copyright © 2017. Published by Elsevier Inc.

  11. Developmental Rainbow: Early Childhood Development Profile.

    ERIC Educational Resources Information Center

    Mahoney, Gerald; Mahoney, Frida

    One of the most important skills of professionals who work with young children is the ability to assess developmental functioning through informal observation. This skill serves as the foundation for screening or identifying children in need of developmental services, conducting play-based developmental assessments, and helping parents to…

  12. Developmental Rainbow: Early Childhood Development Profile.

    ERIC Educational Resources Information Center

    Mahoney, Gerald; Mahoney, Frida

    One of the most important skills of professionals who work with young children is the ability to assess developmental functioning through informal observation. This skill serves as the foundation for screening or identifying children in need of developmental services, conducting play-based developmental assessments, and helping parents to…

  13. Functional Assays and Alternative Species: Using Larval Zebrafish in Developmental Neurotoxicity Screening

    EPA Science Inventory

    The U.S. Environmental Protection Agency is developing and evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. Towards this goal, we are exploring methods to detect developmental neurotoxicants in very young larval zebrafish. We have...

  14. BRAIN AND BLOOD TIN LEVELS IN A DEVELOPMENTAL NEUROTOXICITY STUDY OF DIBUTYLTIN.

    EPA Science Inventory

    Dibutyltin (DBT), a widely used plastic stabilizer, is detected in the environment and human tissues. While teratological and developmental effects are known, we could find no published report of DBT effects on the developing nervous system. As part of a developmental neurotoxi...

  15. Generation and Characterization of Neurogeninl-GFP Transgenic Medaka for High Throughput Developmental Neurotoxicity Screening

    EPA Science Inventory

    Fish models such as zebrafish and medaka are increasingly used as alternatives to rodents in developmental and toxicological studies. These developmental and toxicological studies can be facilitated by the use of transgenic reporters that permit the real-time, noninvasive observa...

  16. Functional Assays and Alternative Species: Using Larval Zebrafish in Developmental Neurotoxicity Screening

    EPA Science Inventory

    The U.S. Environmental Protection Agency is developing and evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. Towards this goal, we are exploring methods to detect developmental neurotoxicants in very young larval zebrafish. We have...

  17. Zebrafish as a model for investigating developmental lead (Pb) neurotoxicity as a risk factor in adult neurodegenerative disease: a mini-review.

    PubMed

    Lee, Jinyoung; Freeman, Jennifer L

    2014-07-01

    Lead (Pb) exposure has long been recognized to cause neurological alterations in both adults and children. While most of the studies in adults are related to higher dose exposure, epidemiological studies indicate cognitive decline and neurobehavioral alterations in children associated with lower dose environmental Pb exposure (a blood Pb level of 10μg/dL and below). Recent animal studies also now report that an early-life Pb exposure results in pathological hallmarks of Alzheimer's disease later in life. While previous studies evaluating higher Pb exposures in adult animal models and higher occupational Pb exposures in humans have suggested a link between higher dose Pb exposure during adulthood and neurodegenerative disease, these newer studies now indicate a link between an early-life Pb exposure and adult neurodegenerative disease. These studies are supporting the "fetal/developmental origin of adult disease" hypothesis and present a new challenge in our understanding of Pb neurotoxicity. There is a need to expand research in this area and additional model systems are needed. The zebrafish presents as a complementary vertebrate model system with numerous strengths including high genetic homology. Several zebrafish genes orthologous to human genes associated with neurodegenerative diseases including Alzheimer's and Parkinson's diseases are identified and this model is starting to be applied in neurodegenerative disease research. Moreover, the zebrafish is being used in developmental Pb neurotoxicity studies to define genetic mechanisms of toxicity and associated neurobehavioral alterations. While these studies are in their infancy, the genetic and functional conservation of genes associated with neurodegenerative diseases and application in developmental Pb neurotoxicity studies supports the potential for this in vivo model to further investigate the link between developmental Pb exposure and adult neurodegenerative disease pathogenesis. In this review, the

  18. HIGH-CONTENT ANALYSIS OF PRIMARY RAT NEURAL CORTICALCULTURES FOR DEVELOPMENTAL NEUROTOXICITY SCREENING

    EPA Science Inventory

    Development of the vertebrate nervous system proceeds through a number of critical processes, ultimately concluding with the extension of neurites and establishment of synaptic networks. Early-life exposure to toxicants that perturb these critical developmental processes can po...

  19. HIGH-CONTENT ANALYSIS OF PRIMARY RAT NEURAL CORTICALCULTURES FOR DEVELOPMENTAL NEUROTOXICITY SCREENING

    EPA Science Inventory

    Development of the vertebrate nervous system proceeds through a number of critical processes, ultimately concluding with the extension of neurites and establishment of synaptic networks. Early-life exposure to toxicants that perturb these critical developmental processes can po...

  20. Mechanisms involved in the neurotoxic and cognitive effects of developmental methamphetamine exposure.

    PubMed

    Jablonski, Sarah A; Williams, Michael T; Vorhees, Charles V

    2016-06-01

    Methamphetamine exposure in utero leads to a variety of higher-order cognitive deficits, such as decreased attention and working, and spatial memory impairments in exposed children (Piper et al., 2011; Roussotte et al., 2011; Kiblawi et al., 2011). As with other teratogens, the timing of methamphetamine exposure greatly determines its effects on both neuroanatomical and behavioral outcomes. Methamphetamine exposure in rodents during the third trimester human equivalent period of brain development results in distinct and long-lasting route-based and spatial navigation deficits (Williams et al., 2003; Vorhees et al., 2005, 2008, 2009;). Here, we examine the impact of neonatal methamphetamine-induced neurotoxicity on behavioral outcomes, neurotransmission, receptor changes, plasticity proteins, and DNA damage. Birth Defects Research (Part C) 108:131-141, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Cognitive Profiling and Preliminary Subtyping in Chinese Developmental Dyslexia

    ERIC Educational Resources Information Center

    Ho, Connie Suk-Han; Chan, David Wai-Ock; Lee, Suk-Han; Tsang, Suk-Man; Luan, Vivian Hui

    2004-01-01

    The present study examined the cognitive profile and subtypes of developmental dyslexia in a nonalphabetic script, Chinese. One hundred and forty-seven Chinese primary school children with developmental dyslexia were tested on a number of literacy and cognitive tasks. The results showed that rapid naming deficit and orthographic deficit were the…

  2. Prenatal dexamethasone augments the sex-selective developmental neurotoxicity of chlorpyrifos: implications for vulnerability after pharmacotherapy for preterm labor.

    PubMed

    Slotkin, Theodore A; Card, Jennifer; Infante, Alice; Seidler, Frederic J

    2013-01-01

    Glucocorticoids are routinely given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so coexposures to these two agents are pervasive. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of dexamethasone and chlorpyrifos given individually. Dexamethasone did not enhance the systemic toxicity of chlorpyrifos, as evidenced by weight gain and measurements of cholinesterase inhibition during chlorpyrifos treatment. Nevertheless, it enhanced the loss of presynaptic ACh function selectively in females, who ordinarily show sparing of organophosphate developmental neurotoxicity relative to males. Females receiving the combined treatment showed decrements in choline transporter binding and choline acetyltransferase activity that were unique (not found with either treatment alone), as well as additive decrements in nicotinic receptor binding. On the other hand, males given dexamethasone showed no augmentation of the effects of chlorpyrifos. Our findings indicate that prior dexamethasone exposure could create a subpopulation that is especially vulnerable to the adverse effects of organophosphates or other developmental neurotoxicants. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: neuropathology.

    PubMed Central

    Garman, R H; Fix, A S; Jortner, B S; Jensen, K F; Hardisty, J F; Claudio, L; Ferenc, S

    2001-01-01

    Neuropathologic assessment of chemically induced developmental alterations in the nervous system for regulatory purposes is a multifactorial, complex process. This calls for careful qualitative and quantitative morphologic study of numerous brains at several developmental stages in rats. Quantitative evaluation may include such basic methods as determination of brain weight and dimensions as well as the progressively more complex approaches of linear, areal, or stereologic measurement of brain sections. Histologic evaluation employs routine stains (such as hematoxylin and eosin), which can be complemented by a variety of special and immunohistochemical procedures. These brain studies are augmented by morphologic assessment of selected peripheral nervous system structures. Studies of this nature require a high level of technical skill as well as special training on the part of the pathologist. The pathologist should have knowledge of normal microscopic neuroanatomy/neuronal circuitry and an understanding of basic principles of developmental neurobiology, such as familiarity with the patterns of physiologic or programmed cell de PMID:11250809

  4. A human pluripotent carcinoma stem cell-based model for in vitro developmental neurotoxicity testing: effects of methylmercury, lead and aluminum evaluated by gene expression studies.

    PubMed

    Laurenza, Incoronata; Pallocca, Giorgia; Mennecozzi, Milena; Scelfo, Bibiana; Pamies, David; Bal-Price, Anna

    2013-11-01

    The major advantage of the neuronal cell culture models derived from human stem cells is their ability to replicate the crucial stages of neurodevelopment such as the commitment of human stem cells to the neuronal lineage and their subsequent stages of differentiation into neuronal and glial-like cell. In these studies we used mixed neuronal/glial culture derived from the NTERA-2 (NT-2) cell line, which has been established from human pluripotent testicular embryonal carcinoma cells. After characterization of the different stages of cell differentiation into neuronal- and glial-like phenotype toxicity studies were performed to evaluate whether this model would be suitable for developmental neurotoxicity studies. The cells were exposed during the differentiation process to non-cytotoxic concentrations of methylmercury chloride, lead chloride and aluminum nitrate for two weeks. The toxicity was then evaluated by measuring the mRNA levels of cell specific markers (neuronal and glial). The results obtained suggest that lead chloride and aluminum nitrate at low concentrations were toxic primarily to astrocytes and at the higher concentrations it also induced neurotoxicity. In contrast, MetHgCl was toxic for both cell types, neuronal and glial, as mRNA specific for astrocytes and neuronal markers were affected. The results obtained suggest that a neuronal mixed culture derived from human NT2 precursor cells is a suitable model for developmental neurotoxicity studies and gene expression could be used as a sensitive endpoint for initial screening of potential neurotoxic compounds.

  5. Functional Assays and Alternative Species: Using Larval Zebrafish in Developmental Neurotoxicity Screening**

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. As such, we are exploring a behavioral testing paradigm, which can assess the effect of sublethal and subteratogenic concentrations of de...

  6. Functional Assays and Alternative Species: Using Larval Zebrafish in Developmental Neurotoxicity Screening**

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity. As such, we are exploring a behavioral testing paradigm, which can assess the effect of sublethal and subteratogenic concentrations of de...

  7. Assessment of the developmental and neurotoxicity of the mosquito control larvicide, pyriproxyfen, using embryonic zebrafish.

    PubMed

    Truong, Lisa; Gonnerman, Greg; Simonich, Michael T; Tanguay, Robert L

    2016-11-01

    In 2014, as an attempt to address the Zika health crisis by controlling the mosquito population, Brazil took the unprecedented action of applying a chemical larvicide, pyriproxyfen, to drinking water sources. The World Health Organization has established an acceptable daily intake of pyriproxyfen to be 100 μg per kg of body weight per day, but studies have demonstrated that at elevated doses (>5000 mg/kg), there are adverse effects in mice, rats and dogs. To better understand the potential developmental toxicity of pyriproxyfen, we utilized the embryonic zebrafish. Our results demonstrate that the concentration resulting in 50% of animals presenting adverse morphological effects (EC50), including craniofacial defects, was 5.2 μM for daily renewal exposure, and above this concentration, adverse behavioral effects were also observed in animals that followed a static exposure regimen. Thus, zebrafish data suggest that the developmental toxicity of pyriproxyfen may not be limited to insects.

  8. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. I: behavioral effects.

    PubMed Central

    Cory-Slechta, D A; Crofton, K M; Foran, J A; Ross, J F; Sheets, L P; Weiss, B; Mileson, B

    2001-01-01

    Alterations in nervous system function after exposure to a developmental neurotoxicant may be identified and characterized using neurobehavioral methods. A number of methods can evaluate alterations in sensory, motor, and cognitive functions in laboratory animals exposed to toxicants during nervous system development. Fundamental issues underlying proper use and interpretation of these methods include a) consideration of the scientific goal in experimental design, b) selection of an appropriate animal model, c) expertise of the investigator, d) adequate statistical analysis, and e) proper data interpretation. Strengths and weaknesses of the assessment methods include sensitivity, selectivity, practicality, and variability. Research could improve current behavioral methods by providing a better understanding of the relationship between alterations in motor function and changes in the underlying structure of these systems. Research is also needed to develop simple and sensitive assays for use in screening assessments of sensory and cognitive function. Assessment methods are being developed to examine other nervous system functions, including social behavior, autonomic processes, and biologic rhythms. Social behaviors are modified by many classes of developmental neurotoxicants and hormonally active compounds that may act either through neuroendocrine mechanisms or by directly influencing brain morphology or neurochemistry. Autonomic and thermoregulatory functions have been the province of physiologists and neurobiologists rather than toxicologists, but this may change as developmental neurotoxicology progresses and toxicologists apply techniques developed by other disciplines to examine changes in function after toxicant exposure. PMID:11250808

  9. Developmental neurotoxicity of the hippocampus following in utero exposure to methylmercury: impairment in cell signaling.

    PubMed

    Heimfarth, Luana; Delgado, Jeferson; Mignori, Moara Rodrigues; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca; Pessoa-Pureur, Regina

    2017-08-18

    In this study, we assessed some hippocampal signaling cascades and behavioral impairments in 30-day-old rat pups prenatally exposed to methylmercury (MeHg). Pregnant rats were exposed to 1.0 or 2.0 mg/kg MeHg by gavage in alternated days from gestational day 5 until parturition. We found increased anxiety-like and decreased exploration behavior evaluated by open field test and deficit of both short- and long-term memories by novel object recognition task, respectively, in MeHg-treated pups. Downregulated PI3K/Akt/mTOR pathway and activated/hypophosphorylated (Ser9) GSK3β in MeHg-treated pups could be upstream of hyperphosphorylated Tau (Ser396) destabilizing microtubules and contributing to neural dysfunction in the hippocampus of these rats. Hyperphosphorylated/activated p38MAPK and downregulated phosphoErk1/2 support a role for mitogen-activated protein kinase (MAPK) cascade on MeHg neurotoxicity. Decreased receptor of advanced glycation end products (RAGE) immunocontent supports the assumption that downregulated RAGE/Erk1/2 pathway could be involved in hypophosphorylated lysine/serine/proline (KSP) repeats on neurofilament subunits and disturbed axonal transport. Downregulated myelin basic protein (MBP), the major myelin protein, is compatible with dysmyelination and neurofilament hypophosphorylation. Increased glial fibrillary acidic protein (GFAP) levels suggest reactive astrocytes, and active apoptotic pathways BAD/BCL-2, BAX/BCL-XL, and caspase 3 suggest cell death. Taken together, our findings get light on important signaling mechanisms that could underlie the behavioral deficits in 30-day-old pups prenatally exposed to MeHg.

  10. Cognitive Profiles of Adult Developmental Dyslexics: Theoretical Implications

    ERIC Educational Resources Information Center

    Reid, Agnieszka A.; Szczerbinski, Marcin; Iskierka-Kasperek, Ewa; Hansen, Peter

    2007-01-01

    The aim of this study was to establish cognitive profiles of dyslexic adults on tests developed within the three main theories of developmental dyslexia: phonological, visual magnocellular and cerebellar and to investigate which theory can account for these profiles. The sample consisted of 15 Polish university students or alumni with a formal…

  11. Cognitive Profiles of Adult Developmental Dyslexics: Theoretical Implications

    ERIC Educational Resources Information Center

    Reid, Agnieszka A.; Szczerbinski, Marcin; Iskierka-Kasperek, Ewa; Hansen, Peter

    2007-01-01

    The aim of this study was to establish cognitive profiles of dyslexic adults on tests developed within the three main theories of developmental dyslexia: phonological, visual magnocellular and cerebellar and to investigate which theory can account for these profiles. The sample consisted of 15 Polish university students or alumni with a formal…

  12. Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward cholinergic systems: better, worse, or just "different?".

    PubMed

    Slotkin, Theodore A; Seidler, Frederic J

    2015-01-01

    This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability.

  13. Workgroup Report: Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity into International Hazard and Risk Assessment Strategies

    PubMed Central

    Coecke, Sandra; Goldberg, Alan M; Allen, Sandra; Buzanska, Leonora; Calamandrei, Gemma; Crofton, Kevin; Hareng, Lars; Hartung, Thomas; Knaut, Holger; Honegger, Paul; Jacobs, Miriam; Lein, Pamela; Li, Abby; Mundy, William; Owen, David; Schneider, Steffen; Silbergeld, Ellen; Reum, Torsten; Trnovec, Tomas; Monnet-Tschudi, Florianne; Bal-Price, Anna

    2007-01-01

    This is the report of the first workshop on Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity (DNT) Testing into International Hazard and Risk Assessment Strategies, held in Ispra, Italy, on 19–21 April 2005. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and jointly organized by ECVAM, the European Chemical Industry Council, and the Johns Hopkins University Center for Alternatives to Animal Testing. The primary aim of the workshop was to identify and catalog potential methods that could be used to assess how data from in vitro alternative methods could help to predict and identify DNT hazards. Working groups focused on two different aspects: a) details on the science available in the field of DNT, including discussions on the models available to capture the critical DNT mechanisms and processes, and b) policy and strategy aspects to assess the integration of alternative methods in a regulatory framework. This report summarizes these discussions and details the recommendations and priorities for future work. PMID:17589601

  14. Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson's disease.

    PubMed

    Richardson, Jason R; Caudle, W Michael; Wang, Minzheng; Dean, E Danielle; Pennell, Kurt D; Miller, Gary W

    2006-08-01

    Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.

  15. Evaluation of developmental neurotoxicity of organotins via drinking water in rats: monomethyltin.

    PubMed

    Moser, Virginia C; Barone, Stanley; Phillips, Pamela M; McDaniel, Katherine L; Ehman, Kimberly D

    2006-05-01

    Organotins such as monomethyltin (MMT) are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for neurotoxicity produced by organotin exposure during development has been raised by published findings of a deficit on a runway learning task in rat pups perinatally exposed to MMT (Noland EA, Taylor DH, Bull RJ. Monomethyl and trimethyltin compounds induce learning deficiencies in young rats. Neurobehav Toxicol Teratol 1982;4:539-44). The objective of these studies was to replicate the earlier publication and further define the dose-response characteristics of MMT following perinatal exposure. In Experiment 1, female Sprague-Dawley rats were exposed via drinking water to MMT (0, 10, 50, 245 ppm) before mating and throughout gestation and lactation (until weaning at postnatal day [PND] 21). Behavioral assessments of the offspring included: a runway test (PND 11) in which the rat pups learned to negotiate a runway for dry suckling reward; motor activity habituation (PNDs 13, 17, and 21); learning in the Morris water maze (as adults). Other endpoints in the offspring included measures of apoptosis (DNA fragmentation) at PND 22 and as adults, as well as brain weights and neuropathological evaluation at PND 2, 12, 22, and as adults. There were no effects on any measure of growth, development, cognitive function, or apoptosis following MMT exposure. There was a trend towards decreased brain weight in the high dose group. In addition, there was vacuolation of the neuropil in a focal area of the cerebral cortex of the adult offspring in all MMT dose groups (1-3 rats per treatment group). In Experiment 2, pregnant rats were exposed from gestational day 6 until weaning to 500 ppm MMT in drinking water. The offspring behavioral assessments again included the runway task (PND 11), motor activity habituation (PND 17), and Morris water maze (as adults). In this second study, MMT-exposed females consumed

  16. Low-level arsenic exposure and developmental neurotoxicity in children: A systematic review and risk assessment.

    PubMed

    Tsuji, Joyce S; Garry, Michael R; Perez, Vanessa; Chang, Ellen T

    2015-11-04

    chronic lifetime exposure, thus indicating protectiveness of the existing value for potential neurotoxicity in children. This reference dose is undergoing revision as EPA considers various health endpoints in the reassessment of inorganic arsenic health risks. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  17. Antineuropathic Profile of N-Palmitoylethanolamine in a Rat Model of Oxaliplatin-Induced Neurotoxicity

    PubMed Central

    Di Cesare Mannelli, Lorenzo; Pacini, Alessandra; Corti, Francesca; Boccella, Serena; Luongo, Livio; Esposito, Emanuela; Cuzzocrea, Salvatore; Maione, Sabatino; Calignano, Antonio; Ghelardini, Carla

    2015-01-01

    Neurotoxicity is a main side effect of the anticancer drug oxaliplatin. The development of a neuropathic syndrome impairs quality of life and potentially results in chemotherapy dose reductions and/or early discontinuation. In the complex pattern of molecular and morphological alterations induced by oxaliplatin in the nervous system, an important activation of glia has been preclinically evidenced. N-Palmitoylethanolamine (PEA) modulates glial cells and exerts antinociceptive effects in several animal models. In order to improve the therapeutic chances for chemotherapy-dependent neuropathy management, the role of PEA was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mg kg-1 daily, intraperitoneally). On day 21, a single administration of PEA (30 mg kg-1 i.p.) was able to reduce oxaliplatin-dependent pain induced by mechanical and thermal stimuli. The repeated treatment with PEA (30 mg kg-1 daily i.p. for 21 days, from the first oxaliplatin injection) prevented lowering of pain threshold as well as increased pain on suprathreshold stimulation. Ex vivo histological and molecular analysis of dorsal root ganglia, peripheral nerves and spinal cord highlighted neuroprotective effects and glia-activation prevention induced by PEA repeated administration. The protective effect of PEA resulted in the normalization of the electrophysiological activity of the spinal nociceptive neurons. Finally, PEA did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. The efficacy of PEA in neuropathic pain control and in preventing nervous tissue alteration candidates this endogenous compound as disease modifying agent. These characteristics, joined to the safety profile, suggest the usefulness of PEA in chemotherapy-induced neuropathy. PMID:26039098

  18. TRANSFORMATION OF DEVELOPMENTAL NEUROTOXICITY DATA INTO STRUCTURE-SEARCHABLE TOXML DATABASE IN SUPPORT OF STRUCTURE-ACTIVITY RELATIONSHIP (SAR) WORKFLOW.

    EPA Science Inventory

    Early hazard identification of new chemicals is often difficult due to lack of data on the novel material for toxicity endpoints, including neurotoxicity. At present, there are no structure searchable neurotoxicity databases. A working group was formed to construct a database to...

  19. TRANSFORMATION OF DEVELOPMENTAL NEUROTOXICITY DATA INTO STRUCTURE-SEARCHABLE TOXML DATABASE IN SUPPORT OF STRUCTURE-ACTIVITY RELATIONSHIP (SAR) WORKFLOW.

    EPA Science Inventory

    Early hazard identification of new chemicals is often difficult due to lack of data on the novel material for toxicity endpoints, including neurotoxicity. At present, there are no structure searchable neurotoxicity databases. A working group was formed to construct a database to...

  20. Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons.

    PubMed

    Hogberg, Helena T; Sobanski, Tomasz; Novellino, Antonio; Whelan, Maurice; Weiss, Dieter G; Bal-Price, Anna K

    2011-01-01

    Due to lack of knowledge only a few industrial chemicals have been identified as developmental neurotoxicants. Current developmental neurotoxicity (DNT) guidelines (OECD and EPA) are based entirely on in vivo studies that are both time consuming and costly. Consequently, there is a high demand to develop alternative in vitro methods for initial screening to prioritize chemicals for further DNT testing. One of the most promising tools for neurotoxicity assessment is the measurement of neuronal electrical activity using micro-electrode arrays (MEAs) that provides a functional and neuronal specific endpoint that until now has been used mainly to detect acute neurotoxicity. Here, electrical activity measurements were evaluated to be a suitable endpoint for the detection of potential developmental neurotoxicants. Initially, primary cortical neurons grown on MEA chips were characterized for different cell markers over time, using immunocytochemistry. Our results show that primary cortical neurons could be a promising in vitro model for DNT testing since some of the most critical neurodevelopment processes such as progenitor cell commitment, proliferation and differentiation of astrocytes and maturation of neurons are present. To evaluate if electrical activity could be a suitable endpoint to detect chemicals with DNT effects, our model was exposed to domoic acid (DomA), a potential developmental neurotoxicant for up to 4 weeks. Long-term exposure to a low concentration (50nM) of DomA increased the basal spontaneous electrical activity as measured by spike and burst rates. Moreover, the effect induced by the GABA(A) receptor antagonist bicuculline was significantly lower in the DomA treated cultures than in the untreated ones. The MEA measurements indicate that chronic exposure to DomA changed the spontaneous electrical activity leading to the possible neuronal mal functioning. The obtained results suggest that the MEAs could be a useful tool to identify compounds with

  1. Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos

    SciTech Connect

    Qiao, Dan; Seidler, Frederic J.; Slotkin, Theodore A. . E-mail: t.slotkin@duke.edu

    2005-08-01

    Nicotine and chlorpyrifos are developmental neurotoxicants that, despite their differences in structure and mechanism of action, share many aspects for damage to the developing brain. Both are thought to generate oxidative radicals; in the current study, we evaluated their ability to produce lipid peroxidation in two in vitro models of neural cell development (PC12 and SH-SY5Y cells) and for nicotine, with treatment of adolescent rats in vivo. Nicotine and chlorpyrifos, in concentrations relevant to human exposures, elicited an increase in thiobarbituric-acid-reactive species (TBARS) in undifferentiated cells, an effect that was prevented by addition of the antioxidant, Vitamin E. Initiating differentiation with nerve growth factor, which enhances nicotinic acetylcholine receptor expression, increased the TBARS response to nicotine but not chlorpyrifos, suggesting that the two agents act by different originating mechanisms to converge on the endpoint of oxidative damage. Furthermore, nicotine protected the cells from oxidative damage evoked by chlorpyrifos and similarly blocked the antimitotic effect of chlorpyrifos. Treatment of adolescent rats with nicotine elicited increases in TBARS in multiple brain regions when given in doses that simulate plasma nicotine concentrations found in smokers or at one-tenth the dose. Our results indicate that nicotine and chlorpyrifos elicit oxidative damage to developing neural cells both in vitro and in vivo, a mechanism that explains some of the neurodevelopmental endpoints that are common to the two agents. The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults.

  2. Studies of (±)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile.

    PubMed

    Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie; McCann, Una D; Ricaurte, George A

    2013-02-01

    The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

  3. Autism Developmental Profiles and Cooperation with Oral Health Screening

    ERIC Educational Resources Information Center

    Du, Rennan Y.; Yiu, Cynthia C. Y.; Wong, Virginia C. N.; McGrath, Colman P.

    2015-01-01

    To determine the associations between autism developmental profiles and cooperation with an oral health screening among preschool children with autism spectrum disorders (ASDs). A random sample of Special Child Care Centres registered with the Government Social Welfare Department in Hong Kong was selected (19 out of 37 Centres). All preschool…

  4. Spanish Developmental Dyslexia: Prevalence, Cognitive Profile, and Home Literacy Experiences

    ERIC Educational Resources Information Center

    Jimenez, Juan E.; Rodriguez, Cristina; Ramirez, Gustavo

    2009-01-01

    This study was designed to examine the prevalence, cognitive profile, and home literacy experiences in subtypes of Spanish developmental dyslexia. The subtyping procedure used comparison with chronological-age-matched and reading-level controls on reaction times and accuracy responses to high-frequency words and pseudowords. Using regression-based…

  5. Autism Developmental Profiles and Cooperation with Oral Health Screening

    ERIC Educational Resources Information Center

    Du, Rennan Y.; Yiu, Cynthia C. Y.; Wong, Virginia C. N.; McGrath, Colman P.

    2015-01-01

    To determine the associations between autism developmental profiles and cooperation with an oral health screening among preschool children with autism spectrum disorders (ASDs). A random sample of Special Child Care Centres registered with the Government Social Welfare Department in Hong Kong was selected (19 out of 37 Centres). All preschool…

  6. Effect of Gestational Intake of Fisetin (3,3',4',7-Tetrahydroxyflavone) on Developmental Methyl Mercury Neurotoxicity in F1 Generation Rats.

    PubMed

    Jacob, Sherin; Thangarajan, Sumathi

    2017-06-01

    Methyl mercury (MeHg) is a developmental neurotoxin that causes irreversible cognitive damage in offspring of gestationally exposed mothers. Currently, no preventive drugs are established against MeHg developmental neurotoxicity. The neuroprotective effect of gestational administration of a flavanoid against in utero toxicity of MeHg is not explored much. Hence, the present study validated the effect of a bioactive flavanoid, fisetin, on MeHg developmental neurotoxicity outcomes in rat offspring at postnatal weaning age. Pregnant Wistar rats were simultaneously given MeHg (1.5 mg/kg b.w.) and two doses of fisetin (10 and 50 mg/kg b.w. in two separate groups) orally from gestational day (GD) 5 till parturition. Accordingly, after parturition, on postnatal day (PND) 24, weaning F1 generation rats were studied for motor and cognitive behavioural changes. Biochemical and histopathological changes were also studied in the cerebral cortex, cerebellum and hippocampus on PND 25. Administration of fisetin during pregnancy prevented behavioural impairment due to transplacental MeHg exposure in weaning rats. Fisetin decreased the levels of oxidative stress markers, increased enzymatic and non-enzymatic antioxidant levels and increased the activity of membrane-bound ATPases and cholinergic function in F1 generation rats. In light microscopic studies, fisetin treatment protected the specific offspring brain regions from significant morphological aberrations. Between the two doses of fisetin studied, 10 mg/kg b.w. was found to be more satisfactory and effective than 50 mg/kg b.w. The present study shows that intake of fisetin during pregnancy in rats ameliorated in utero MeHg exposure-induced neurotoxicity outcomes in postnatal weaning F1 generation rats.

  7. Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action

    SciTech Connect

    Royland, Joyce E.; Kodavanti, Prasada Rao S.

    2008-09-01

    Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms for PCB-induced developmental neurotoxicity. In order to understand the role of these proposed mechanisms and to identify other mechanisms in PCB-induced neurotoxicity, we have chosen a global approach utilizing oligonucleotide microarrays to examine gene expression profiles in the brain following developmental exposure to Aroclor 1254 (0 or 6 mg/kg/day from gestation day 6 through postnatal day (PND) 21) in Long-Evans rats. Gene expression levels in the cerebellum and hippocampus from PNDs 7 and 14 animals were determined on Affymetrix rat 230A{sub 2}.0 chips. In the cerebellum, 87 transcripts were altered at PND7 compared to 27 transcripts at PND14 by Aroclor 1254 exposure, with only one transcript affected at both ages. In hippocampus, 175 transcripts and 50 transcripts were altered at PND7 and PND14, respectively, by Aroclor 1254 exposure with five genes commonly affected. Functional analysis suggests that pathways related to calcium homeostasis (Gng3, Ryr2, Trdn, Cacna1a), intracellular signaling (Camk2d, Stk17b, Pacsin2, Ryr2, Trio, Fert2, Ptk2b), axonal guidance (Lum, Mxd3, Akap11, Gucy1b3), aryl hydrocarbon receptor signaling (Nfia, Col1a2), and transcripts involved in cell proliferation (Gspt2, Cdkn1c, Ptk2b) and differentiation (Ifitm31, Hpca, Zfp260, Igsf4a, Hes5) leading to the development of nervous system were significantly altered by Aroclor 1254 exposure. Of the two brain regions examined, Aroclor 1254-induced genomic changes were greater in the hippocampus than the cerebellum. The genomic data suggests that PCB-induced neurotoxic effects were due to disruption of normal ontogenetic pattern of nervous system growth and development by altering intracellular signaling pathways

  8. In Vitro Developmental Neurotoxicity Following Chronic Exposure to 50 Hz Extremely Low-Frequency Electromagnetic Fields in Primary Rat Cortical Cultures.

    PubMed

    de Groot, Martje W G D M; van Kleef, Regina G D M; de Groot, Aart; Westerink, Remco H S

    2016-02-01

    Exposure to 50-60 Hz extremely low-frequency electromagnetic fields (ELF-EMFs) has increased considerably over the last decades. Several epidemiological studies suggested that ELF-EMF exposure is associated with adverse health effects, including neurotoxicity. However, these studies are debated as results are often contradictory and the possible underlying mechanisms are unknown. Since the developing nervous system is particularly vulnerable to insults, we investigate effects of chronic, developmental ELF-EMF exposure in vitro. Primary rat cortical neurons received 7 days developmental exposure to 50 Hz block-pulsed ELF-EMF (0-1000 μT) to assess effects on cell viability (Alamar Blue/CFDA assay), calcium homeostasis (single cell fluorescence microscopy), neurite outgrowth (β(III)-Tubulin immunofluorescent staining), and spontaneous neuronal activity (multi-electrode arrays). Our data demonstrate that cell viability is not affected by developmental ELF-EMF (0-1000 μT) exposure. Depolarization- and glutamate-evoked increases in intracellular calcium concentration ([Ca(2+)]i) are slightly increased at 1 μT, whereas both basal and stimulation-evoked [Ca(2+)]i show a modest inhibition at 1000 μT. Subsequent morphological analysis indicated that neurite length is unaffected up to 100 μT, but increased at 1000 μT. However, neuronal activity appeared largely unaltered following chronic ELF-EMF exposure up to 1000 μT. The effects of ELF-EMF exposure were small and largely restricted to the highest field strength (1000 μT), ie, 10 000 times above background exposure and well above current residential exposure limits. Our combined data therefore indicate that chronic ELF-EMF exposure has only limited (developmental) neurotoxic potential in vitro.

  9. Autism in community pre-schoolers: developmental profiles.

    PubMed

    Kantzer, Anne-Katrin; Fernell, Elisabeth; Gillberg, Christopher; Miniscalco, Carmela

    2013-09-01

    Autism is often a complex developmental disorder. The aim of the present study was to describe the developmental characteristics of 129 1-4-year-old children (102 boys, 27 girls) referred for clinical assessment (mean age 2.9 years) due to suspicion of autism spectrum disorder (ASD) after community screening at Child Health Care centers. All children were clinically assessed at the Child Neuropsychiatry Clinic (CNC) in Gothenburg by a research team (neurodevelopmental examination, structured interviews and general cognitive and language examinations). Of the 129 children, 100 met diagnostic criteria for ASD (69 with autistic disorder, and 31 with atypical autism/pervasive developmental disorder-not otherwise specified). The remaining 29 children had a variety of developmental disorders, most often attention-deficit/hyperactivity disorder (ADHD), language disorder, borderline intellectual functioning, and intellectual developmental disorder (IDD) with (n=25) or without (n=4) autistic traits (AT). IDD was found in 36% of the 100 children with ASD, and in 4% of the 25 children with AT. Of the children with ASD, 56% had language disorder with no or just a few words at the initial assessment at the CNC, many of whom in combination with IDD. Hyperactivity was found in 37% of those with ASD and in 40% of those with AT. Epilepsy was found in 6% of the total group and in 7% of those with a diagnosis of ASD. Of the latter group 11% had a history of regression, while none of the AT cases had a similar background. When results were compared with a non-screened preschool ASD group of 208 children, referred for ASD intervention at a mean age of 3.4 years, very similar developmental profiles were seen. In conclusion, early community ASD screening appears to systematically identify those children who are in need of intervention and follow-up.

  10. Motor and Cognitive Developmental Profiles in Children With Down Syndrome

    PubMed Central

    2017-01-01

    Objective To investigate motor and cognitive developmental profiles and to evaluate the correlation between two developmental areas and assess the influencing factors of the developmental process in children with Down syndrome (DS). Methods Seventy-eight children with DS participated in this study. The medical history was taken and motoric milestone achievements recorded. The Korean Wechsler Preschool and Primary Scale of Intelligence (K-WPPSI) and Bayley Scales of Infant Development-II (BSID-II) were administered. Subjects were divided into severe motor delay group (severe group) and typical motor delay group (typical group). Results Children with DS follow the same sequence of motor development and generally displayed double times of acquisition of developmental milestones compared with healthy children. Furthermore, having surgery for associated complications showed negative influence to the motor development. Almost of all children with DS showed moderate degree of intellectual disability and motor and cognitive development do not seem to correlate one another. Conclusion Surgery of associated complications can be negatively related to motor development. However, early motor development did not have any significant effects on the achievement of later cognitive functioning. PMID:28289641

  11. Cognitive profiling and preliminary subtyping in Chinese developmental dyslexia.

    PubMed

    Ho, Connie Suk-Han; Chan, David Wai-Ock; Lee, Suk-Han; Tsang, Suk-Man; Luan, Vivian Hui

    2004-02-01

    The present study examined the cognitive profile and subtypes of developmental dyslexia in a nonalphabetic script, Chinese. One hundred and forty-seven Chinese primary school children with developmental dyslexia were tested on a number of literacy and cognitive tasks. The results showed that rapid naming deficit and orthographic deficit were the two most dominant types of cognitive deficits in Chinese developmental dyslexia, and that rapid naming and orthographic processing had significant unique contributions to literacy performance. Seven subtypes of dyslexia--global deficit, orthographic deficit, phonological memory deficit, mild difficulty, and three other subtypes with rapid-naming-related deficits--were identified using scores of the cognitive tasks as classification measures in cluster analyses. These subtypes were validated with a behaviour checklist and three literacy measures. The authors suggested that orthographic and rapid naming deficits in Chinese dyslexic children might pose an interrelated problem in developing orthographic knowledge and representation. Therefore, orthographic-related difficulties may be the crux of the problem in Chinese developmental dyslexia.

  12. Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

    PubMed Central

    Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie; McCann, Una D.

    2013-01-01

    The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition. PMID:23209329

  13. Autism Developmental Profiles and Cooperation with Oral Health Screening.

    PubMed

    Du, Rennan Y; Yiu, Cynthia C Y; Wong, Virginia C N; McGrath, Colman P

    2015-09-01

    To determine the associations between autism developmental profiles and cooperation with an oral health screening among preschool children with autism spectrum disorders (ASDs). A random sample of Special Child Care Centres registered with the Government Social Welfare Department in Hong Kong was selected (19 out of 37 Centres). All preschool children with ASDs were invited to participate in the oral health survey and 347 children agreed to participate (among 515 invited). A checklist of autism developmental profiles: (1) level of cognitive functioning, (2) social skills development, (3) communication skills development, (4) reading skills and (5) challenging behaviours was ascertained. Feasibility of conducting oral health screening in preschool children with ASDs was associated with their cognitive functioning (p = 0.001), social skills development (p = 0.002), communication skills development (p < 0.001), reading skills (p < 0.001) and challenging behaviours (p = 0.06). In regression analyses accounting for age (in months) and gender, inability to cooperate with an oral health screening was associated with high level of challenging behaviours (OR 10.50, 95 % CI 2.89-38.08, p < 0.001) and reduced cognitive functioning (OR 5.29, 95 % CI 1.14-24.61, p = 0.034). Age (in months) was positively associated with likelihood of cooperative behaviour with an oral health screening (OR 1.06, 95 % CI 1.03, 1.08, p < 0.001). Feasibility of conducting population-wide oral health screening among preschool children with ASDs is associated with their developmental profiles; and in particular levels of cognitive functioning, and challenging behaviours.

  14. Transcriptome profiling of developmental leaf senescence in sorghum (Sorghum bicolor).

    PubMed

    Wu, Xiao-Yuan; Hu, Wei-Juan; Luo, Hong; Xia, Yan; Zhao, Yi; Wang, Li-Dong; Zhang, Li-Min; Luo, Jing-Chu; Jing, Hai-Chun

    2016-11-01

    This piece of the submission is being sent via mail. Leaf senescence is essential for the nutrient economy of crops and is executed by so-called senescence-associated genes (SAGs). Here we explored the monocot C4 model crop Sorghum bicolor for a holistic picture of SAG profiles by RNA-seq. Leaf samples were collected at four stages during developmental senescence, and in total, 3396 SAGs were identified, predominantly enriched in GO categories of metabolic processes and catalytic activities. These genes were enriched in 13 KEGG pathways, wherein flavonoid and phenylpropanoid biosynthesis and phenylalanine metabolism were overrepresented. Seven regions on Chromosomes 1, 4, 5 and 7 contained SAG 'hotspots' of duplicated genes or members of cupin superfamily involved in manganese ion binding and nutrient reservoir activity. Forty-eight expression clusters were identified, and the candidate orthologues of the known important senescence transcription factors such as ORE1, EIN3 and WRKY53 showed "SAG" expression patterns, implicating their possible roles in regulating sorghum leaf senescence. Comparison of developmental senescence with salt- and dark- induced senescence allowed for the identification of 507 common SAGs, 1996 developmental specific SAGs as well as 176 potential markers for monitoring senescence in sorghum. Taken together, these data provide valuable resources for comparative genomics analyses of leaf senescence and potential targets for the manipulation of genetic improvement of Sorghum bicolor.

  15. Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-01-01

    A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD.

  16. Heterogeneity of Developmental Dyscalculia: Cases with Different Deficit Profiles.

    PubMed

    Träff, Ulf; Olsson, Linda; Östergren, Rickard; Skagerlund, Kenny

    2016-01-01

    Developmental Dyscalculia (DD) has long been thought to be a monolithic learning disorder that can be attributed to a specific neurocognitive dysfunction. However, recent research has increasingly recognized the heterogeneity of DD, where DD can be differentiated into subtypes in which the underlying cognitive deficits and neural dysfunctions may differ. The aim was to further understand the heterogeneity of developmental dyscalculia (DD) from a cognitive psychological perspective. Utilizing four children (8-9 year-old) we administered a comprehensive cognitive test battery that shed light on the cognitive-behavioral profile of each child. The children were compared against norm groups of aged-matched peers. Performance was then contrasted against predominant hypotheses of DD, which would also give insight into candidate neurocognitive correlates. Despite showing similar mathematical deficits, these children showed remarkable interindividual variability regarding cognitive profile and deficits. Two cases were consistent with the approximate number system deficit account and also the general magnitude-processing deficit account. These cases showed indications of having domain-general deficits as well. One case had an access deficit in combination with a general cognitive deficit. One case suffered from general cognitive deficits only. The results showed that DD cannot be attributed to a single explanatory factor. These findings support a multiple deficits account of DD and suggest that some cases have multiple deficits, whereas other cases have a single deficit. We discuss a previously proposed distinction between primary DD and secondary DD, and suggest hypotheses of dysfunctional neurocognitive correlates responsible for the displayed deficits.

  17. Developmental gene expression profiles of the human pathogen Schistosoma japonicum

    PubMed Central

    Gobert, Geoffrey N; Moertel, Luke; Brindley, Paul J; McManus, Donald P

    2009-01-01

    Background The schistosome blood flukes are complex trematodes and cause a chronic parasitic disease of significant public health importance worldwide, schistosomiasis. Their life cycle is characterised by distinct parasitic and free-living phases involving mammalian and snail hosts and freshwater. Microarray analysis was used to profile developmental gene expression in the Asian species, Schistosoma japonicum. Total RNAs were isolated from the three distinct environmental phases of the lifecycle – aquatic/snail (eggs, miracidia, sporocysts, cercariae), juvenile (lung schistosomula and paired but pre-egg laying adults) and adult (paired, mature males and egg-producing females, both examined separately). Advanced analyses including ANOVA, principal component analysis, and hierarchal clustering provided a global synopsis of gene expression relationships among the different developmental stages of the schistosome parasite. Results Gene expression profiles were linked to the major environmental settings through which the developmental stages of the fluke have to adapt during the course of its life cycle. Gene ontologies of the differentially expressed genes revealed a wide range of functions and processes. In addition, stage-specific, differentially expressed genes were identified that were involved in numerous biological pathways and functions including calcium signalling, sphingolipid metabolism and parasite defence. Conclusion The findings provide a comprehensive database of gene expression in an important human pathogen, including transcriptional changes in genes involved in evasion of the host immune response, nutrient acquisition, energy production, calcium signalling, sphingolipid metabolism, egg production and tegumental function during development. This resource should help facilitate the identification and prioritization of new anti-schistosome drug and vaccine targets for the control of schistosomiasis. PMID:19320991

  18. Rearing Conditions Differentially Affect the Locomotor Behavior of Larval Zebrafish, but not Their Response to Valproate-Induced Developmental Neurotoxicity*

    EPA Science Inventory

    Zebrafish (Danio rerio) are widely used in developmental research, but still not much is known about the role of the environment in their development. Zebrafish are a highly social organism; thus exposure to, or isolation from, social environments may have profound developmental ...

  19. Rearing Conditions Differentially Affect the Locomotor Behavior of Larval Zebrafish, but not Their Response to Valproate-Induced Developmental Neurotoxicity*

    EPA Science Inventory

    Zebrafish (Danio rerio) are widely used in developmental research, but still not much is known about the role of the environment in their development. Zebrafish are a highly social organism; thus exposure to, or isolation from, social environments may have profound developmental ...

  20. Developmental Profiles of Task-Avoidant Behaviour and Reading Skills in Grades 1 and 2

    ERIC Educational Resources Information Center

    Magi, Katrin; Torppa, Minna; Lerkkanen, Marja-Kristiina; Poikkeus, Anna-Maija; Rasku-Puttonen, Helena; Nurmi, Jari-Erik

    2013-01-01

    A latent profile analysis approach was used to examine the developmental profiles of task-avoidant behaviour and reading skills in Grades 1 and 2, as well as their antecedents in kindergarten. The participants in this study were 448 children. Four different developmental profiles of task-avoidant behaviour and reading skills were identified. Our…

  1. Developmental Profiles of Task-Avoidant Behaviour and Reading Skills in Grades 1 and 2

    ERIC Educational Resources Information Center

    Magi, Katrin; Torppa, Minna; Lerkkanen, Marja-Kristiina; Poikkeus, Anna-Maija; Rasku-Puttonen, Helena; Nurmi, Jari-Erik

    2013-01-01

    A latent profile analysis approach was used to examine the developmental profiles of task-avoidant behaviour and reading skills in Grades 1 and 2, as well as their antecedents in kindergarten. The participants in this study were 448 children. Four different developmental profiles of task-avoidant behaviour and reading skills were identified. Our…

  2. Cognitive profiles of adult developmental dyslexics: theoretical implications.

    PubMed

    Reid, Agnieszka A; Szczerbinski, Marcin; Iskierka-Kasperek, Ewa; Hansen, Peter

    2007-02-01

    The aim of this study was to establish cognitive profiles of dyslexic adults on tests developed within the three main theories of developmental dyslexia: phonological, visual magnocellular and cerebellar and to investigate which theory can account for these profiles. The sample consisted of 15 Polish university students or alumni with a formal diagnosis of dyslexia, without ADHD and 15 controls matched on education, age, gender, IQ and handedness. The results revealed a striking heterogeneity of profiles. Nine dyslexics exhibited only a phonological deficit; one a phonological and a visual magnocellular deficit; a further three a phonological and a cerebellar deficit; two either a cerebellar or a visual magnocellular deficit. None of the three main theories of dyslexia can account for all the cases studied here. It is suggested that the best account of these data is in terms of different sub-types of dyslexia with different underlying causes, such as phonological, visual magnocellular and cerebellar, or a combination of these. However, an account in terms of Ramus' (Trends, Neurosci. 2004; 27(12): 720-726) model, according to which the phonological deficit is a core deficit in dyslexia and other deficits (magnocellular and cerebellar), are just co-morbid markers without a causal relationship to dyslexics' literacy difficulties, cannot currently be ruled out.

  3. Developmental gene expression profiling of mammalian, fetal orofacial tissue.

    PubMed

    Mukhopadhyay, Partha; Greene, Robert M; Zacharias, Wolfgang; Weinrich, Martin C; Singh, Saurabh; Young, William W; Pisano, M Michele

    2004-12-01

    The embryonic orofacial region is an excellent developmental paradigm that has revealed the centrality of numerous genes encoding proteins with diverse and important biological functions in embryonic growth and morphogenesis. DNA microarray technology presents an efficient means of acquiring novel and valuable information regarding the expression, regulation, and function of a panoply of genes involved in mammalian orofacial development. To identify differentially expressed genes during mammalian orofacial ontogenesis, the transcript profiles of GD-12, GD-13, and GD-14 murine orofacial tissue were compared utilizing GeneChip arrays from Affymetrix. Changes in gene expression were verified by TaqMan quantitative real-time PCR. Cluster analysis of the microarray data was done with the GeneCluster 2.0 Data Mining Tool and the GeneSpring software. Expression of >50% of the approximately 12,000 genes and expressed sequence tags examined in this study was detected in GD-12, GD-13, and GD-14 murine orofacial tissues and the expression of several hundred genes was up- and downregulated in the developing orofacial tissue from GD-12 to GD-13, as well as from GD-13 to GD-14. Such differential gene expression represents changes in the expression of genes encoding growth factors and signaling molecules; transcription factors; and proteins involved in epithelial-mesenchymal interactions, extracellular matrix synthesis, cell adhesion, proliferation, differentiation, and apoptosis. Following cluster analysis of the microarray data, eight distinct patterns of gene expression during murine orofacial ontogenesis were selected for graphic presentation of gene expression patterns. This gene expression profiling study identifies a number of potentially unique developmental participants and serves as a valuable aid in deciphering the complex molecular mechanisms crucial for mammalian orofacial development.

  4. Heterogeneity of Developmental Dyscalculia: Cases with Different Deficit Profiles

    PubMed Central

    Träff, Ulf; Olsson, Linda; Östergren, Rickard; Skagerlund, Kenny

    2017-01-01

    Developmental Dyscalculia (DD) has long been thought to be a monolithic learning disorder that can be attributed to a specific neurocognitive dysfunction. However, recent research has increasingly recognized the heterogeneity of DD, where DD can be differentiated into subtypes in which the underlying cognitive deficits and neural dysfunctions may differ. The aim was to further understand the heterogeneity of developmental dyscalculia (DD) from a cognitive psychological perspective. Utilizing four children (8–9 year-old) we administered a comprehensive cognitive test battery that shed light on the cognitive-behavioral profile of each child. The children were compared against norm groups of aged-matched peers. Performance was then contrasted against predominant hypotheses of DD, which would also give insight into candidate neurocognitive correlates. Despite showing similar mathematical deficits, these children showed remarkable interindividual variability regarding cognitive profile and deficits. Two cases were consistent with the approximate number system deficit account and also the general magnitude-processing deficit account. These cases showed indications of having domain-general deficits as well. One case had an access deficit in combination with a general cognitive deficit. One case suffered from general cognitive deficits only. The results showed that DD cannot be attributed to a single explanatory factor. These findings support a multiple deficits account of DD and suggest that some cases have multiple deficits, whereas other cases have a single deficit. We discuss a previously proposed distinction between primary DD and secondary DD, and suggest hypotheses of dysfunctional neurocognitive correlates responsible for the displayed deficits. PMID:28101068

  5. Young Children with Cri-du-Chat: Genetic, Developmental, and Behavioral Profiles.

    ERIC Educational Resources Information Center

    Baird, Samera M.; Campbell, Dennis; Ingram, Rebecca; Gomez, Caroline

    2001-01-01

    This paper describes the developmental and behavioral patterns of 13 prelinguistic children (ages 11 to 47 months) with Cri-du-chat syndrome (CDCS). Parents provided demographic and genetic information, descriptions of their child's typical behavior, and completed a developmental checklist. Developmental, behavioral, and genetic profiles are…

  6. Rearing Conditions Differentially Affect the Locomotor Behavior of Larval Zebrafish, but not their Response to Valproate-Induced Developmental Neurotoxicity

    EPA Science Inventory

    Zebrafish (Dania rerio) are widely used in developmental research, but little is known about the role environment may play in their development. Zebrafish are a highly social organism; thus exposure to or isolation from social environments may have profound effects. Details of re...

  7. Neurotoxicity of FireMaster 550® in zebrafish (Danio rerio): Chronic developmental and acute adolescent exposures

    PubMed Central

    Bailey, J.M.; Levin, E.D.

    2015-01-01

    BACKGROUND FireMaster® 550 (FM 550) is the second most commonly used flame retardant (FR) product in consumer goods and has been detected in household dust samples. However, neurobehavioral effects associated with exposure have not been characterized in detail. We investigated the behavioral effects of FM 550 in zebrafish to facilitate the integration of the cellular and molecular effects of FM 550 with its behavioral consequences. The effects of developmental FM 550 exposure on zebrafish larvae swimming shortly after the end of exposure as well as the persisting effects of this exposure on adolescent behavior were studied. In addition, the acute effects of FM 550 on behavior with exposure during adolescence in zebrafish were studied. METHODS Developmental exposure to 0, 0.01, 0.1 or 1 mg/L of FM 550 via immersion spanned 0–5 days post fertilization, with larval testing on day 6 and adolescent testing on days 40–45. Acute adolescent (45 dpf) exposure was to 0, 1.0 or 3.0 mg/L of FM 550 via immersion, for 24 hrs, with testing 2 hr or 1 week later. The vehicle condition was colony tank water with .0004% (developmental) or .0012% (adolescent) DMSO. Zebrafish behavior was characterized across several domains including learning, social affiliation, sensorimotor function, predator escape, and novel environment exploration. RESULTS Persisting effects of developmental FM 550 exposure included a significant (p < 0.01) reduction in social behavior among all dose groups. Acute FM550 exposure during adolescence caused hypoactivity and reduced social behavior (p’s < 0.05) when the fish were tested 2 hr after exposure. These effects were attenuated at the 1 week post exposure testing point. DISCUSSION Taken together, these data indicate that FM 550 may cause persisting neurobehavioral alterations to social behavior in the absence of perturbations along other behavioral domains and that developmental exposure is more costly to the organism than acute adolescent exposure

  8. Identification of neurotoxic cytokines by profiling Alzheimer's disease tissues and neuron culture viability screening.

    PubMed

    Wood, Levi B; Winslow, Ashley R; Proctor, Elizabeth A; McGuone, Declan; Mordes, Daniel A; Frosch, Matthew P; Hyman, Bradley T; Lauffenburger, Douglas A; Haigis, Kevin M

    2015-11-13

    Alzheimer's disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death.

  9. Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles.

    PubMed

    Melega, William P; Jorgensen, Matthew J; Laćan, Goran; Way, Baldwin M; Pham, Jamie; Morton, Grenvill; Cho, Arthur K; Fairbanks, Lynn A

    2008-05-01

    Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 microM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.

  10. Neurotoxicity and gene-expressed profile in brain-injured mice caused by exposure to titanium dioxide nanoparticles.

    PubMed

    Ze, Yuguan; Hu, Renping; Wang, Xiaochun; Sang, Xuezi; Ze, Xiao; Li, Bi; Su, Junju; Wang, Yuan; Guan, Ning; Zhao, Xiaoyang; Gui, Suxin; Zhu, Liyuan; Cheng, Zhe; Cheng, Jie; Sheng, Lei; Sun, Qingqing; Wang, Ling; Hong, Fashui

    2014-02-01

    Titanium dioxide nanoparticles (TiO2 NPs) are widely used in toothpastes, sunscreens, and products for cosmetic purpose that the human use daily. Although the neurotoxicity induced by TiO2 NPs has been demonstrated, very little is known about the molecular mechanisms underlying the brain cognition and behavioral injury. In this study, mice were exposed to 2.5, 5, and 10 mg/kg body weight (BW) TiO2 NPs by nasal administration for 90 consecutive days, respectively, and their brains' injuries and brain gene-expressed profile were investigated. Our findings showed that TiO2 NPs could be translocated and accumulated in brain, led to oxidative stress, overproliferation of all glial cells, tissue necrosis as well as hippocampal cell apoptosis. Furthermore, microarray data showed significant alterations in the expression of 249 known function genes, including 113 genes upregulation and 136 genes downregulation following exposure to 10 mg/kg BW TiO2 NPs, which were associated with oxidative stress, immune response, apoptosis, memory and learning, brain development, signal transduction, metabolic process, DNA repair, response to stimulus, and cellular process. Especially, significant increases in Col1a1, serine/threonine-protein kinase 1, Ctnnb1, cysteine-serine-rich nuclear protein-1, Ddit4, Cyp2e1, and Krev interaction trapped protein 1 (Krit1) expressions and great decreases in DA receptor D2, Neu1, Fc receptor-like molecules, and Dhcr7 expressions following long-term exposure to TiO2 NPs resulted in neurogenic disease states in mice. Therefore, these genes may be potential biomarkers of brain toxicity caused by TiO2 NPs exposure, and the application of TiO2 NPs should be carried out cautiously.

  11. Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs.

    PubMed

    Beker van Woudenberg, Anna; Snel, Cor; Rijkmans, Eke; de Groot, Didima; Bouma, Marga; Hermsen, Sanne; Piersma, Aldert; Menke, Aswin; Wolterbeek, André

    2014-11-01

    To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH) and levetiracetam (LEV). For VPA, histopathology was the most sensitive parameter, showing effects already at 60μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180μM. For ETH, all endpoints showed similar sensitivity (6.6mM), whereas MA was the most sensitive parameter for LEV (40mM). Inclusion of kinetics did not alter the absolute ranking of the compounds, but the relative potency was changed considerably. Taking all together, this demo-case study showed that inclusion of multiple-endpoints in ZET may increase the sensitivity of the assay, contribute to the elucidation of the mode of toxic action and to a better definition of the applicability domain of ZET.

  12. Developmental neurotoxicity: do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria.

    PubMed

    Costa, L G; Guizzetti, M; Burry, M; Oberdoerster, J

    2002-02-28

    Developmental neurotoxicity can be ascribed to in utero exposure to exogenous substances or to exposure of the fetus to endogenous compounds that accumulate because of genetic mutations. One of the best recognized human neuroteratogens is ethanol. The Fetal Alcohol Syndrome (FAS) is characterized by growth deficiency, particular facial features, and central nervous system (CNS) dysfunctions (mental retardation, microencephaly and brain malformations). Abuse of toluene by pregnant women can lead to an embryopathy (fetal solvent syndrome, (FSS)) whose characteristics are similar to FAS. Phenylketonuria (PKU) is a genetic defect in phenylalanine (Phe) metabolism. Offspring of phenylketonuric mothers not under strict dietary control are born with maternal PKU (mPKU), a syndrome with similar characteristics as FAS and FSS. While ethanol has been shown to cause neuronal death, no such evidence is available for toluene or Phe and/or its metabolites. On the other hand, alterations in astrocyte proliferation and maturation have been found, mostly in in vitro studies, which may represent a potential common mode of action for at least some of the CNS effects found in FAS, mPKU, and FSS. Further in vivo and in vitro studies should validate this hypothesis and elucidate possible molecular targets.

  13. Acrylamide neurotoxicity.

    PubMed

    Erkekoglu, Pinar; Baydar, Terken

    2014-02-01

    Acrylamide, a food contaminant, belongs to a large class of structurally similar toxic chemicals, 'type-2 alkenes', to which humans are widely exposed. Besides, occupational exposure to acrylamide has received wide attention through the last decades. It is classified as a neurotoxin and there are three important hypothesis considering acrylamide neurotoxicity: inhibition of kinesin-based fast axonal transport, alteration of neurotransmitter levels, and direct inhibition of neurotransmission. While many researchers believe that exposure of humans to relatively low levels of acrylamide in the diet will not result in clinical neuropathy, some neurotoxicologists are concerned about the potential for its cumulative neurotoxicity. It has been shown in several studies that the same neurotoxic effects can be observed at low and high doses of acrylamide, with the low doses simply requiring longer exposures. This review is focused on the neurotoxicity of acrylamide and its possible outcomes.

  14. Spanish developmental dyslexia: prevalence, cognitive profile, and home literacy experiences.

    PubMed

    Jiménez, Juan E; Rodríguez, Cristina; Ramírez, Gustavo

    2009-06-01

    This study was designed to examine the prevalence, cognitive profile, and home literacy experiences in subtypes of Spanish developmental dyslexia. The subtyping procedure used comparison with chronological-age-matched and reading-level controls on reaction times and accuracy responses to high-frequency words and pseudowords. Using regression-based procedures, 8 phonological dyslexics and 16 surface dyslexics were identified from a sample of 35 dyslexic fourth graders by comparing them with chronological-age-matched controls on reaction times to high-frequency word and pseudoword reading. However, when the dyslexic subtypes were defined by reference to reading-level controls, 12 phonological dyslexics were defined but only 5 surface dyslexics were identified. Both dyslexic subtypes showed a deficit in phonological awareness, but children with surface dyslexia also showed a deficit in orthographical processing assessed by a homophone comprehension task. This deficit was associated with poor home literacy experiences, with the group of parents with children matched in reading age, in comparison with the group of parents with children with surface dyslexia, reporting more literacy home experiences.

  15. Developmental long trace profiler using optimally aligned mirror based pentaprism

    SciTech Connect

    Barber, Samuel K; Morrison, Gregory Y.; Yashchuk, Valeriy V.; Gubarev, Mikhail V.; Geckeler, Ralf D.; Buchheim, Jana; Siewert, Frank; Zeschke, Thomas

    2010-07-21

    A low-budget surface slope measuring instrument, the Developmental Long Trace Profiler (DLTP), was recently brought into operation at the Advanced Light Source Optical Metrology Laboratory [Nucl. Instr. and Meth. A 616, 212-223 (2010)]. The instrument is based on a precisely calibrated autocollimator and a movable pentaprism. The capability of the DLTP to achieve sub-microradian surface slope metrology has been verified via cross-comparison measurements with other high-performance slope measuring instruments when measuring the same high-quality test optics. In the present work, a further improvement of the DLTP is achieved by replacing the existing bulk pentaprism with a specially designed mirror based pentaprism. A mirror based pentaprism offers the possibility to eliminate systematic errors introduced by inhomogeneity of the optical material and fabrication imperfections of a bulk pentaprism. We provide the details of the mirror based pentaprism design and describe an original experimental procedure for precision mutual alignment of the mirrors. The algorithm of the alignment procedure and its efficiency are verified with rigorous ray tracing simulations. Results of measurements of a spherically curved test mirror and a flat test mirror using the original bulk pentaprism are compared with measurements using the new mirror based pentaprism, demonstrating the improved performance.

  16. Developmental long trace profiler using optimally aligned mirror based pentaprism

    SciTech Connect

    Barber, Samuel K; Morrison, Gregory Y; Yashchuk, Valeriy V; Gubarev, Mikhail V; Geckeler, Ralf D.; Buchheim, Jana; Siewert, Frank; Zeschke, Thomas

    2010-12-20

    A low-budget surface slope measuring instrument, the Developmental Long Trace Profiler (DLTP), was recently brought into operation at the Advanced Light Source Optical Metrology Laboratory. The instrument is based on a precisely calibrated autocollimator and a movable pentaprism. The capability of the DLTP to achieve sub-microradian surface slope metrology has been verified via cross-comparison measurements with other high-performance slope measuring instruments when measuring the same high-quality test optics. In the present work, a further improvement of the DLTP is achieved by replacing the existing bulk pentaprism with a specially designed mirror based pentaprism. A mirror based pentaprism offers the possibility to eliminate systematic errors introduced by inhomogeneity of the optical material and fabrication imperfections of a bulk pentaprism. We provide the details of the mirror based pentaprism design and describe an original experimental procedure for precision mutual alignment of the mirrors. The algorithm of the alignment procedure and its efficiency are verified with rigorous ray tracing simulations. Results of measurements of a spherically curved test mirror and a flat test mirror using the original bulk pentaprism are compared with measurements using the new mirror based pentaprism, demonstrating the improved performance.

  17. Developmental Neurotoxic Effects of Percutaneous Drug Delivery: Behavior and Neurochemical Studies in C57BL/6 Mice

    PubMed Central

    Lv, Wenting; Huang, Qiaoling; Fu, Mengsi; Cai, Minxuan; He, Qiangqiang

    2016-01-01

    Dermatosis often as a chronic disease requires effective long-term treatment; a comprehensive evaluation of mental health of dermatology drug does not receive enough attention. An interaction between dermatology and psychiatry has been increasingly described. Substantial evidence has accumulated that psychological stress can be associated with pigmentation, endocrine and immune systems in skin to create the optimal responses against pathogens and other physicochemical stressors to maintain or restore internal homeostasis. Additionally, given the common ectodermal origin shared by the brain and skin, we are interested in assessing how disruption of skin systems (pigmentary, endocrine and immune systems) may play a key role in brain functions. Thus, we selected three drugs (hydroquinone, isotretinoin, tacrolimus) with percutaneous excessive delivery to respectively intervene in these systems and then evaluate the potential neurotoxic effects. Firstly, C57BL/6 mice were administrated a dermal dose of hydroquinone cream, isotretinoin gel or tacrolimus ointment (2%, 0.05%, 0.1%, respectively, 5 times of the clinical dose). Behavioral testing was performed and levels of proteins were measured in the hippocampus. It was found that mice treated with isotretinoin or tacrolimus, presented a lower activity in open-field test and obvious depressive-like behavior in tail suspension test. Besides, they damaged cytoarchitecture, reduced the level of 5-HT-5-HT1A/1B system and increased the expression of apoptosis-related proteins in the hippocampus. To enable sensitive monitoring the dose-response characteristics of the consecutive neurobehavioral disorders, mice received gradient concentrations of hydroquinone (2%, 4%, 6%). Subsequently, hydroquinone induced behavioral disorders and hippocampal dysfunction in a dose-dependent response. When doses were high as 6% which was 3 times higher than 2% dose, then 100% of mice exhibited depressive-like behavior. Certainly, 6% hydroquinone

  18. Dopamine quinones activate microglia and induce a neurotoxic gene expression profile: relationship to methamphetamine-induced nerve ending damage.

    PubMed

    Kuhn, Donald M; Francescutti-Verbeem, Dina M; Thomas, David M

    2006-08-01

    Methamphetamine (METH) intoxication leads to persistent damage of dopamine (DA) nerve endings of the striatum. Recently, we and others have suggested that the neurotoxicity associated with METH is mediated by extensive microglial activation. DA itself has been shown to play an obligatory role in METH neurotoxicity, possibly through the formation of quinone species. We show presently that DA-quinones (DAQ) cause a time-dependent activation of cultured microglial cells. Microarray analysis of the effects of DAQ on microglial gene expression revealed that 101 genes were significantly changed in expression, with 73 genes increasing and 28 genes decreasing in expression. Among those genes differentially regulated by DAQ were those often associated with neurotoxic conditions including inflammation, cytokines, chemokines, and prostaglandins. In addition, microglial genes associated with a neuronally protective phenotype were among those that were downregulated by DAQ. These results implicate DAQ as one species that could cause early activation of microglial cells in METH intoxication, manifested as an alteration in the expression of a broad biomarker panel of genes. These results also link oxidative stress, chemical alterations in DA to its quinone, and microglial activation as part of a cascade of glial-neuronal crosstalk that can amplify METH-induced neurotoxicity.

  19. Neurotrophic factor mediated neuronal differentiation of human cord blood mesenchymal stem cells and their applicability to assess the developmental neurotoxicity.

    PubMed

    Jahan, Sadaf; Kumar, Dipak; Kumar, Ashvini; Rajpurohit, Chetan Singh; Singh, Shripriya; Srivastava, Akriti; Pandey, Ankita; Pant, A B

    2017-01-22

    Plasticity and developmental capacity of stem cells have now been established as a promising tool to restore the degenerative disorders. The linearity differentiation of human mesenchymal stem cells (hMSCs) into adipogenic, chondrogenic, osteogenic and even in neuronal subtypes has been demonstrated. The number of xenobiotics such as dexamethasone, insulin, isobutyl 1-methyle xanthine and retinoic acid has been reported for the potential to differentiate hMSCs into neuronal subtypes. But, the applicability of indigenous neurotrophic factor-nerve growth factor (NGF) has not been explored for the purpose. Thus, the present investigations were carried out to study the NGF induced neuronal differentiation of hMSCs. Following the isolation, purification and characterization of hMSCs were allowed to differentiate into neuronal subtypes under the influence of NGF (50 ng/mL). At various concentrations of NGF, the neuronal makers were analysed at both mRNA and protein levels. Cells, exposed with NGF were showing the significant and gradual increase in the neuronal markers in differentiating cells. The magnitude of expression of markers was maximum at day 4 of differentiation. NGF at 50 ng/mL concentration was found to induce neuronal differentiation of hMSCs into neuronal subtypes. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

    PubMed Central

    Aschner, Michael; Ceccatelli, Sandra; Daneshian, Mardas; Fritsche, Ellen; Hasiwa, Nina; Hartung, Thomas; Hogberg, Helena T.; Leist, Marcel; Li, Abby; Mundy, William R.; Padilla, Stephanie; Piersma, Aldert H.; Bal-Price, Anna; Seiler, Andrea; Westerink, Remco H.; Zimmer, Bastian; Lein, Pamela J.

    2016-01-01

    Summary There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e. alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of >50 endpoint-specific control compounds was identified. For further test development, an additional “test” set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the >100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems. PMID:27452664

  1. Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use.

    PubMed

    Aschner, Michael; Ceccatelli, Sandra; Daneshian, Mardas; Fritsche, Ellen; Hasiwa, Nina; Hartung, Thomas; Hogberg, Helena T; Leist, Marcel; Li, Abby; Mundi, William R; Padilla, Stephanie; Piersma, Aldert H; Bal-Price, Anna; Seiler, Andrea; Westerink, Remco H; Zimmer, Bastian; Lein, Pamela J

    2017-01-01

    There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e., alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of > 50 endpoint-specific control compounds was identified. For further test development, an additional "test" set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the > 100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.

  2. Omnisphero: a high-content image analysis (HCA) approach for phenotypic developmental neurotoxicity (DNT) screenings of organoid neurosphere cultures in vitro.

    PubMed

    Schmuck, Martin R; Temme, Thomas; Dach, Katharina; de Boer, Denise; Barenys, Marta; Bendt, Farina; Mosig, Axel; Fritsche, Ellen

    2017-04-01

    Current developmental neurotoxicity (DNT) testing in animals faces major limitations, such as high cost and time demands as well as uncertainties in their methodology, evaluation and regulation. Therefore, the use of human-based 3D in vitro systems in combination with high-content image analysis (HCA) might contribute to DNT testing with lower costs, increased throughput and enhanced predictivity for human hazard identification. Human neural progenitor cells (hNPCs) grown as 3D neurospheres mimic basic processes of brain development including hNPC migration and differentiation and are therefore useful for DNT hazard identification. HCA of migrated neurospheres creates new challenges for automated evaluations because it encompasses variable cell densities, inconsistent z-layers and heterogeneous cell populations. We tackle those challenges with our Omnisphero software, which assesses multiple endpoints of the 'Neurosphere Assay.' For neuronal identification, Omnisphero reaches a true positive rate (TPR) of 83.8 % and a false discovery rate (FDR) of 11.4 %, thus being comparable to the interindividual difference among two researchers (TPR = 94.3, FDR = 11.0 %) and largely improving the results obtained by an existing HCA approach, whose TPR does not exceed 50 % at a FDR above 50 %. The high FDR of existing methods results in incorrect measurements of neuronal morphological features accompanied by an overestimation of compound effects. Omnisphero additionally includes novel algorithms to assess 'neurosphere-specific' endpoints like radial migration and neuronal density distribution within the migration area. Furthermore, a user-assisted parameter optimization procedure makes Omnisphero accessible to non-expert end users.

  3. Developmental neurotoxicity of Propylthiouracil (PTU) in rats: Relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes

    SciTech Connect

    Axelstad, Marta Hansen, Pernille Reimar; Boberg, Julie; Bonnichsen, Mia; Nellemann, Christine; Lund, Soren Peter; Hougaard, Karin Sorig; Hass, Ulla

    2008-10-01

    Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation day (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T{sub 4}) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T{sub 4} during development. This supports the hypothesis that decreased T{sub 4} may be a relevant predictor for long-lasting developmental neurotoxicity.

  4. Developmental exposure to concentrated ambient ultrafine particulate matter air pollution in mice results in persistent and sex-dependent behavioral neurotoxicity and glial activation.

    PubMed

    Allen, Joshua L; Liu, Xiufang; Weston, Douglas; Prince, Lisa; Oberdörster, Günter; Finkelstein, Jacob N; Johnston, Carl J; Cory-Slechta, Deborah A

    2014-07-01

    The brain appears to be a target of air pollution. This study aimed to further ascertain behavioral and neurobiological mechanisms of our previously observed preference for immediate reward (Allen, J. L., Conrad, K., Oberdorster, G., Johnston, C. J., Sleezer, B., and Cory-Slechta, D. A. (2013). Developmental exposure to concentrated ambient particles and preference for immediate reward in mice. Environ. Health Perspect. 121, 32-38), a phenotype consistent with impulsivity, in mice developmentally exposed to inhaled ultrafine particles. It examined the impact of postnatal and/or adult concentrated ambient ultrafine particles (CAPS) or filtered air on another behavior thought to reflect impulsivity, Fixed interval (FI) schedule-controlled performance, and extended the assessment to learning/memory (novel object recognition (NOR)), and locomotor activity to assist in understanding behavioral mechanisms of action. In addition, levels of brain monoamines and amino acids, and markers of glial presence and activation (GFAP, IBA-1) were assessed in mesocorticolimbic brain regions mediating these cognitive functions. This design produced four treatment groups/sex of postnatal/adult exposure: Air/Air, Air/CAPS, CAPS/Air, and CAPS/CAPS. FI performance was adversely influenced by CAPS/Air in males, but by Air/CAPS in females, effects that appeared to reflect corresponding changes in brain mesocorticolimbic dopamine/glutamate systems that mediate FI performance. Both sexes showed impaired short-term memory on the NOR. Mechanistically, cortical and hippocampal changes in amino acids raised the potential for excitotoxicity, and persistent glial activation was seen in frontal cortex and corpus callosum of both sexes. Collectively, neurodevelopment and/or adulthood CAPS can produce enduring and sex-dependent neurotoxicity. Although mechanisms of these effects remain to be fully elucidated, findings suggest that neurodevelopment and/or adulthood air pollution exposure may represent

  5. Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese.

    PubMed

    Andrade, Vanda; Mateus, M Luísa; Batoréu, M Camila; Aschner, Michael; Marreilha dos Santos, A P

    2014-12-01

    The neurotoxic metals lead (Pb), arsenic (As) and manganese (Mn) are ubiquitous contaminants occurring as mixtures in environmental settings. The three metals may interfere with enzymes of the heme bioshyntetic pathway, leading to excessive porphyrin accumulation, which per se may trigger neurotoxicity. Given the multi-mechanisms associated with metal toxicity, we posited that a single biomarker is unlikely to predict neurotoxicity that is induced by a mixture of metals. Our objective was to evaluate the ability of a combination of urinary porphyrins to predict the magnitude of motor activity impairment induced by a mixture of Pb/As/Mn. Five groups of Wistar rats were treated for 8 days with Pb (5mg/kg), As (60 mg/L) or Mn (10mg/kg), and the 3-metal mixture (same doses as the single metals) along with a control group. Motor activity was evaluated after the administration of the last dose and 24-hour (h) urine was also collected after the treatments. Porphyrin profiles were determined both in the urine and brain. Rats treated with the metal-mixture showed a significant decrease in motor parameters compared with controls and the single metal-treated groups. Both brain and urinary porphyrin levels, when combined and analyzed by multiple linear regressions, were predictable of motor activity (p<0.05). The magnitude of change in urinary porphyrin profiles was consistent with the greatest impairments in motor activity as determined by receiver operating characteristic (ROC) curves, with a sensitivity of 88% and a specificity of 96%. Our work strongly suggests that the use of a linear combination of urinary prophyrin levels accurately predicts the magnitude of motor impairments in rats that is induced by a mixture of Pb, As and Mn. Copyright © 2014. Published by Elsevier B.V.

  6. Synthesis and Neurotoxicity Profile of 2,4,5-Trihydroxymethamphetamine and its 6-(N-Acetylcystein-S-yl) Conjugate

    PubMed Central

    Neudörffer, Anne; Mueller, Melanie; Martinez, Claire-Marie; Mechan, Annis; McCann, Una; Ricaurte, George A.; Largeron, Martine

    2011-01-01

    The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, “ecstasy”) or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), plays a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in brains of these animals was not related to the unstable nature of the THMA molecule, because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA, or oxidized cyclic forms (e.g. the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo. PMID:21557581

  7. Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity.

    PubMed

    Escubedo, E; Abad, S; Torres, I; Camarasa, J; Pubill, D

    2011-01-01

    The neurotoxicity of MDMA or "Ecstasy" in rats is selectively serotonergic, while in mice it is both dopaminergic and serotonergic. MDMA metabolism may play a key role in this neurotoxicity. The function of serotonin and dopamine transporter and the effect of MDMA and its metabolites on them are essential to understand MDMA neurotoxicity. The aim of the present study was to investigate and compare the effects of MDMA and its metabolite alpha-methyldopamine (MeDA) on several molecular targets, mainly the dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA had no affinity for the serotonin transporter but competed with serotonin for its uptake. It had no persistent effects on the functionalism of the serotonin transporter, in contrast to the effect of MDMA. Moreover, MeDA inhibited the uptake of dopamine into the serotonergic terminal and also MAO(B) activity. MeDA inhibited dopamine uptake with a lower IC(50) value than MDMA. After drug washout, the inhibition by MeDA persisted while that of MDMA was significantly reduced. The effect of MDMA on the dopamine transporter is related with dopamine release from vesicular stores, as this inhibition disappeared in reserpine-treated animals. However, the effect of MeDA seems to be a persistent conformational change of this transporter. Moreover, in contrast with MDMA, MeDA did not show affinity for nicotinic receptors, so no effects of MeDA derived from these interactions can be expected. The metabolite reduced cell viability at lower concentrations than MDMA. Apoptosis plays a key role in MDMA induced cellular toxicity but necrosis is the major process involved in MeDA cytotoxicity. We conclude that MeDA could protect against the serotonergic lesion induced by MDMA but potentiate the dopaminergic lesion as a result of the persistent blockade of the dopamine transporter induced this metabolite.

  8. Vineland Adaptive Behavior Profiles in Children with Autism and Moderate to Severe Developmental Delay.

    ERIC Educational Resources Information Center

    Fenton, Gemma; D'Ardia, Caterina; Valente, Donatella; Vecchio, Ilaria del; Fabrizi, Anna; Bernabei, Paola

    2003-01-01

    A study examined adaptive behavior profiles in children (ages 21-108 months) with moderate to severe developmental delay and autism (n=23) and without autism (n=27). The Vineland Adaptive Behavior Scales was administered, and contrary to initial predictions, the sample presented fairly homogeneous adaptive behavior profiles. (Contains references.)…

  9. Vineland Adaptive Behavior Profiles in Children with Autism and Moderate to Severe Developmental Delay.

    ERIC Educational Resources Information Center

    Fenton, Gemma; D'Ardia, Caterina; Valente, Donatella; Vecchio, Ilaria del; Fabrizi, Anna; Bernabei, Paola

    2003-01-01

    A study examined adaptive behavior profiles in children (ages 21-108 months) with moderate to severe developmental delay and autism (n=23) and without autism (n=27). The Vineland Adaptive Behavior Scales was administered, and contrary to initial predictions, the sample presented fairly homogeneous adaptive behavior profiles. (Contains references.)…

  10. Developmental Assets: Profile of Youth in a Juvenile Justice Facility

    ERIC Educational Resources Information Center

    Chew, Weslee; Osseck, Jenna; Raygor, Desiree; Eldridge-Houser, Jennifer; Cox, Carol

    2010-01-01

    Background: Possessing high numbers of developmental assets greatly reduces the likelihood of a young person engaging in health-risk behaviors. Since youth in the juvenile justice system seem to exhibit many high-risk behaviors, the purpose of this study was to assess the presence of external, internal, and social context areas of developmental…

  11. Cognitive Profiles of Italian Children with Developmental Dyslexia

    ERIC Educational Resources Information Center

    Tobia, Valentina; Marzocchi, Gian Marco

    2014-01-01

    The aim of this study was to investigate verbal and nonverbal cognitive deficits in Italian students with developmental dyslexia. The performances of 32 dyslexic students, 64 age-matched typically reading controls, and 64 reading age-matched controls were compared on tests of lexical knowledge, phonological awareness, rapid automatized naming,…

  12. Cognitive Profiles of Italian Children with Developmental Dyslexia

    ERIC Educational Resources Information Center

    Tobia, Valentina; Marzocchi, Gian Marco

    2014-01-01

    The aim of this study was to investigate verbal and nonverbal cognitive deficits in Italian students with developmental dyslexia. The performances of 32 dyslexic students, 64 age-matched typically reading controls, and 64 reading age-matched controls were compared on tests of lexical knowledge, phonological awareness, rapid automatized naming,…

  13. [Developmental neurotoxicity of industrial chemicals].

    PubMed

    Labie, Dominique

    2007-10-01

    "A Silent Pandemic : Industrial Chemicals Are Impairing the Brain Development of Children Worldwide" Fetal and early childhood exposures to industrial chemicals in the environment can damage the developing brain and can lead to neurodevelopmental disorders (NDDs)--autism, attention deficit disorder (ADHD), and mental retardation. In a new review study, published in The Lancet, Philip Grandjean and Philip Landrigan from the Harvard School of Public Health systematically examined publicly available data on chemical toxicity in order to identify the industrial chemicals that are the most likely to damage the developing brain. The researchers found that 202 industrial chemicals have the capacity to damage the human brain, and they conclude that chemical pollution may have harmed the brains of millions of children worldwide. The authors conclude further that the toxic effects of industrial chemicals on children have generally been overlooked. In North Amercia, the commission for environmental cooperation, and in European Union the DEVNERTOX projects had reached to the same conclusions. We analyse this review and discuss these rather pessimistic conclusions.

  14. Transcriptomic profiling of hemp bast fibres at different developmental stages.

    PubMed

    Guerriero, Gea; Behr, Marc; Legay, Sylvain; Mangeot-Peter, Lauralie; Zorzan, Simone; Ghoniem, Mohammad; Hausman, Jean-Francois

    2017-07-10

    Bast fibres are long extraxylary cells which mechanically support the phloem and they are divided into xylan- and gelatinous-type, depending on the composition of their secondary cell walls. The former, typical of jute/kenaf bast fibres, are characterized by the presence of xylan and a high degree of lignification, while the latter, found in tension wood, as well as flax, ramie and hemp bast fibres, have a high abundance of crystalline cellulose. During their differentiation, bast fibres undergo specific developmental stages: the cells initially elongate rapidly by intrusive growth, subsequently they cease elongation and start to thicken. The goal of the present study is to provide a transcriptomic close-up of the key events accompanying bast fibre development in textile hemp (Cannabis sativa L.), a fibre crop of great importance. Bast fibres have been sampled from different stem regions. The developmental stages corresponding to active elongation and cell wall thickening have been studied using RNA-Seq. The results show that the fibres sampled at each stem region are characterized by a specific transcriptomic signature and that the major changes in cell wall-related processes take place at the internode containing the snap point. The data generated also identify several interesting candidates for future functional analysis.

  15. Anxiety Profiles in Children with and without Developmental Coordination Disorder

    ERIC Educational Resources Information Center

    Pratt, Michelle L.; Hill, Elisabeth L.

    2011-01-01

    Previous work has highlighted that children diagnosed with DCD may be at risk of greater problems related to emotional wellbeing. However, to date much work has relied on population based samples, and anxiety has not been examined within a group of children given a clinical diagnosis of DCD. Additionally, the profile of individual differences has…

  16. Pathway Profiling and Tissue Modeling of Developmental Toxicity

    EPA Science Inventory

    High-throughput and high-content screening (HTS-HCS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. EPA’s ToxCast™ project, and the broader Tox21 consortium, in addition t...

  17. Pathway Profiling and Tissue Modeling of Developmental Toxicity

    EPA Science Inventory

    High-throughput and high-content screening (HTS-HCS) studies are providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential toxicity. EPA’s ToxCast™ project, and the broader Tox21 consortium, in addition t...

  18. Developmental expression profiles of Celsr (Flamingo) genes in the mouse.

    PubMed

    Tissir, F; De-Backer, O; Goffinet, A M; Lambert de Rouvroit, C

    2002-03-01

    Celsr, also called Flamingo (Fmi) genes encode proteins of the cadherin superfamily. Celsr cadherins are seven-pass transmembrane proteins with nine cadherin repeats in the extracellular domain, and an anonymous intracellular C-terminus. The Drosophila Fmi gene regulates epithelial planar cell polarity and dendritic field deployment. The three Flamingo gene orthologs in man and rodents are named, respectively, CELSR1-3 and Celsr1-3. Celsr1 and 2 are expressed during early development, in the brain and epithelia. In this report, we characterized further Celsr genes in the mouse, and examined their developmental pattern of expression. Each Celsr is expressed prominently in the developing brain following a specific pattern, suggesting that they serve distinct functions.

  19. Developmental Profiles of Infant EEG: Overlap with Transient Cortical Circuits

    PubMed Central

    Myers, M.M.; Grieve, P.G.; Izraelit, A.; Fifer, W.P.; Isler, J.R.; Darnall, R.A.; Stark, R.I.

    2012-01-01

    Objective To quantify spectral power in frequency specific bands and commonly observed types of bursting activities in the EEG during early human development. Methods An extensive archive of EEG data from human infants from 35 to 52 weeks postmenstrual age obtained in a prior multi-center study was analyzed using power spectrum analyses and a high frequency burst detection algorithm. Results Low frequency power increased with age; however, high frequency power decreased from 35 to 45 weeks. This unexpected decrease was largely attributable to a rapid decline in the number of high frequency bursts. Conclusions The decline in high frequency bursting activity overlaps with a developmental shift in GABA's actions on neurons from depolarizing to hyperpolarizing and the dissolution of the gap junction circuitry of the cortical subplate. PMID:22341979

  20. Cyclosporine neurotoxicity.

    PubMed

    Hauben, M

    1996-01-01

    A comprehensive search of the published literature was undertaken to identify reports providing patient-specific data relating to adverse neurologic events with cyclosporine. References cited in the articles identified by the search were manually reviewed to ensure that articles were pertinent. Studies and case reports on cyclosporine neurotoxicity in which individualized patient data were provided were included for review and analysis. Information pertaining to all aspects of cyclosporine neurotoxicity, including epidemiology, clinical manifestations, postulated mechanisms, and management implications, was evaluated. Estimates from case series suggest a 0.5-35% frequency of the disorder. Risk factors include supratherapeutic blood concentrations of cyclosporine, and pharmacokinetic and pharmacodynamic drug interactions, hypocholesterolemia, and other metabolic abnormalities. Postulated mechanisms include a vasculopathy based on cyclosporine's effect on endothelial cell synthesis of prostaglandin, and release and uptake of endothelin as well as inhibition of mitochondrial steroid 26-hydroxylase. Reported adverse events involved all levels of the neuraxis. Associated abnormalities include elevated cerebrospinal fluid protein and pleocytosis, various electroencephalogram abnormalities, and characteristic neuroimaging findings. In most patients these events were reversible with dosage reduction or withdrawal of therapy. Many reports described positive rechallenge, and in rare instances the events regressed despite continuing or reintroducing the drug.

  1. Developmental Profiles of Infants and Toddlers with Autism Spectrum Disorders Identified Prospectively in a Community-Based Setting

    ERIC Educational Resources Information Center

    Barbaro, Josephine; Dissanayake, Cheryl

    2012-01-01

    This prospective, longitudinal, study charted the developmental profiles of young children with Autism Spectrum Disorders (ASD) identified through routine developmental surveillance. 109 children with Autistic Disorder (AD), "broader" ASD, and developmental and/or language delays (DD/LD) were assessed using the Mullen Scales of Early Learning…

  2. Developmental Profiles of Infants and Toddlers with Autism Spectrum Disorders Identified Prospectively in a Community-Based Setting

    ERIC Educational Resources Information Center

    Barbaro, Josephine; Dissanayake, Cheryl

    2012-01-01

    This prospective, longitudinal, study charted the developmental profiles of young children with Autism Spectrum Disorders (ASD) identified through routine developmental surveillance. 109 children with Autistic Disorder (AD), "broader" ASD, and developmental and/or language delays (DD/LD) were assessed using the Mullen Scales of Early Learning…

  3. Utility of the Revised Denver Developmental Screening Test and the Developmental Profile II in Identifying Preschool Children with Cognitive, Language, and Motor Problems.

    ERIC Educational Resources Information Center

    German, Michael L.

    1982-01-01

    Scores of 84 referred preschoolers on the Revised Denver Developmental Screening Test and the Developmental Profile II were compared with subsequent standardized tests of cognitive, motor, and language ability. Results suggested that both instruments are imperfect yet useful tools. (Author/CL)

  4. Number Processing and Heterogeneity of Developmental Dyscalculia: Subtypes with Different Cognitive Profiles and Deficits

    ERIC Educational Resources Information Center

    Skagerlund, Kenny; Träff, Ulf

    2016-01-01

    This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with…

  5. Specific Syntactic Complexity: Developmental Profiling of Individuals Based on an Annotated Learner Corpus

    ERIC Educational Resources Information Center

    Vyatkina, Nina

    2013-01-01

    This study tracks the development of syntactic complexity in the writing of two beginning German as a second language learners with English as a first language over four semesters of collegiate language study by using developmental profiling techniques applied to an annotated learner corpus. The focus of the investigation is on individual…

  6. Specific Syntactic Complexity: Developmental Profiling of Individuals Based on an Annotated Learner Corpus

    ERIC Educational Resources Information Center

    Vyatkina, Nina

    2013-01-01

    This study tracks the development of syntactic complexity in the writing of two beginning German as a second language learners with English as a first language over four semesters of collegiate language study by using developmental profiling techniques applied to an annotated learner corpus. The focus of the investigation is on individual…

  7. Cognitive Profiling in Chinese Developmental Dyslexia with Attention-Deficit/Hyperactivity Disorders

    ERIC Educational Resources Information Center

    Chan, Won Shing Raymond; Hung, Se Fong; Liu, Suet Nga; Lee, Cheuk Kiu Kathy

    2008-01-01

    The cognitive profiles of children with Developmental Reading Disorder (RD) and Attention-Deficit/Hyperactivity Disorders (ADHD) have been extensively studied in alphabetic language communities. Deficits in phonological processing and rapid naming have been implicated as core features of RD although whether the latter is a deficit specific to RD…

  8. WISC-III Index Score Profiles of 520 Swedish Children with Pervasive Developmental Disorders

    ERIC Educational Resources Information Center

    Zander, Eric; Dahlgren, Sven Olof

    2010-01-01

    WISC-III (Wechsler, 1991) index score profiles and their characteristics were examined with traditional statistics in a large Swedish sample consisting of children with autistic disorder (n = 85), Asperger's disorder (n = 341), or pervasive developmental disorders not otherwise specified (PDD-NOS; n = 94). There was a clear and significant…

  9. Number Processing and Heterogeneity of Developmental Dyscalculia: Subtypes with Different Cognitive Profiles and Deficits

    ERIC Educational Resources Information Center

    Skagerlund, Kenny; Träff, Ulf

    2016-01-01

    This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with…

  10. Epigenetic profile of developmentally important genes in bovine oocytes.

    PubMed

    Heinzmann, J; Hansmann, T; Herrmann, D; Wrenzycki, C; Zechner, U; Haaf, T; Niemann, H

    2011-03-01

    Assisted reproductive technologies are associated with an increased incidence of epigenetic aberrations, specifically in imprinted genes. Here, we used the bovine oocyte as a model to determine putative epigenetic mutations at three imprinted gene loci caused by the type of maturation, either in vitro maturation (IVM) in Tissue Culture Medium 199 (TCM) or modified synthetic oviduct fluid (mSOF) medium, or in vivo maturation. We applied a limiting dilution approach and direct bisulfite sequencing to analyze the methylation profiles of individual alleles (DNA molecules) for H19/IGF2, PEG3, and SNRPN, which are each associated with imprinting defects in humans and/or the mouse model, and are known to be differentially methylated in bovine embryos. Altogether, we obtained the methylation patterns of 203 alleles containing 4,512 CpG sites from immature oocytes, 213 alleles with 4,779 CpG sites from TCM-matured oocytes, 215 alleles/4,725 CpGs in mSOF-matured oocytes, and 78 alleles/1,672 CpGs from in vivo-matured oocytes. The total rate of individual CpGs and entire allele methylation errors did not differ significantly between the two IVM and the in vivo group, indicating that current IVM protocols have no or only marginal effects on these critical epigenetic marks. Furthermore, the mRNA expression profiles of the three imprinted genes and a panel of eight other genes indicative of oocyte competence were determined by quantitative real-time PCR. We found different mRNA expression profiles between in vivo-matured oocytes versus their in vitro-matured counterparts, suggesting an influence on regulatory mechanisms other than DNA methylation.

  11. [Cognitive Profiles of Preschool Children with Developmental Coordination Disorders and ADHD].

    PubMed

    Jascenoka, Julia; Korsch, Franziska; Petermann, Franz; Petermann, Ulrike

    2015-01-01

    Cognitive Profiles of Preschool Children with Developmental Coordination Disorders and ADHD Studies confirm that developmental coordination disorders (DCD) are often accompanied by ADHD. It is important to know why children with combined disorders show a special profile in a common intelligence test (WPPSI-III). For this purpose, the WPPSI-III results of a total of 125 children aged five to six years with diagnosed isolated DCD, isolated ADHD, combined disorders and a normative sample were compared. Children with isolated ADHD showed the best cognitive profile. Children of all three diagnosis subgroups presented significantly poorer abilities in all WPPSI-III scales than the normative sample. In comparison with preschoolers showing isolated ADHD, children with DCD and ADHD have a significant lower Processing Speed Quotient.

  12. Does "Tiger Parenting" Exist? Parenting Profiles of Chinese Americans and Adolescent Developmental Outcomes.

    PubMed

    Kim, Su Yeong; Wang, Yijie; Orozco-Lapray, Diana; Shen, Yishan; Murtuza, Mohammed

    2013-03-01

    "Tiger parenting," as described by Chua (2011), has put parenting in Asian American families in the spotlight. The current study identified parenting profiles in Chinese American families and explored their effects on adolescent adjustment. In a three-wave longitudinal design spanning eight years, from early adolescence to emerging adulthood, adolescents (54% female), fathers and mothers from 444 Chinese American families reported on eight parenting dimensions (e.g., warmth and shaming) and six developmental outcomes (e.g., GPA and academic pressure). Latent profile analyses on the eight parenting dimensions demonstrated four parenting profiles: supportive, tiger, easygoing, and harsh parenting. Over time, the percentage of parents classified as tiger parents decreased among mothers but increased among fathers. Path analyses showed that the supportive parenting profile, which was the most common, was associated with the best developmental outcomes, followed by easygoing parenting, tiger parenting, and harsh parenting. Compared with the supportive parenting profile, a tiger parenting profile was associated with lower GPA and educational attainment, as well as less of a sense of family obligation; it was also associated with more academic pressure, more depressive symptoms and a greater sense of alienation. The current study suggests that, contrary to the common perception, tiger parenting is not the most typical parenting profile in Chinese American families, nor does it lead to optimal adjustment among Chinese American adolescents.

  13. Does “Tiger Parenting” Exist? Parenting Profiles of Chinese Americans and Adolescent Developmental Outcomes

    PubMed Central

    Kim, Su Yeong; Wang, Yijie; Orozco-Lapray, Diana; Shen, Yishan; Murtuza, Mohammed

    2013-01-01

    “Tiger parenting,” as described by Chua (2011), has put parenting in Asian American families in the spotlight. The current study identified parenting profiles in Chinese American families and explored their effects on adolescent adjustment. In a three-wave longitudinal design spanning eight years, from early adolescence to emerging adulthood, adolescents (54% female), fathers and mothers from 444 Chinese American families reported on eight parenting dimensions (e.g., warmth and shaming) and six developmental outcomes (e.g., GPA and academic pressure). Latent profile analyses on the eight parenting dimensions demonstrated four parenting profiles: supportive, tiger, easygoing, and harsh parenting. Over time, the percentage of parents classified as tiger parents decreased among mothers but increased among fathers. Path analyses showed that the supportive parenting profile, which was the most common, was associated with the best developmental outcomes, followed by easygoing parenting, tiger parenting, and harsh parenting. Compared with the supportive parenting profile, a tiger parenting profile was associated with lower GPA and educational attainment, as well as less of a sense of family obligation; it was also associated with more academic pressure, more depressive symptoms and a greater sense of alienation. The current study suggests that, contrary to the common perception, tiger parenting is not the most typical parenting profile in Chinese American families, nor does it lead to optimal adjustment among Chinese American adolescents. PMID:23646228

  14. Gene expression profile of brain regions reflecting aberrations in nervous system development targeting the process of neurite extension of rat offspring exposed developmentally to glycidol.

    PubMed

    Akane, Hirotoshi; Saito, Fumiyo; Shiraki, Ayako; Imatanaka, Nobuya; Akahori, Yumi; Itahashi, Megu; Wang, Liyun; Shibutani, Makoto

    2014-12-01

    We previously found that exposure to glycidol at 1000 ppm in drinking water caused axonopathy in maternal rats and aberrations in late-stage hippocampal neurogenesis, targeting the process of neurite extension in offspring. To identify the profile of developmental neurotoxicity of glycidol, pregnant Sprague-Dawley rats were given drinking water containing glycidol from gestational day 6 until weaning on day 21 after delivery, and offspring at 0, 300 and 1000 ppm were subjected to region-specific global gene expression profiling. Four brain regions were selected to represent both cerebral and cerebellar tissues, i.e., the cingulate cortex, corpus callosum, hippocampal dentate gyrus and cerebellar vermis. Downregulated genes in the dentate gyrus were related to axonogenesis (Nfasc), myelination (Mal, Mrf and Ugt8), and cell proliferation (Aurkb and Ndc80) at ≥ 300 ppm, and upregulated genes were related to neural development (Frzb and Fzd6) at 1000 ppm. Upregulation was observed for genes related to myelination (Kl, Igf2 and Igfbp2) in the corpus callosum and axonogenesis and neuritogenesis (Efnb3, Tnc and Cd44) in the cingulate cortex, whereas downregulation was observed for genes related to synaptic transmission (Thbs2 and Ccl2) in the cerebellar vermis; all of these changes were mostly observed at 1000 ppm. Altered gene expression of Cntn3, which functions on neurite outgrowth-promotion, was observed in all four brain regions at 1000 ppm. Gene expression profiles suggest that developmental exposure to glycidol affected plasticity of neuronal networks in the broad brain areas, and dentate gyrus neurogenesis may be the sensitive target of this type of toxicity.

  15. Beyond optimal performance: mental toughness profiles and developmental success in adolescent cricketers.

    PubMed

    Gucciardi, Daniel F; Jones, Martin Ian

    2012-02-01

    The purposes of the current study were to identify mental toughness profiles in adolescent cricketers and examine differences between these profiles on developmental assets and negative emotional states. A sample of 226 community cricketers (125 New Zealanders and 101 Australians; male n = 210) aged between 10 and 18 years (M(age) = 14.41 years; SD = 2.11) completed a multisection, online survey containing measures of mental toughness, developmental assets, and negative emotional states. The results of hierarchical (Ward's method) and nonhierarchical (k means) cluster analyses revealed three mental toughness profiles characterized by low, moderate, and high levels of all five mental toughness assets (i.e., affective intelligence, desire to achieve, self-belief, attentional control, resilience). Those cricketers with high levels of mental toughness reported possession of more developmental assets and lower levels of negative emotional states when compared with cricketers with the moderate levels of mental toughness. No statistically significant differences existed between the moderate and low levels of mental toughness profiles. These findings provided preliminary evidence to suggest that mental toughness might be viewed not only from the traditional view of optimal performance but also from a stance that may represent a contextually salient representation of thriving in youth sport settings.

  16. Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay.

    PubMed

    Colaianna, Marilena; Ilmjärv, Sten; Peterson, Hedi; Kern, Ilse; Julien, Stephanie; Baquié, Mathurin; Pallocca, Giorgia; Bosgra, Sieto; Sachinidis, Agapios; Hengstler, Jan G; Leist, Marcel; Krause, Karl-Heinz

    2017-01-01

    Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration-response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration-response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds.

  17. Hope in context: developmental profiles of trust, hopeful future expectations, and civic engagement across adolescence.

    PubMed

    Callina, Kristina Schmid; Johnson, Sara K; Buckingham, Mary H; Lerner, Richard M

    2014-06-01

    Hopeful expectations for the future have been shown to play an important role in the positive development of youth, including youth contributions to society. Although theory and some research suggest that familial socialization may influence future-oriented cognitions, little work has focused on the possible interrelation of parent-child relationships and the development of hope, particularly during adolescence. Accordingly, the first goal of this study was to identify developmental profiles of youth with respect to hopeful future expectations (HFE) and parental trust across adolescence. Next, we explored whether these developmental trajectories were related to youth Contribution, indexed by community leadership, service, and helping attitudes and behaviors. We used growth mixture modeling to simultaneously examine trajectories of adolescents' perceived connections with parents (indexed by parent trust) and HFE among 1,432 participants (59% female) from Waves 3 through 6 (Grades 7 through 10) of the 4-H Study of Positive Youth Development. A four-profile model provided the best fit to the data, with the following profiles: Moderate HFE/U-shaped Trust; Moderate HFE/Increasing Trust; Both Decreasing; and Both High Stable profiles. We then explored whether hope-trust profiles were related to youth Contribution in Wave 7. Contrary to hypotheses, results indicated that the profile reflecting the greatest discrepancy in HFE and trust across early to middle adolescence (i.e., Moderate Hope/U-shaped Trust) was associated with the highest mean Contribution scores. The implications of the findings for future theory and research are discussed.

  18. Clinical profiles for seizure remission and developmental gains after total corpus callosotomy.

    PubMed

    Iwasaki, Masaki; Uematsu, Mitsugu; Hino-Fukuyo, Naomi; Osawa, Shin-ichiro; Shimoda, Yoshiteru; Jin, Kazutaka; Nakasato, Nobukazu; Tominaga, Teiji

    2016-01-01

    This study was aimed to determine what preoperative profiles were associated with seizure remission after corpus callosotomy and whether such seizure outcome was associated with the postoperative developmental outcome. This retrospective study included 26 consecutive patients with childhood onset epilepsy who underwent one-stage total corpus callosotomy at our institution and were followed up for a minimum of 1 year. The age at surgery ranged from 13 months to 32 years (median 6 years). The association between postoperative seizure freedom and preoperative profiles, post-operative developmental gains was examined. Five patients achieved seizure freedom (Engel class I), and 10 patients achieved worthwhile reduction of seizures (class III), whereas the remaining patients had a class IV outcome. All five seizure-free patients had "lack of abnormal magnetic resonance imaging findings", "lack of proven etiology of seizures", and underwent "surgery at age 6 years or younger". These three factors were associated with seizure freedom (p<0.05, Fisher exact test). Post-operative gains in developmental quotient were significantly better in patients with seizure freedom than in those without (p<0.05, Mann Whitney U test). Our study replicated the notion that seizure remission can be achieved after total corpus callosotomy in subsets of patients with medically-uncontrolled epilepsy, and suggested that a better developmental outcome can be expected in patients benefiting from seizure freedom. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  19. Developmental changes in the protein profiles of human cardiac and skeletal muscle.

    PubMed

    Tipler, T D; Edwards, Y H; Hopkinson, D A

    1978-05-01

    1. The use of SDS electrophoresis as a tool for the analysis of development processes in man has been evaluated. 2. The protein profiles of cardiac and skeletal muscle from foetal (10--24 weeks gestation) infant and adult specimens have been analysed and striking developmental changes were found which involved all the major proteins. 3. Before 20 weeks gestation the soluble protein profile of skeletal muscle appears to consist largely of extracellular proteins. 4. Myoglobin was found in foetal cardiac muscle from 20 weeks gestation but was not demonstrable in foetal (greater than 24 weeks) skeletal muscle. Foetal and adult myoglobin were indistinguishable. 5. A limited survey of the protein patterns of brain, liver and kidney was carried out. In general these tissues show less developmental change than skeletal or cardiac muscle.

  20. Sub-microradian Surface Slope Metrology with the ALS Developmental Long Trace Profiler

    SciTech Connect

    Yashchuk, Valeriy V; Barber, Samuel; Domning, Edward E.; Kirschman, Jonathan L.; Morrison, Gregory Y.; Smith, Brian V; Siewert, Frank; Zeschke, Thomas; Geckeler, Ralf; Just, Andreas

    2009-09-11

    A new low budget slope measuring instrument, the Developmental Long Trace Profiler (DLTP), was recently brought to operation at the ALS Optical Metrology Laboratory. The design, instrumental control and data acquisition system, initial alignment and calibration procedures, as well as the developed experimental precautions and procedures are described in detail. The capability of the DLTP to achieve sub-microradian surface slope metrology is verified via cross-comparison measurements with other high performance slope measuring instruments when measuring the same high quality test optics. The directions of future work to develop a surface slope measuring profiler with nano-radian performance are also discussed.

  1. Defining Developmental Potency and Cell Lineage Trajectories by Expression Profiling of Differentiating Mouse Embryonic Stem Cells

    PubMed Central

    Aiba, Kazuhiro; Nedorezov, Timur; Piao, Yulan; Nishiyama, Akira; Matoba, Ryo; Sharova, Lioudmila V.; Sharov, Alexei A.; Yamanaka, Shinya; Niwa, Hitoshi; Ko, Minoru S. H.

    2009-01-01

    Biologists rely on morphology, function and specific markers to define the differentiation status of cells. Transcript profiling has expanded the repertoire of these markers by providing the snapshot of cellular status that reflects the activity of all genes. However, such data have been used only to assess relative similarities and differences of these cells. Here we show that principal component analysis of global gene expression profiles map cells in multidimensional transcript profile space and the positions of differentiating cells progress in a stepwise manner along trajectories starting from undifferentiated embryonic stem (ES) cells located in the apex. We present three ‘cell lineage trajectories’, which represent the differentiation of ES cells into the first three lineages in mammalian development: primitive endoderm, trophoblast and primitive ectoderm/neural ectoderm. The positions of the cells along these trajectories seem to reflect the developmental potency of cells and can be used as a scale for the potential of cells. Indeed, we show that embryonic germ cells and induced pluripotent cells are mapped near the origin of the trajectories, whereas mouse embryo fibroblast and fibroblast cell lines are mapped near the far end of the trajectories. We suggest that this method can be used as the non-operational semi-quantitative definition of cell differentiation status and developmental potency. Furthermore, the global expression profiles of cell lineages provide a framework for the future study of in vitro and in vivo cell differentiation. PMID:19112179

  2. WISC-III cognitive profiles in children with developmental dyslexia: specific cognitive disability and diagnostic utility.

    PubMed

    Moura, Octávio; Simões, Mário R; Pereira, Marcelino

    2014-02-01

    This study analysed the usefulness of the Wechsler Intelligence Scale for Children-Third Edition in identifying specific cognitive impairments that are linked to developmental dyslexia (DD) and the diagnostic utility of the most common profiles in a sample of 100 Portuguese children (50 dyslexic and 50 normal readers) between the ages of 8 and 12 years. Children with DD exhibited significantly lower scores in the Verbal Comprehension Index (except the Vocabulary subtest), Freedom from Distractibility Index (FDI) and Processing Speed Index subtests, with larger effect sizes than normal readers in Information, Arithmetic and Digit Span. The Verbal-Performance IQs discrepancies, Bannatyne pattern and the presence of FDI; Arithmetic, Coding, Information and Digit Span subtests (ACID) and Symbol Search, Coding, Arithmetic and Digit Span subtests (SCAD) profiles (full or partial) in the lowest subtests revealed a low diagnostic utility. However, the receiver operating characteristic curve and the optimal cut-off score analyses of the composite ACID; FDI and SCAD profiles scores showed moderate accuracy in correctly discriminating dyslexic readers from normal ones. These results suggested that in the context of a comprehensive assessment, the Wechsler Intelligence Scale for Children-Third Edition provides some useful information about the presence of specific cognitive disabilities in DD. Practitioner Points. Children with developmental dyslexia revealed significant deficits in the Wechsler Intelligence Scale for Children-Third Edition subtests that rely on verbal abilities, processing speed and working memory. The composite Arithmetic, Coding, Information and Digit Span subtests (ACID); Freedom from Distractibility Index and Symbol Search, Coding, Arithmetic and Digit Span subtests (SCAD) profile scores showed moderate accuracy in correctly discriminating dyslexics from normal readers. Wechsler Intelligence Scale for Children-Third Edition may provide some useful

  3. DEVELOPMENTAL CIGARETTE SMOKE EXPOSURE: HIPPOCAMPUS PROTEOME AND METABOLOME PROFILES IN LOW BIRTH WEIGHT PUPS

    PubMed Central

    Neal, Rachel E.; Chen, Jing; Jagadapillai, Rekha; Jang, HyeJeong; Abomoelak, Bassam; Brock, Guy; Greene, Robert M.; Pisano, M. Michele

    2014-01-01

    Exposure to cigarette smoke during development is linked to neurodevelopmental delays and cognitive impairment including impulsivity, attention deficit disorder, and lower IQ. However, brain region specific biomolecular alterations induced by developmental cigarette smoke exposure (CSE) remain largely unexplored. In the current molecular phenotyping study, a mouse model of ‘active’ developmental CSE (serum cotinine>50 ng/mL) spanning pre-implantation through third trimester-equivalent brain development (gestational day (GD) 1 through postnatal day (PD) 21) was utilized. Hippocampus tissue collected at the time of cessation of exposure was processed for gel-based proteomic and non-targeted metabolomic profiling with Partial Least Squares-Discriminant Analysis (PLS-DA) for selection of features of interest. Ingenuity Pathway Analysis was utilized to identify candidate molecular and metabolic pathways impacted within the hippocampus. CSE impacted glycolysis, oxidative phosphorylation, fatty acid metabolism, and neurodevelopment pathways within the developing hippocampus. PMID:24486158

  4. Developmental profiles in preschool children with autism spectrum disorders referred for intervention.

    PubMed

    Fernell, Elisabeth; Hedvall, Asa; Norrelgen, Fritiof; Eriksson, Mats; Höglund-Carlsson, Lotta; Barnevik-Olsson, Martina; Svensson, Liselotte; Holm, Annette; Westerlund, Joakim; Gillberg, Christopher

    2010-01-01

    The aim was to characterize the panorama of developmental disorders in 208 preschool children with a clinical diagnosis of autism spectrum disorder (ASD), referred to a specialized centre, the Autism Centre for Young Children (ACYC), for intervention. At the centre, a research team examined all children according to structured protocols and interviews. All available test data from their assessments prior to referral were scrutinized. The boy:girl ratio was 5.5:1. In 22% of the total group a period of regression, including speech and language, had occurred. Epilepsy had been diagnosed in 6% of the children. In 38% of the children there was a definite or highly suspected learning disability/mental retardation according to cognitive test results. About the same proportion had a developmental delay that at the time of assessment could not be definitely classified and in 23% there were clear indications of a normal intellectual function. About 40% of the group exhibited hyperactivity. Differences in expressive vocabulary and adaptive functioning were strongly related to cognitive level. About 20% of the group had AD as the dominating developmental disorder, i.e., they represented a clinical picture of "classic" autism. The majority in this group also had learning disability. Another 20%, had ASD combined with a normal intellectual level, some of these conformed to the clinical picture of Asperger syndrome. In a relatively large group (more than half) learning disability or a general developmental delay was as evident as the ASD. In a smaller group (8%) ASD criteria were questionably met. In this group attention deficits in connection with speech and language problems were prominent. The highly individual developmental profiles seen in children with ASDs have to be taken into account when planning intervention and follow-up. The children's medical characteristics also vary considerably and will be detailed in a further report. 2010 Elsevier Ltd. All rights reserved.

  5. Using Neural Progenitor Cells in High-Throughput Screens for Developmental Neurotoxicants: Triumphs and Tragedies

    EPA Science Inventory

    Current protocols for developmental neurotoxicity testing are insufficient to test thousands of commercial chemicals. Thus, development of highthroughput screens (HTS) to detect and prioritize chemicals that may cause developmental neurotoxicity is needed to improve protection of...

  6. Using Neural Progenitor Cells in High-Throughput Screens for Developmental Neurotoxicants: Triumphs and Tragedies

    EPA Science Inventory

    Current protocols for developmental neurotoxicity testing are insufficient to test thousands of commercial chemicals. Thus, development of highthroughput screens (HTS) to detect and prioritize chemicals that may cause developmental neurotoxicity is needed to improve protection of...

  7. Empirically Based Phenotypic Profiles of Children with Pervasive Developmental Disorders: Interpretation in the Light of the DSM-5

    ERIC Educational Resources Information Center

    Greaves-Lord, Kirstin; Eussen, Mart L. J. M.; Verhulst, Frank C.; Minderaa, Ruud B.; Mandy, William; Hudziak, James J.; Steenhuis, Mark Peter; de Nijs, Pieter F.; Hartman, Catharina A.

    2013-01-01

    This study aimed to contribute to the Diagnostic and Statistical Manual (DSM) debates on the conceptualization of autism by investigating (1) whether empirically based distinct phenotypic profiles could be distinguished within a sample of mainly cognitively able children with pervasive developmental disorder (PDD), and (2) how profiles related to…

  8. Empirically Based Phenotypic Profiles of Children with Pervasive Developmental Disorders: Interpretation in the Light of the DSM-5

    ERIC Educational Resources Information Center

    Greaves-Lord, Kirstin; Eussen, Mart L. J. M.; Verhulst, Frank C.; Minderaa, Ruud B.; Mandy, William; Hudziak, James J.; Steenhuis, Mark Peter; de Nijs, Pieter F.; Hartman, Catharina A.

    2013-01-01

    This study aimed to contribute to the Diagnostic and Statistical Manual (DSM) debates on the conceptualization of autism by investigating (1) whether empirically based distinct phenotypic profiles could be distinguished within a sample of mainly cognitively able children with pervasive developmental disorder (PDD), and (2) how profiles related to…

  9. Sex Biased Gene Expression Profiling of Human Brains at Major Developmental Stages.

    PubMed

    Shi, Lei; Zhang, Zhe; Su, Bing

    2016-02-16

    There are many differences in brain structure and function between males and females. However, how these differences were manifested during development and maintained through adulthood are still unclear. Here we present a time series analyses of genome-wide transcription profiles of the human brain, and we identified genes showing sex biased expression at major developmental stages (prenatal time, early childhood, puberty time and adulthood). We observed a great number of genes (>2,000 genes) showing between-sex expression divergence at all developmental stages with the greatest number (4,164 genes) at puberty time. However, there are little overlap of sex-biased genes among the major developmental stages, an indication of dynamic expression regulation of the sex-biased genes in the brain during development. Notably, the male biased genes are highly enriched for genes involved in neurological and psychiatric disorders like schizophrenia, bipolar disorder, Alzheimer's disease and autism, while no such pattern was seen for the female-biased genes, suggesting that the differences in brain disorder susceptibility between males and females are likely rooted from the sex-biased gene expression regulation during brain development. Collectively, these analyses reveal an important role of sex biased genes in brain development and neurodevelopmental disorders.

  10. Transcriptome Characterization of Dendrolimus punctatus and Expression Profiles at Different Developmental Stages

    PubMed Central

    Li, Jing; Yang, Fan; Zhang, Ai-Bing

    2016-01-01

    The pine moth Dendrolimus punctatus (Walker) is a common insect pest that confers serious damage to conifer forests in south of China. Extensive physiology and ecology studies on D. punctatus have been carried out, but the lack of genetic information has limited our understanding of the molecular mechanisms behind its development and resistance. Using RNA-seq approach, we characterized the transcriptome of this pine moth and investigated its developmental expression profiles during egg, larval, pupal, and adult stages. A total of 107.6 million raw reads were generated that were assembled into 70,664 unigenes. More than 30% unigenes were annotated by searching for homology in protein databases. To better understand the process of metamorphosis, we pairwise compared four developmental phases and obtained 17,624 differential expression genes. Functional enrichment analysis of differentially expressed genes showed positive correlation with specific physiological activities of each stage, and these results were confirmed by qRT-PCR experiments. This study provides a valuable genomic resource of D. punctatus covering all its developmental stages, and will promote future studies on biological processes at the molecular level. PMID:27560151

  11. Metabolic Profiles and Free Radical Scavenging Activity of Cordyceps bassiana Fruiting Bodies According to Developmental Stage

    PubMed Central

    Hyun, Sun-Hee; Lee, Seok-Young; Sung, Gi-Ho; Kim, Seong Hwan; Choi, Hyung-Kyoon

    2013-01-01

    The metabolic profiles of Cordyceps bassiana according to fruiting body developmental stage were investigated using gas chromatography-mass spectrometry. We were able to detect 62 metabolites, including 48 metabolites from 70% methanol extracts and 14 metabolites from 100% n-hexane extracts. These metabolites were classified as alcohols, amino acids, organic acids, phosphoric acids, purine nucleosides and bases, sugars, saturated fatty acids, unsaturated fatty acids, or fatty amides. Significant changes in metabolite levels were found according to developmental stage. Relative levels of amino acids, purine nucleosides, and sugars were higher in development stage 3 than in the other stages. Among the amino acids, valine, isoleucine, lysine, histidine, glutamine, and aspartic acid, which are associated with ABC transporters and aminoacyl-tRNA biosynthesis, also showed higher levels in stage 3 samples. The free radical scavenging activities, which were significantly higher in stage 3 than in the other stages, showed a positive correlation with purine nucleoside metabolites such as adenosine, guanosine, and inosine. These results not only show metabolic profiles, but also suggest the metabolic pathways associated with fruiting body development stages in cultivated C. bassiana. PMID:24058459

  12. Developmental profile of motor cortex transcallosal inhibition in children and adolescents.

    PubMed

    Ciechanski, Patrick; Zewdie, Ephrem; Kirton, Adam

    2017-04-05

    Transcallosal fibers facilitate interhemispheric networks involved in motor tasks. Despite their clinical relevance, interhemispheric motor control systems have not been completely defined in the developing brain. The objective of this study was to examine the developmental profile of transcallosal inhibition in healthy children and adolescents. Nineteen typically-developing right-handed participants were recruited. Two transcranial magnetic stimulation (TMS) paradigms assessed transcallosal inhibition: ipsilateral silent periods (iSP) and paired-pulse interhemispheric inhibition (IHI). TMS was applied to the motor hotspot of the first dorsal interosseous muscle. Resting motor threshold (RMT), iSP latency, duration and suppression strength, and paired-pulse IHI were measured from both hemispheres. The Purdue Pegboard Test assessed unimanual motor function. Hemispheric differences were evident for RMT and iSP latency and suppression strength, where the left hemisphere had a lower RMT, prolonged latency and greater suppression strength. iSP duration showed hemispheric symmetry. RMT and iSP latency decreased with age, whereas iSP suppression strength increased. Females showed shorter iSP latency. Children typically displayed IHI, although hemispheric differences were observed. iSP suppression strength was uniquely associated with IHI within individuals. iSP duration correlated with motor performance. TMS can characterize transcallosal inhibition in normal children and adolescents with effects of age, directionality, gender, and motor performance. Establishing this developmental profile of interhemispheric interactions will advance understanding and therapeutic strategies for pediatric motor disorders such as cerebral palsy.

  13. The sea urchin embryo as a model for mammalian developmental neurotoxicity: ontogenesis of the high-affinity choline transporter and its role in cholinergic trophic activity.

    PubMed

    Qiao, Dan; Nikitina, Lyudmila A; Buznikov, Gennady A; Lauder, Jean M; Seidler, Frederic J; Slotkin, Theodore A

    2003-11-01

    Embryonic development in the sea urchin requires trophic actions of the same neurotransmitters that participate in mammalian brain assembly. We evaluated the development of the high-affinity choline transporter, which controls acetylcholine synthesis. A variety of developmental neurotoxicants affect this transporter in mammalian brain. [3H]Hemicholinium-3 binding to the transporter was found in the cell membrane fraction at stages from the unfertilized egg to pluteus, with a binding affinity comparable with that seen in mammalian brain. Over the course of development, the concentration of transporter sites rose more than 3-fold, achieving concentrations comparable with those of cholinergically enriched mammalian brain regions. Dimethylaminoethanol (DMAE), a competitive inhibitor of choline transport, elicited dysmorphology beginning at the mid-blastula stage, with anomalies beginning progressively later as the concentration of DMAE was lowered. Pretreatment, cotreatment, or delayed treatment with acetylcholine or choline prevented the adverse effects of DMAE. Because acetylcholine was protective at a lower threshold, the DMAE-induced defects were most likely mediated by its effects on acetylcholine synthesis. Transient removal of the hyaline layer enabled a charged transport inhibitor, hemicholinium-3, to penetrate sufficiently to elicit similar anomalies, which were again prevented by acetylcholine or choline. These results indicate that the developing sea urchin possesses a high-affinity choline transporter analogous to that found in the mammalian brain, and, as in mammals, the functioning of this transporter plays a key role in the developmental, trophic activity of acetylcholine. The sea urchin model may thus be useful in high-throughput screening of suspected developmental neurotoxicants.

  14. Neurotoxic Profiles of HIV, Psychostimulant Drugs of Abuse, and their Concerted Effect on the Brain: Current Status of Dopamine System Vulnerability in NeuroAIDS

    PubMed Central

    Ferris, Mark J.; Mactutus, Charles F.; Booze, Rosemarie M.

    2008-01-01

    There are roughly 30 to 40 million HIV infected individuals in the world as of December 2007, and drug abuse directly contributes to one-third of all HIV-infections in the United States. Antiretroviral therapy has increased the lifespan of HIV-seropositives, but CNS function often remains diminished, effectively decreasing quality of life. A modest proportion may develop HIV-associated dementia, the severity and progression of which is increased with drug abuse. HIV and drugs of abuse in the CNS target subcortical brain structures and DA systems in particular. This toxicity is mediated by a number of neurotoxic mechanisms, including but not limited to, aberrant immune response and oxidative stress. Therefore, novel therapeutic strategies must be developed that can address a wide variety of disparate neurotoxic mechanisms and apoptotic cascades. This paper reviews the research pertaining to the where, what, and how of HIV and cocaine/methamphetamine toxicity in the CNS. Specifically, where these toxins most affect the brain, what aspects of the virus are neurotoxic, and how these toxins mediate neurotoxicity. PMID:18430470

  15. Reversible Lithium Neurotoxicity: Review of the Literature

    PubMed Central

    Netto, Ivan

    2012-01-01

    preventive measures were also described. Conclusions: Reversible lithium neurotoxicity presents with a certain clinical profile and precipitating factors for which there are appropriate preventive measures. This recognition will help in early diagnosis and prompt treatment of lithium neurotoxicity. PMID:22690368

  16. Developmental Profiles of Eczema, Wheeze, and Rhinitis: Two Population-Based Birth Cohort Studies

    PubMed Central

    2014-01-01

    Background The term “atopic march” has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level. Methods and Findings Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time. Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts. Conclusions The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (∼7% of those with symptoms) follow trajectory profiles resembling the atopic march. Please see later

  17. Neurotoxicity in Aquatic Systems: Evaluation of Anthropogenic Trace Substances

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity, as well as acute and developmental neurotoxicity. In this endeavor, one of our focuses is on contaminants found in drinking water. To exp...

  18. Neurotoxicity in Aquatic Systems: Evaluation of Anthropogenic Trace Substances

    EPA Science Inventory

    The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental toxicity, as well as acute and developmental neurotoxicity. In this endeavor, one of our focuses is on contaminants found in drinking water. To exp...

  19. Developmental neurotoxicity of 3,3',4,4'-tetrachloroazobenzene with thyroxine deficit: Sensitivity of glia and dentate granule neurons in the absence of behavioral changes.

    PubMed

    Harry, G Jean; Hooth, Michelle J; Vallant, Molly; Behl, Mamta; Travlos, Gregory S; Howard, James L; Price, Catherine J; McBride, Sandra; Mervis, Ron; Mouton, Peter R

    2014-09-01

    Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3',4,4'-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3'- triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND)4-21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations.

  20. Gene Expression Profiles of Chlamydophila pneumoniae during the Developmental Cycle and Iron Depletion–Mediated Persistence

    PubMed Central

    Mäurer, André P; Mehlitz, Adrian; Mollenkopf, Hans J; Meyer, Thomas F

    2007-01-01

    The obligate intracellular, gram-negative bacterium Chlamydophila pneumoniae (Cpn) has impact as a human pathogen. Little is known about changes in the Cpn transcriptome during its biphasic developmental cycle (the acute infection) and persistence. The latter stage has been linked to chronic diseases. To analyze Cpn CWL029 gene expression, we designed a pathogen-specific oligo microarray and optimized the extraction method for pathogen RNA. Throughout the acute infection, ratio expression profiles for each gene were generated using 48 h post infection as a reference. Based on these profiles, significantly expressed genes were separated into 12 expression clusters using self-organizing map clustering and manual sorting into the “early”, “mid”, “late”, and “tardy” cluster classes. The latter two were differentiated because the “tardy” class showed steadily increasing expression at the end of the cycle. The transcriptome of the Cpn elementary body (EB) and published EB proteomics data were compared to the cluster profile of the acute infection. We found an intriguing association between “late” genes and genes coding for EB proteins, whereas “tardy” genes were mainly associated with genes coding for EB mRNA. It has been published that iron depletion leads to Cpn persistence. We compared the gene expression profiles during iron depletion–mediated persistence with the expression clusters of the acute infection. This led to the finding that establishment of iron depletion–mediated persistence is more likely a mid-cycle arrest in development rather than a completely distinct gene expression pattern. Here, we describe the Cpn transcriptome during the acute infection, differentiating “late” genes, which correlate to EB proteins, and “tardy” genes, which lead to EB mRNA. Expression profiles during iron mediated–persistence led us to propose the hypothesis that the transcriptomic “clock” is arrested during acute mid-cycle. PMID

  1. Sub-microradian Surface Slope Metrology with the ALS Developmental Long Trace Profiler

    SciTech Connect

    Yashchuk, Valeriy V.; Barber, Samuel; Domning, Edward E.; Kirschman, Jonathan L.; Morrison, Gregory Y.; Smith, Brian V.; Siewert, Frank; Zeschke, Thomas; Geckeler, Ralf; Just, Andreas

    2009-06-15

    Development of X-ray optics for 3rd and 4th generation X-ray light sources with a level of surface slope precision of 0.1-0.2 {micro}rad requires the development of adequate fabrication technologies and dedicated metrology instrumentation and methods. Currently, the best performance of surface slope measurement has been achieved with the NOM (Nanometer Optical Component Measuring Machine) slope profiler at BESSY (Germany) [1] and the ESAD (Extended Shear Angle Difference) profiler at the PTB (Germany) [2]. Both instruments are based on electronic autocollimators (AC) precisely calibrated for the specific application [3] with small apertures of 2.5-5 mm in diameter. In the present work, we describe the design, initial alignment and calibration procedures, the instrumental control and data acquisition system, as well as the measurement performance of the Developmental Long Trace Profiler (DLTP) slope measuring instrument recently brought into operation at the Advanced Light Source (ALS) Optical Metrology Laboratory (OML). Similar to the NOM and ESAD, the DLTP is based on a precisely calibrated autocollimator. However, this is a reasonably low budget instrument used at the ALS OML for the development and testing of new measuring techniques and methods. Some of the developed methods have been implemented into the ALS LTP-II (slope measuring long trace profiler [4]) which was recently upgraded and has demonstrated a capability for 0.25 {micro}rad surface metrology [5]. Performance of the DLTP was verified via a number of measurements with high quality reference mirrors. A comparison with the corresponding results obtained with the world's best slope measuring instrument, the BESSY NOM, proves the accuracy of the DLTP measurements on the level of 0.1-0.2 {micro}rad depending on the curvature of a surface under test. The directions of future work to develop a surface slope measuring profiler with nano-radian performance are also discussed.

  2. Understanding developmental and adaptive cues in pine through metabolite profiling and co-expression network analysis

    PubMed Central

    Cañas, Rafael A.; Canales, Javier; Muñoz-Hernández, Carmen; Granados, Jose M.; Ávila, Concepción; García-Martín, María L.; Cánovas, Francisco M.

    2015-01-01

    Conifers include long-lived evergreen trees of great economic and ecological importance, including pines and spruces. During their long lives conifers must respond to seasonal environmental changes, adapt to unpredictable environmental stresses, and co-ordinate their adaptive adjustments with internal developmental programmes. To gain insights into these responses, we examined metabolite and transcriptomic profiles of needles from naturally growing 25-year-old maritime pine (Pinus pinaster L. Aiton) trees over a year. The effect of environmental parameters such as temperature and rain on needle development were studied. Our results show that seasonal changes in the metabolite profiles were mainly affected by the needles’ age and acclimation for winter, but changes in transcript profiles were mainly dependent on climatic factors. The relative abundance of most transcripts correlated well with temperature, particularly for genes involved in photosynthesis or winter acclimation. Gene network analysis revealed relationships between 14 co-expressed gene modules and development and adaptation to environmental stimuli. Novel Myb transcription factors were identified as candidate regulators during needle development. Our systems-based analysis provides integrated data of the seasonal regulation of maritime pine growth, opening new perspectives for understanding the complex regulatory mechanisms underlying conifers’ adaptive responses. Taken together, our results suggest that the environment regulates the transcriptome for fine tuning of the metabolome during development. PMID:25873654

  3. New Insights on Developmental Dyslexia Subtypes: Heterogeneity of Mixed Reading Profiles

    PubMed Central

    Zoubrinetzky, Rachel; Bielle, Frédérique; Valdois, Sylviane

    2014-01-01

    We examined whether classifications based on reading performance are relevant to identify cognitively homogeneous subgroups of dyslexic children. Each of the 71 dyslexic participants was selected to have a mixed reading profile, i.e. poor irregular word and pseudo-word reading performance (accuracy and speed). Despite their homogeneous reading profile, the participants were found to split into four distinct cognitive subgroups, characterized by a single phonological disorder, a single visual attention span disorder, a double deficit or none of these disorders. The two subgroups characterized by single and contrasted cognitive disorders were found to exhibit a very similar reading pattern but more contrasted spelling performance (quantitative analysis). A qualitative analysis of the error types produced in reading and spelling provided some cues about the participants' underlying cognitive deficit. The overall findings disqualify subtyping based on reading profiles as a classification method to identify cognitively homogeneous subgroups of dyslexic children. They rather show an opaque relationship between the cognitive underpinnings of developmental dyslexia and their behavioral manifestations in reading and spelling. Future neuroimaging and genetic studies should take this issue into account since synthesizing over cognitively heterogeneous children would entail potential pitfalls. PMID:24918441

  4. New insights on developmental dyslexia subtypes: heterogeneity of mixed reading profiles.

    PubMed

    Zoubrinetzky, Rachel; Bielle, Frédérique; Valdois, Sylviane

    2014-01-01

    We examined whether classifications based on reading performance are relevant to identify cognitively homogeneous subgroups of dyslexic children. Each of the 71 dyslexic participants was selected to have a mixed reading profile, i.e. poor irregular word and pseudo-word reading performance (accuracy and speed). Despite their homogeneous reading profile, the participants were found to split into four distinct cognitive subgroups, characterized by a single phonological disorder, a single visual attention span disorder, a double deficit or none of these disorders. The two subgroups characterized by single and contrasted cognitive disorders were found to exhibit a very similar reading pattern but more contrasted spelling performance (quantitative analysis). A qualitative analysis of the error types produced in reading and spelling provided some cues about the participants' underlying cognitive deficit. The overall findings disqualify subtyping based on reading profiles as a classification method to identify cognitively homogeneous subgroups of dyslexic children. They rather show an opaque relationship between the cognitive underpinnings of developmental dyslexia and their behavioral manifestations in reading and spelling. Future neuroimaging and genetic studies should take this issue into account since synthesizing over cognitively heterogeneous children would entail potential pitfalls.

  5. Sex-specific developmental profiles of juvenile hormone synthesis in honey bee larvae.

    PubMed

    Hartfelder, Klaus; de Oliveira Tozetto, Sibele; Rachinsky, Anna

    1993-02-01

    Juvenile hormone synthesis in drone larvae of the honey bee was measured by an in vitro radiochemical assay. The developmental profile of corpora allata activity in male larvae showed considerable differences from queen larvae, the presumptive reproductive females, and was comparable to workers, the sterile female morph. Drone and worker larvae, however, differed drastically in the regulation of juvenile hormone biosynthesis, as revealed by the addition of farnesoic acid to the culture medium. This precursor stimulated juvenile hormone synthesis of drone glands nearly eightfold, whereas in worker larvae it is known to lead to an accumulation of methyl farnesoate. The sex-specific differences in endocrine activity indicate a role for juvenile hormone in the expression of genetically determined sexually dimorphic characters during metamorphosis, a role not currently accounted for in models describing endocrine regulation of insect development.

  6. Neuropsychological profiles of patients with 2q37.3 deletion associated with developmental dyspraxia.

    PubMed

    Ogura, Kaeko; Takeshita, Kenzo; Arakawa, Chikako; Shimojima, Keiko; Yamamoto, Toshiyuki

    2014-12-01

    Patients with 2q37 deletions manifest brachydactyly mental retardation syndrome (BDMR). Recent advances in human molecular research have revealed that alterations in the histone deacetylase 4 gene (HDAC4) are responsible for the clinical manifestations of BDMR. Here, we report two male patients with 2q37.3 deletions. One of the patients showed a typical BDMR phenotype, and HDAC4 was included in the deletion region. HDAC4 was preserved in the other patient, and he showed a normal intelligence level with the delayed learning of complex motor skills. Detailed neuropsychological examinations revealed similar neuropsychological profiles in these two patients (visuo-spatial dyspraxia) that suggested developmental dyspraxia. These observations suggested that some other candidate genes for neuronal development exist in the telomeric region of HDAC4.

  7. Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo.

    PubMed

    Venkatesh, Ishwariya; Simpson, Matthew T; Coley, Denise M; Blackmore, Murray G

    2016-12-01

    Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro-regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve axon growth in other cell types, including combinatorial overexpression of AP1 factors, overexpression of histone acetyltransferases, and pharmacological inhibitors of histone deacetylases. This insensitivity could be due to intermediate chromatin closure at the time of culture, and highlights important differences in cell culture models used to test potential pro-regenerative interventions.

  8. Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo

    PubMed Central

    Venkatesh, Ishwariya; Simpson, Matthew T.; Coley, Denise M.; Blackmore, Murray G.

    2016-01-01

    Axon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the ability of injured neurons to re-express needed regeneration associated genes (RAGs). Adult CNS neurons may lack appropriate pro-regenerative transcription factors, or may display chromatin structure that restricts transcriptional access to RAGs. Here we performed epigenetic profiling around the promoter regions of key RAGs, and found progressive restriction across a time course of cortical maturation. These data identify a potential intrinsic constraint to axon growth in adult CNS neurons. Neurite outgrowth from cultured postnatal cortical neurons, however, proved insensitive to treatments that improve axon growth in other cell types, including combinatorial overexpression of AP1 factors, overexpression of histone acetyltransferases, and pharmacological inhibitors of histone deacetylases. This insensitivity could be due to intermediate chromatin closure at the time of culture, and highlights important differences in cell culture models used to test potential pro-regenerative interventions. PMID:27990351

  9. Developmental Exposure to Valproate or Ethanol Alters Locomotor Activity and Retino-Tectal Projection Area in Zebrafish Embryos

    EPA Science Inventory

    Given the minimal developmental neurotoxicity data available for the large number of new and existing chemicals, there is a critical need for alternative methods to identify and prioritize chemicals for further testing. We outline a developmental neurotoxicity screening approach ...

  10. Developmental Exposure to Valproate or Ethanol Alters Locomotor Activity and Retino-Tectal Projection Area in Zebrafish Embryos

    EPA Science Inventory

    Given the minimal developmental neurotoxicity data available for the large number of new and existing chemicals, there is a critical need for alternative methods to identify and prioritize chemicals for further testing. We outline a developmental neurotoxicity screening approach ...

  11. Postnatal developmental changes in activation profiles of the respiratory neuronal network in the rat ventral medulla

    PubMed Central

    Oku, Yoshitaka; Masumiya, Haruko; Okada, Yasumasa

    2007-01-01

    Two putative respiratory rhythm generators (RRGs), the para-facial respiratory group (pFRG) and the pre-Bötzinger complex (preBötC), have been identified in the neonatal rodent brainstem. To elucidate their functional roles during the neonatal period, we evaluated developmental changes of these RRGs by optical imaging using a voltage-sensitive dye. Optical signals, recorded from the ventral medulla of brainstem–spinal cord preparations of neonatal (P0–P4) rats (n = 44), were analysed by a cross correlation method. With development during the first few postnatal days, the respiratory-related activity in the pFRG reduced and shifted from a preinspiratory (P0–P1) to an inspiratory (P2–P4) pattern, whereas preBötC activity remained unchanged. The μ-opioid agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) augmented preinspiratory activity in the pFRG, while the μ-opioid antagonist naloxone induced changes in spatiotemporal activation profiles that closely mimicked the developmental changes. These results are consistent with the recently proposed hypothesis by Janczewski and Feldman that the pFRG is activated to compensate for the depression of the preBötC by perinatal opiate surge. We conclude that significant reorganization of the respiratory neuronal network, characterized by a reduction of preinspiratory activity in the pFRG, occurs at P1–P2 in rats. The changes in spatiotemporal activation profiles of the pFRG neurones may reflect changes in the mode of coupling of the two respiratory rhythm generators. PMID:17884928

  12. Accurate identification of Culicidae at aquatic developmental stages by MALDI-TOF MS profiling.

    PubMed

    Dieme, Constentin; Yssouf, Amina; Vega-Rúa, Anubis; Berenger, Jean-Michel; Failloux, Anna-Bella; Raoult, Didier; Parola, Philippe; Almeras, Lionel

    2014-12-02

    The identification of mosquito vectors is generally based on morphological criteria, but for aquatic stages, morphological characteristics may be missing, leading to incomplete or incorrect identification. The high cost of molecular biology techniques requires the development of an alternative strategy. In the last decade, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has proved to be efficient for arthropod identification at the species level. To investigate the usefulness of MALDI-TOF MS for the identification of mosquitoes at aquatic stages, optimizations of sample preparation, diet, body parts and storage conditions were tested. Protein extracts of whole specimens from second larval stage to pupae were selected for the creation of a reference spectra database. The database included a total of 95 laboratory-reared specimens of 6 mosquito species, including Anopheles gambiae (S form), Anopheles coluzzi (M form), Culex pipiens pipiens, Culex pipiens molestus, Aedes aegypti and 2 colonies of Aedes albopictus. The present study revealed that whole specimens at aquatic stages produced reproducible and singular spectra according to the mosquito species. Moreover, MS protein profiles appeared weakly affected by the diet provided. Despite the low diversity of some MS profiles, notably for cryptic species, clustering analyses correctly classified all specimens tested at the species level followed by the clustering of early vs. late aquatic developmental stages. Discriminant mass peaks were recorded for the 6 mosquito species analyzed at larval stage 3 and the pupal stage. Querying against the reference spectra database of 149 new specimens at different aquatic stages from the 6 mosquito species revealed that 147 specimens were correctly identified at the species level and that early and late developmental stages were also distinguished. The present work highlights that MALDI-TOF MS profiling may be useful for the

  13. Developmental Onset of Bilirubin-induced Neurotoxicity Involves Toll-like Receptor 2-dependent Signaling in Humanized UDP-glucuronosyltransferase1 Mice*

    PubMed Central

    Yueh, Mei-Fei; Chen, Shujuan; Nguyen, Nghia; Tukey, Robert H.

    2014-01-01

    Biological and signaling events that connect developmentally induced hyperbilirubinemia to bilirubin-induced neurological dysfunction (BIND) and CNS toxicity in humans are poorly understood. In mammals, UDP-glucuronosyltransferase 1A1 (UGT1A1) is the sole enzyme responsible for bilirubin glucuronidation, a rate-limiting step necessary for bilirubin metabolism and clearance. Humanized mice that express the entire UGT1 locus (hUGT1) and the UGT1A1 gene, develop neonatal hyperbilirubinemia, with 8–10% of hUGT1 mice succumbing to CNS damage, a phenotype that is presented by uncontrollable seizures. We demonstrate that neuroinflammation and reactive gliosis are prominent features of bilirubin brain toxicity, and a disturbed redox status resulting from activation of NADPH oxidase is an important contributing mechanism found in BIND. Using knock-out mice and primary brain cells, we connect a key pattern recognition receptor, Toll-like receptor 2 (TLR2), to hyperbilirubinemia-induced signaling. We illustrate a requirement for TLR2 signaling in regulating gliosis, proinflammatory mediators, and oxidative stress when neonatal mice encounter severe hyperbilirubinemia. TLR2-mediated gliosis strongly correlates with pronounced neuroinflammation in the CNS with up-regulation of TNFα, IL-1β, and IL-6, creating a pro-inflammatory CNS environment. Gene expression and immunohistochemistry staining show that hUGT1/Tlr2−/− mice fail to activate glial cells, proinflammatory cytokines, and stress response genes. In addition, bilirubin-induced apoptosis was significantly enhanced by blocking TLR2 signaling indicating its anti-apoptotic property. Consequently, a higher neonatal death rate (57.1%) in hUGT1/Tlr2−/− mice was observed when compared with hUGT1 mice (8.7%). These results suggest that TLR2 signaling and microglia neuroinflammation are linked to a repair and/or protection mode against BIND. PMID:24403077

  14. CHANGES IN PROTEOMIC PROFILES OF CEREBELLUM FOLLOWING DEVELOPMENTAL EXPOSURE TO AROCLOR 1254 OR DE-71.

    EPA Science Inventory

    Chronic low level exposure to polychlorinated biphenyls (PCBs) has been shown to adversely affect human health, including learning and memory. Polybromiated diphenyl ethers (PBDEs) are structurally similar to PCBs and have been shown to have neurotoxic effects in vitro and in viv...

  15. CHANGES IN PROTEOMIC PROFILES OF CEREBELLUM FOLLOWING DEVELOPMENTAL EXPOSURE TO AROCLOR 1254 OR DE-71.

    EPA Science Inventory

    Chronic low level exposure to polychlorinated biphenyls (PCBs) has been shown to adversely affect human health, including learning and memory. Polybromiated diphenyl ethers (PBDEs) are structurally similar to PCBs and have been shown to have neurotoxic effects in vitro and in viv...

  16. Metabolic Profiles in Ovine Carotid Arteries with Developmental Maturation and Long-Term Hypoxia

    PubMed Central

    Goyal, Ravi; Longo, Lawrence D.

    2015-01-01

    Background Long-term hypoxia (LTH) is an important stressor related to health and disease during development. At different time points from fetus to adult, we are exposed to hypoxic stress because of placental insufficiency, high-altitude residence, smoking, chronic anemia, pulmonary, and heart disorders, as well as cancers. Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia. Similarly, prolonged hypoxic exposure during adult life can lead to acute mountain sickness, chronic fatigue, chronic headache, cognitive impairment, acute cerebral and/or pulmonary edema, and death. Aim LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression. Importantly, during the intrauterine life, a fetus is under a relative hypoxic environment, as compared to newborn or adult. Thus, the changes in gene expression with development from fetus to newborn to adult may be as a consequence of underlying changes in the metabolic profile because of the hypoxic environment along with developmental maturation. To examine this possibility, we examined the metabolic profile in carotid arteries from near-term fetus, newborn, and adult sheep in both normoxic and long-term hypoxic acclimatized groups. Results Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation. PMID:26110419

  17. Identification and Developmental Profiling of microRNAs in Diamondback Moth, Plutellaxylostella (L.)

    PubMed Central

    Zhou, Xuguo; Gao, Xiwu

    2013-01-01

    MicroRNAs (miRNAs) are a group of small RNAs involved in various biological processes through negative regulation of mRNAs at the post-transcriptional level. Although miRNA profiles have been documented in over two dozen insect species, few are agricultural pests. In this study, both conserved and novel miRNAs in the diamondback moth, Plutella xylostella L., a devastating insect pest of cruciferous crops worldwide, were documented. High-throughput sequencing of a small RNA library constructed from a mixed life stages of P. xylostella, including eggs, 1st to 4th (last) instar larvae, pupae and adults, identified 384 miRNAs, of which 174 were P. xylostella specific. In addition, temporal expressions of 234 miRNAs at various developmental stages were investigated using a customized microarray analysis. Among the 91 differentially expressed miRNAs, qRT-PCR analysis was used to validate highly expressed miRNAs at each stage. The combined results not only systematically document miRNA profiles in an agriculturally important insect pest, but also provide molecular targets for future functional analysis and, ultimately, genetic-based pest control practice. PMID:24236051

  18. Gene expression profiling of in Moniezia expansa at different developmental proglottids using cDNA microarray.

    PubMed

    Bo, Xinwen; Zhao, Wenjuan; Zhang, Hui; Kang, Lichao; Wang, Xinhua

    2012-04-01

    Gene expression profiles of Moniezia expansa proglottids at varying developmental stages were analysed using cDNA microarray. A total of 4,056 spots, including full length and partial complementary DNAs that represent novel, known, and control genes, were studied. Results indicated an up-regulation of 55 genes in immature proglottids, 134 genes in mature proglottids and 103 genes in gravid proglottids were up-regulated, and a down-regulation of 7 genes in immature proglottids, 68 genes in mature proglottids and 78 genes in gravid proglottids compared to controls (scolex-neck proglottids). Many of these genes were identified as transcription factors and were involved in functions such as metabolism, transport, protein biosynthesis, apoptosis, cell differentiation, cell communication and nucleic acid binding. Expression level alterations in UBE2A, Cavβ, RAD51, DAZ, PKAc and 2 unknown genes were confirmed by real-time quantitative polymerase chain reaction (RT-PCR). The complete microarray data set has been deposited in the NCBI Gene Expression Omnibus, GEO Series accession number GSE13982. Results provide a gene expression profile at various development stages of M. expansa proglottids, which prove invaluable in understanding the pathogenesis of the tapeworm and studying the genes concerned with reproductive organ development.

  19. Identification and developmental profiling of microRNAs in diamondback moth, Plutellaxylostella (L.).

    PubMed

    Liang, Pei; Feng, Bing; Zhou, Xuguo; Gao, Xiwu

    2013-01-01

    MicroRNAs (miRNAs) are a group of small RNAs involved in various biological processes through negative regulation of mRNAs at the post-transcriptional level. Although miRNA profiles have been documented in over two dozen insect species, few are agricultural pests. In this study, both conserved and novel miRNAs in the diamondback moth, Plutella xylostella L., a devastating insect pest of cruciferous crops worldwide, were documented. High-throughput sequencing of a small RNA library constructed from a mixed life stages of P. xylostella, including eggs, 1st to 4th (last) instar larvae, pupae and adults, identified 384 miRNAs, of which 174 were P. xylostella specific. In addition, temporal expressions of 234 miRNAs at various developmental stages were investigated using a customized microarray analysis. Among the 91 differentially expressed miRNAs, qRT-PCR analysis was used to validate highly expressed miRNAs at each stage. The combined results not only systematically document miRNA profiles in an agriculturally important insect pest, but also provide molecular targets for future functional analysis and, ultimately, genetic-based pest control practice.

  20. Number Processing and Heterogeneity of Developmental Dyscalculia: Subtypes With Different Cognitive Profiles and Deficits.

    PubMed

    Skagerlund, Kenny; Träff, Ulf

    2016-01-01

    This study investigated if developmental dyscalculia (DD) in children with different profiles of mathematical deficits has the same or different cognitive origins. The defective approximate number system hypothesis and the access deficit hypothesis were tested using two different groups of children with DD (11-13 years old): a group with arithmetic fact dyscalculia (AFD) and a group with general dyscalculia (GD). Several different aspects of number magnitude processing were assessed in these two groups and compared with age-matched typically achieving children. The GD group displayed weaknesses with both symbolic and nonsymbolic number processing, whereas the AFD group displayed problems only with symbolic number processing. These findings provide evidence that the origins of DD in children with different profiles of mathematical problems diverge. Children with GD have impairment in the innate approximate number system, whereas children with AFD suffer from an access deficit. These findings have implications for researchers' selection procedures when studying dyscalculia, and also for practitioners in the educational setting. © Hammill Institute on Disabilities 2014.

  1. SLA Developmental Stages and Teachers' Assessment of Written French: Exploring Direkt Profil as a Diagnostic Assessment Tool

    ERIC Educational Resources Information Center

    Granfeldt, Jonas; Ågren, Malin

    2014-01-01

    One core area of research in Second Language Acquisition is the identification and definition of developmental stages in different L2s. For L2 French, Bartning and Schlyter (2004) presented a model of six morphosyntactic stages of development in the shape of grammatical profiles. The model formed the basis for the computer program Direkt Profil…

  2. On the Importance of Considering Individual Profiles when Investigating the Role of Auditory Sequential Deficits in Developmental Dyslexia

    ERIC Educational Resources Information Center

    Lallier, Marie; Thierry, Guillaume; Tainturier, Marie-Josephe

    2013-01-01

    The goal of this study was to gain a better understanding of the relationship between non-verbal auditory disorders and developmental dyslexia. This question has led to conflicting results in the literature, which we argued might be due to a failure to consider the heterogeneity of dyslexic profiles. This study included three groups of adult…

  3. On the Importance of Considering Individual Profiles when Investigating the Role of Auditory Sequential Deficits in Developmental Dyslexia

    ERIC Educational Resources Information Center

    Lallier, Marie; Thierry, Guillaume; Tainturier, Marie-Josephe

    2013-01-01

    The goal of this study was to gain a better understanding of the relationship between non-verbal auditory disorders and developmental dyslexia. This question has led to conflicting results in the literature, which we argued might be due to a failure to consider the heterogeneity of dyslexic profiles. This study included three groups of adult…

  4. Expression Profiles of Long Noncoding RNAs and Messenger RNAs in Mn-Exposed Hippocampal Neurons of Sprague-Dawley Rats Ascertained by Microarray: Implications for Mn-Induced Neurotoxicity.

    PubMed

    Ma, Shuyan; Qing, Li; Yang, Xiaobo; Liang, Guiqiang; Zhang, Li'e; Li, Qin; Xiong, Feng; Peng, Suwan; Ma, Yifei; Huang, Xiaowei; Zou, Yunfeng

    2016-01-01

    Manganese (Mn) is an essential trace element, while excessive expose may induce neurotoxicity. Recently, lncRNAs have been extensively studied and it has been confirmed that lncRNAs participate in neural functions and aberrantly expressed lncRNAs are involved in neurological diseases. However, the pathological effects of lncRNAs on Mn-induced neurotoxicity remain unclear. In this study, the expression profiles of lncRNAs and messenger RNAs (mRNAs) were identified in Mn-treated hippocampal neurons and control neurons via microarray. Bioinformatic methods and intersection analysis were also employed. Results indicated that 566, 1161, and 1474 lncRNAs meanwhile 1848, 3228, and 4022 mRNAs were aberrantly expressed in low, intermediate, and high Mn-exposed groups compared with the control group, respectively. Go analysis determined that differentially expressed mRNAs were targeted to biological processes, cellular components, and molecular functions. Pathway analysis indicated that these mRNAs were enriched in insulin secretion, cell cycle, and DNA replication. Intersection analysis denominated that 135 lncRNAs and 373 mRNAs were consistently up-regulated while 150 lncRNAs and 560 mRNAs were consistently down-regulated. Meanwhile, lncRNA BC079195 was significantly up-regulated while lncRNAs uc.229- and BC089928 were significantly down-regulated in three comparison groups. The relative expression levels of 3 lncRNAs and 4 mRNAs were validated through qRT-PCR. To the best of our knowledge, this study is the first to identify the expression patterns of lncRNAs and mRNAs in hippocampal neurons of Sprague-Dawley rats. The results may provide evidence on underlying mechanisms of Mn-induced neurotoxicity, and aberrantly expressed lncRNAs/mRNAs may be useful in further investigations to detect early symptoms of Mn-induced neuropsychiatric disorders in the central nervous system.

  5. Expression Profiles of Long Noncoding RNAs and Messenger RNAs in Mn-Exposed Hippocampal Neurons of Sprague–Dawley Rats Ascertained by Microarray: Implications for Mn-Induced Neurotoxicity

    PubMed Central

    Yang, Xiaobo; Liang, Guiqiang; Zhang, Li’e; Li, Qin; Xiong, Feng; Peng, Suwan; Ma, Yifei; Huang, Xiaowei; Zou, Yunfeng

    2016-01-01

    Manganese (Mn) is an essential trace element, while excessive expose may induce neurotoxicity. Recently, lncRNAs have been extensively studied and it has been confirmed that lncRNAs participate in neural functions and aberrantly expressed lncRNAs are involved in neurological diseases. However, the pathological effects of lncRNAs on Mn-induced neurotoxicity remain unclear. In this study, the expression profiles of lncRNAs and messenger RNAs (mRNAs) were identified in Mn-treated hippocampal neurons and control neurons via microarray. Bioinformatic methods and intersection analysis were also employed. Results indicated that 566, 1161, and 1474 lncRNAs meanwhile 1848, 3228, and 4022 mRNAs were aberrantly expressed in low, intermediate, and high Mn-exposed groups compared with the control group, respectively. Go analysis determined that differentially expressed mRNAs were targeted to biological processes, cellular components, and molecular functions. Pathway analysis indicated that these mRNAs were enriched in insulin secretion, cell cycle, and DNA replication. Intersection analysis denominated that 135 lncRNAs and 373 mRNAs were consistently up-regulated while 150 lncRNAs and 560 mRNAs were consistently down-regulated. Meanwhile, lncRNA BC079195 was significantly up-regulated while lncRNAs uc.229- and BC089928 were significantly down-regulated in three comparison groups. The relative expression levels of 3 lncRNAs and 4 mRNAs were validated through qRT-PCR. To the best of our knowledge, this study is the first to identify the expression patterns of lncRNAs and mRNAs in hippocampal neurons of Sprague–Dawley rats. The results may provide evidence on underlying mechanisms of Mn-induced neurotoxicity, and aberrantly expressed lncRNAs/mRNAs may be useful in further investigations to detect early symptoms of Mn-induced neuropsychiatric disorders in the central nervous system. PMID:26745496

  6. Developmental Gene Expression Profiling along the Tonotopic Axis of the Mouse Cochlea

    PubMed Central

    Son, Eun Jin; Wu, Ling; Yoon, Heejei; Kim, Sunhee; Choi, Jae Young; Bok, Jinwoong

    2012-01-01

    The mammalian cochlear duct is tonotopically organized such that the basal cochlea is tuned to high frequency sounds and the apical cochlea to low frequency sounds. In an effort to understand how this tonotopic organization is established, we searched for genes that are differentially expressed along the tonotopic axis during neonatal development. Cochlear tissues dissected from P0 and P8 mice were divided into three equal pieces, representing the base, middle and apex, and gene expression profiles were determined using the microarray technique. The gene expression profiles were grouped according to changes in expression levels along the tonotopic axis as well as changes during neonatal development. The classified groups were further analyzed by functional annotation clustering analysis to determine whether genes associated with specific biological function or processes are particularly enriched in each group. These analyses identified several candidate genes that may be involved in cochlear development and acquisition of tonotopy. We examined the expression domains for a few candidate genes in the developing mouse cochlea. Tnc (tenacin C) and Nov (nephroblastoma overexpressed gene) are expressed in the basilar membrane, with increased expression toward the apex, which may contribute to graded changes in the structure of the basilar membrane along the tonotopic axis. In addition, Fst (Follistatin), an antagonist of TGF-β/BMP signaling, is expressed in the lesser epithelial ridge and at gradually higher levels towards the apex. The graded expression pattern of Fst is established at the time of cochlear specification and maintained throughout embryonic and postnatal development, suggesting its possible role in the organization of tonotopy. Our data will provide a good resource for investigating the developmental mechanisms of the mammalian cochlea including the acquisition of tonotopy. PMID:22808246

  7. Developmental MicroRNA Expression Profiling of Murine Embryonic Orofacial Tissue

    PubMed Central

    Mukhopadhyay, Partha; Brock, Guy; Pihur, Vasyl; Webb, Cynthia; Pisano, M. Michele; Greene, Robert M.

    2011-01-01

    BACKGROUND Orofacial development is a multifaceted process involving precise, spatio-temporal expression of a panoply of genes. MicroRNAs (miRNAs), the largest family of noncoding RNAs involved in gene silencing, represent critical regulators of cell and tissue differentiation. MicroRNA gene expression profiling is an effective means of acquiring novel and valuable information regarding the expression and regulation of genes, under the control of miRNA, involved in mammalian orofacial development. METHODS To identify differentially expressed miRNAs during mammalian orofacial ontogenesis, miRNA expression profiles from gestation day (GD) -12, -13 and -14 murine orofacial tissue were compared utilizing miRXplore microarrays from Miltenyi Biotech. Quantitative real-time PCR was utilized for validation of gene expression changes. Cluster analysis of the microarray data was conducted with the clValid R package and the UPGMA clustering method. Functional relationships between selected miRNAs were investigated using Ingenuity Pathway Analysis. RESULTS Expression of over 26% of the 588 murine miRNA genes examined was detected in murine orofacial tissues from GD-12–GD-14. Among these expressed genes, several clusters were seen to be developmentally regulated. Differential expression of miRNAs within such clusters were shown to target genes encoding proteins involved in cell proliferation, cell adhesion, differentiation, apoptosis and epithelial-mesenchymal transformation, all processes critical for normal orofacial development. CONCLUSIONS Using miRNA microarray technology, unique gene expression signatures of hundreds of miRNAs in embryonic orofacial tissue were defined. Gene targeting and functional analysis revealed that the expression of numerous protein-encoding genes, crucial to normal orofacial ontogeny, may be regulated by specific miRNAs. PMID:20589883

  8. Developmental long trace profiler using optimally aligned mirror-based pentaprism

    NASA Astrophysics Data System (ADS)

    Barber, Samuel K.; Morrison, Gregory Y.; Yashchuk, Valeriy V.; Gubarev, Mikhail V.; Geckeler, Ralf D.; Buchheim, Jana; Siewert, Frank; Zeschke, Thomas

    2010-08-01

    A low-budget surface slope measuring instrument, the Developmental Long Trace Profiler (DLTP), was recently brought into operation at the Advanced Light Source Optical Metrology Laboratory [Nucl. Instr. and Meth. A 616, 212- 223 (2010)]. The instrument is based on a precisely calibrated autocollimator and a movable pentaprism. The capability of the DLTP to achieve sub-microradian surface slope metrology has been verified via cross-comparison measurements with other high-performance slope measuring instruments when measuring the same high-quality test optics. In the present work, a further improvement of the DLTP is achieved by replacing the existing bulk pentaprism with a specially designed mirror based pentaprism. A mirror based pentaprism offers the possibility to eliminate systematic errors introduced by inhomogeneity of the optical material and fabrication imperfections of a bulk pentaprism. We provide the details of the mirror based pentaprism design and describe an original experimental procedure for precision mutual alignment of the mirrors. The algorithm of the alignment procedure and its efficiency are verified with rigorous ray tracing simulations. Results of measurements of a spherically curved test mirror and a flat test mirror using the original bulk pentaprism are compared with measurements using the new mirror based pentaprism, demonstrating the improved performance.

  9. Developmental and behavioral profile in a domestic adoptees sample: a new challenge for the pediatrician.

    PubMed

    Ferrara, Pietro; Cutrona, Costanza; Guadagno, Chiara; Amato, Maria; Sbordone, Annamaria; Sacco, Roberto; Bona, Gianni

    2016-09-06

    To investigate the changes of developmental and behavioral profile in a domestic adoptees sample. 36 domestic adoptive families were recruited, resulting in a sample of 39 children. Families were sent a general questionnaire for collecting data related to the children demographic variables, infant's background (time spent in institutional care, age at adoption), children's health status and anthropometric measures at T0 , T1, T2 and T3 . Moreover, the Infant Behavior Questionnaire-Revised Very Short Form and a modified version of parent-report of Child Behavior Checklist were used to assess temperament and to detect behavioral problems. As regards the psychopathological evaluation, behavior problems were more common in older children, especially among girls. In particular they exhibited a higher frequency of internalizing problems versus externalizing. Children in foster care suffer discontinuity of care that negatively affects their emotional and physical development. It's important for pediatricians to be aware of the special needs of adopted children, providing adequate support to adoptive families.

  10. Developmental profiling of postnatal dentate gyrus progenitors provides evidence for dynamic cell-autonomous regulation

    PubMed Central

    Gilley, Jennifer A.; Yang, Cui-Ping; Kernie, Steven G.

    2009-01-01

    The dentate gyrus of the hippocampus is one of the most prominent regions in the postnatal mammalian brain where neurogenesis continues throughout life. There is tremendous speculation regarding the potential implications of adult hippocampal neurogenesis, though it remains unclear to what extent this ability becomes attenuated during normal aging, and what genetic changes in the progenitor population ensue over time. Using defined elements of the nestin promoter, we developed a transgenic mouse that reliably labels neural stem and early progenitors with green fluorescent protein (GFP). Using a combination of immunohistochemical and flow cytometry techniques, we characterized the progenitor cells within the dentate gyrus and created a developmental profile from postnatal day 7 (P7) until 6 months of age. In addition, we demonstrate that the proliferative potential of these progenitors is controlled at least in part by cell-autonomous cues. Finally, in order to identify what may underlie these differences, we performed stem cell-specific microarrays on GFP-expressing sorted cells from isolated P7 and postnatal day 28 (P28) dentate gyrus. We identified several differentially expressed genes that may underlie the functional differences that we observe in neurosphere assays from sorted cells and differentiation assays at these different ages. These data suggest that neural progenitors from the dentate gyrus are differentially regulated by cell-autonomous factors that change over time. PMID:20014381

  11. Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome.

    PubMed

    DiStefano, Charlotte; Gulsrud, Amanda; Huberty, Scott; Kasari, Connie; Cook, Edwin; Reiter, Lawrence T; Thibert, Ronald; Jeste, Shafali Spurling

    2016-01-01

    One of the most common genetic variants associated with autism spectrum disorder (ASD) are duplications of chromosome 15q11.2-q13.1 (Dup15q syndrome). To identify distinctive developmental and behavioral features in Dup15q syndrome, we examined the social communication, adaptive, and cognitive skills in clinic-referred subjects and compared the characteristics of children with Dup15q syndrome to age/IQ-matched children with non-syndromic ASD. Behavior and development were also analyzed within the Dup15q group for differences related to copy number or epilepsy. Participants included 13 children with Dup15q syndrome and 13 children with non-syndromic ASD, matched on chronological and mental age, ages 22 months-12 years. In the Dup15q group, ten participants had isodicentric and three had interstitial duplications. Four children had active epilepsy (all isodicentric). Participants were assessed for verbal and non-verbal cognition, ASD characteristics based on the Autism Diagnostic Observation Schedule (ADOS), and adaptive function based on the Vineland Adaptive Behavior Scales (VABS). Group comparisons were performed between Dup15q and ASD participants, as well as within the Dup15q group based on duplication type and epilepsy status. All children with Dup15q syndrome met the criteria for ASD; ASD severity scores were significantly lower than children in the non-syndromic ASD group. ADOS profiles demonstrated a relative strength in items related to social interest. Children with Dup15q syndrome also demonstrated significantly more impairment in motor and daily living skills. Within the Dup15q group, children with epilepsy demonstrated significantly lower cognitive and adaptive function than those without epilepsy. The relative strength observed in social interest and responsiveness in the context of impaired motor skills represents an important avenue for intervention, including aggressive treatment of epilepsy, early and consistent focus on motor skills, and

  12. Predictions of developmental neurotoxicity potential of TDCPP

    EPA Science Inventory

    Tris(1 ,3-dichloro-2-propyl)phosphate (TDCPP) is an organophosphate flame retardant with widespread usage and documented human exposures through food, inhalation, dust ingestion, and breast milk. Concern for neurodevelopmental effects in infants and children has been raised by fi...

  13. Predictions of developmental neurotoxicity potential of TDCPP

    EPA Science Inventory

    Tris(1 ,3-dichloro-2-propyl)phosphate (TDCPP) is an organophosphate flame retardant with widespread usage and documented human exposures through food, inhalation, dust ingestion, and breast milk. Concern for neurodevelopmental effects in infants and children has been raised by fi...

  14. BROMATE: A CONCERN FOR DEVELOPMENTAL NEUROTOXICITY?

    EPA Science Inventory

    In February of 2005 a workshop was held to evaluate the state-of-the-science of bromate toxicity. The workshop was sponsored by the American Water Works Association - Research Foundation, the Southern Nevada Water Authority, Fairfax Water Authority, and Miami University. This m...

  15. NEW METHODS TO SCREEN FOR DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    The development of alternative methods for toxicity testing is driven by the need for scientifically valid data (i.e. predictive of a toxic effect) that can be obtained in a rapid and cost-efficient manner. These predictions will enable decisions to be made as to whether further ...

  16. Developmental neurotoxicity testing: Past, present and future.

    EPA Science Inventory

    Adverse effects on the nervous system following exposure to environmental contaminants during development have been well documented. Indeed, in a number of cases (e.g., lead, methyl mercury) the developing human nervous system appears to be a highly susceptible target. There ar...

  17. Developmental neurotoxicity testing: Past, present and future.

    EPA Science Inventory

    Adverse effects on the nervous system following exposure to environmental contaminants during development have been well documented. Indeed, in a number of cases (e.g., lead, methyl mercury) the developing human nervous system appears to be a highly susceptible target. There ar...

  18. NEW METHODS TO SCREEN FOR DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    The development of alternative methods for toxicity testing is driven by the need for scientifically valid data (i.e. predictive of a toxic effect) that can be obtained in a rapid and cost-efficient manner. These predictions will enable decisions to be made as to whether further ...

  19. BROMATE: A CONCERN FOR DEVELOPMENTAL NEUROTOXICITY?

    EPA Science Inventory

    In February of 2005 a workshop was held to evaluate the state-of-the-science of bromate toxicity. The workshop was sponsored by the American Water Works Association - Research Foundation, the Southern Nevada Water Authority, Fairfax Water Authority, and Miami University. This m...

  20. Neurotoxicity in risk assessment

    SciTech Connect

    Weiss, B.

    1988-01-01

    Neurotoxicity is a property of many metals, even those deemed biologically essential. Manganese, one of the essential elements, can induce a syndrome displaying aspects of both Parkinsonism and dystonia, but accompanied, as well, by psychological abnormalities. At low exposure levels, however, neurotoxicity may be detectable with psychological tests. Mercury vapor exposure also induces neurological signs, psychological aberrations, and subtle evidence of dysfunction on psychological tests. Methylmercury and lead are particularly toxic to the developing brain. The most recent research indicates that psychological testing may uncover deficits even in children showing no evidence of impairment. Because of their special features, neurotoxic endpoints may have to be evaluated for risks by a process that diverges significantly from the standard program based on carcinogenicity.

  1. Nucleus Accumbens Invulnerability to Methamphetamine Neurotoxicity

    PubMed Central

    Kuhn, Donald M.; Angoa-Pérez, Mariana; Thomas, David M.

    2016-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure. PMID:23382149

  2. Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

    PubMed

    Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M

    2011-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure.

  3. Environmental neurotoxicity of chemicals and radiation

    SciTech Connect

    Verity, M.A. )

    1993-06-01

    Epidemiologic and societal concerns continue to stimulate studies in the field of environmental neurotoxicology. Although the role of heavy metals, aluminum, and iron are unclear in the etiology of human neurodegenerative disorders, these toxins have provided fertile ground for in vivo and in vitro experimental studies to elucidate their role in neurotoxic injury. Experimental models of clinical syndromes are discussed with special relevance to developmental neurotoxicology. Cycloleucine, tellurium, and 1,3-dinitrobenzene provide models of subacute combined degeneration, primary peripheral nerve demyelination, and thiamine deficiency-like lesions, respectively. Increasing attention is being given to irradiation neurotoxicity, especially in the developing or young central nervous system. A fuller understanding of the pathogenesis of low-dose irradiation injury allows for a clearer understanding of its neurobiology and also provides a more rational approach to understanding an interventional therapy associated with brain irradiation for childhood neoplasia. 43 refs.

  4. Developmental alcohol-specific parenting profiles in adolescence and their relationships with adolescents' alcohol use.

    PubMed

    Koning, Ina M; van den Eijnden, Regina J J M; Verdurmen, Jacqueline E E; Engels, Rutger C M E; Vollebergh, Wilma A M

    2012-11-01

    Previous studies on general parenting have demonstrated the relevance of strict parenting within a supportive social context for a variety of adolescent behaviors, such as alcohol use. Yet, alcohol-specific parenting practices are generally examined as separate predictors of adolescents' drinking behavior. The present study examined different developmental profiles of alcohol-specific parenting (rule-setting, quality and frequency of communication about alcohol use) and how these patterns relate to the initiation and growth of adolescents' drinking. A longitudinal sample of 883 adolescents (47 % female) including four measurements (between ages 12 and 16) was used. Latent class growth analysis revealed that five classes of parenting could be distinguished. Communication about alcohol appeared to be fairly stable over time in all parenting classes, whereas the level of rule-setting declined in all subgroups of parents as adolescents grow older. Strict rule-setting in combination with a high quality and frequency of communication was associated with the lowest amount of drinking; parents scoring low on all these behaviors show to be related to the highest amount of drinking. This study showed that alcohol-specific rule-setting is most effective when it coincides with a good quality and frequency of communication about alcohol use. This indicates that alcohol-specific parenting behaviors should be taken into account as an alcohol-specific parenting context, rather than single parenting practices. Therefore, parent-based alcohol interventions should not only encourage strict rule setting, the way parents communicate with their child about alcohol is also of major importance.

  5. The effects of bispectral index monitoring on hemodynamics and recovery profile in developmentally delayed pediatric patients undergoing dental surgery.

    PubMed

    Sargin, Mehmet; Uluer, Mehmet Selcuk; Ozmen, Sadık

    2015-09-01

    General anesthesia is often preferred for dental surgery or rehabilitation in developmentally delayed pediatric patients. Bispectral index monitoring is used to monitor the depth of anesthesia and to ensure early recovery. However, studies on the topic in developmentally delayed pediatric patients are limited. To evaluate the effects of Bispectral Index Scale (BIS) on hemodynamics and recovery profile in developmentally delayed pediatric patients undergoing dental surgery. Forty children between the ages of 6-16 years were studied in this prospective and randomized study. The children were randomized into two groups. In Group 1 (n = 20), general anesthesia was maintained with 1-2 minimum alveolar concentration (MAC) of sevoflurane in oxygen by standard practice. In Group 2 (n = 20), the depth of anesthesia was monitored by BIS. BIS values were continuously recorded from awake status to tracheal extubation. The duration of the surgical procedure, anesthesia, postanesthesia care unit (PACU) stay was noted. To evaluate recovery profile, time to spontaneous ventilation, extubation, open eyes, and PACU discharge were also noted. There were significant differences between recovery times and Non-communicating Children's Pain Checklist - Postoperative Version (NCCPC-PV) scores of two groups. Time to spontaneous ventilation [Difference in means (95% CI); 3.17 (1.79-4.54) P < 0.001], extubation [Difference in means (95% CI); 3.13 (1.66-4.60) P < 0.001], open eyes [Difference in means (95% CI); 3.97 (2.34-5.59) P < 0.001], and PACU stay time [Difference in means (95% CI); 23.55 (18.08-29.01) P < 0.001] were significantly shorter in Group 2. In conclusion, results suggest that routine BIS monitoring may be beneficial due to its favorable effects on the recovery profile in developmentally delayed pediatric patients. © 2015 John Wiley & Sons Ltd.

  6. Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: Developmental effects

    SciTech Connect

    Royland, Joyce E.; Wu, Jinfang; Zawia, Nasser H.; Kodavanti, Prasada Rao S.

    2008-09-01

    The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive development, causes psychomotor difficulties, and contributes to attention deficits in children, all of which seem to be associated with altered patterns of neuronal connectivity. In the present study, we examined gene expression profiles in the rat nervous system following PCB developmental exposure. Pregnant rats (Long-Evans) were dosed perinatally with 0 or 6 mg/kg/day of Aroclor 1254 from gestation day 6 through postnatal day (PND) 21. Gene expression in cerebellum and hippocampus from PND7 and PND14 animals was analyzed with an emphasis on developmental aspects. Changes in gene expression ({>=} 1.5 fold) in control animals identified normal developmental changes. These basal levels of expression were compared to data from Aroclor 1254-treated animals to determine the impact of gestational PCB exposure on developmental parameters. The results indicate that the expression of a number of developmental genes related to cell cycle, synaptic function, cell maintenance, and neurogenesis is significantly altered from PND7 to PND14. Aroclor 1254 treatment appears to dampen the overall growth-related gene expression levels in both regions with the effect being more pronounced in the cerebellum. Functional analysis suggests that Aroclor 1254 delays maturation of the developing nervous system, with the consequences dependent on the ontological state of the brain area and the functional role of the individual gene. Such changes may underlie learning and memory deficits observed in PCB exposed animals and humans.

  7. Neurotoxicity and Behavior

    EPA Science Inventory

    Neurotoxicity is important to consider as a component of occupational and environmental safety and health programs. The failure to do so has contributed to a number of cases in which workers, consumers of manufactured products, and people exposed in the environment were irreparab...

  8. Neurotoxicity and Behavior

    EPA Science Inventory

    Neurotoxicity is important to consider as a component of occupational and environmental safety and health programs. The failure to do so has contributed to a number of cases in which workers, consumers of manufactured products, and people exposed in the environment were irreparab...

  9. Neurotoxic Weapons and Syndromes.

    PubMed

    Carota, Antonio; Calabrese, Pasquale; Bogousslavsky, Julien

    2016-01-01

    The modern era of chemical and biological warfare began in World War I with the large-scale production and use of blistering and choking agents (chlorine, phosgene and mustard gases) in the battlefield. International treaties (the 1925 Geneva Protocol, the 1975 Biological and Toxin Weapons Convention and the 1993 Chemical Weapons Convention) banned biological and chemical weapons. However, several countries are probably still engaged in their development. Hence, there is risk of these weapons being used in the future. This chapter will focus on neurotoxic weapons (e.g. nerve agents, chemical and biological neurotoxins, psychostimulants), which act specifically or preeminently on the central nervous system and/or the neuromuscular junction. Deeply affecting the function of the nervous system, these agents either have incapacitating effects or cause clusters of casualties who manifest primary symptoms of encephalopathy, seizures, muscle paralysis and respiratory failure. The neurologist should be prepared both to notice patterns of symptoms and signs that are sufficiently consistent to raise the alarm of neurotoxic attacks and to define specific therapeutic interventions. Additionally, extensive knowledge on neurotoxic syndromes should stimulate scientific research to produce more effective antidotes and antibodies (which are still lacking for most neurotoxic weapons) for rapid administration in aerosolized forms in the case of terrorist or warfare scenarios. © 2016 S. Karger AG, Basel.

  10. Developmental profile of speech-language and communicative functions in an individual with the preserved speech variant of Rett syndrome.

    PubMed

    Marschik, Peter B; Vollmann, Ralf; Bartl-Pokorny, Katrin D; Green, Vanessa A; van der Meer, Larah; Wolin, Thomas; Einspieler, Christa

    2014-08-01

    We assessed various aspects of speech-language and communicative functions of an individual with the preserved speech variant of Rett syndrome (RTT) to describe her developmental profile over a period of 11 years. For this study, we incorporated the following data resources and methods to assess speech-language and communicative functions during pre-, peri- and post-regressional development: retrospective video analyses, medical history data, parental checklists and diaries, standardized tests on vocabulary and grammar, spontaneous speech samples and picture stories to elicit narrative competences. Despite achieving speech-language milestones, atypical behaviours were present at all times. We observed a unique developmental speech-language trajectory (including the RTT typical regression) affecting all linguistic and socio-communicative sub-domains in the receptive as well as the expressive modality. Future research should take into consideration a potentially considerable discordance between formal and functional language use by interpreting communicative acts on a more cautionary note.

  11. A 21st Century Update on Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing was proposed in “A 21st Century Update on Neurotoxicity Risk Assessment “ (NRC, 2007), stating that traditional toxicity testing was too slow and expensive to develop information on the potential toxicity of the large number of untested chemicals already used in commerce. In addition, new technologies have compounded the problem as new materials, such as engineered nanomaterials, are introduced at a rate exceeding traditional testing capacity. There is currently much effort to develop higher throughput neurotoxicity testing capabilities, especially for developmental neurotoxicity, but there is no general consensus regarding how alternative testing data should be interpreted for neurotoxicity risk assessment. The dependence of critical functions, such as learning, memory or sensory perception, on the operation of integrated neural systems makes the interpretation of data from simple test assays particularly difficult. The concept of Adverse Outcome Pathways (AOP), in which molecular initiating events (MIE) trigger a sequence of steps leading to an adverse outcome, may provide a conceptual framework in which simple alternative testing data indicative of MIEs can be used to predict neur

  12. A 21st Century Update on Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing was proposed in “A 21st Century Update on Neurotoxicity Risk Assessment “ (NRC, 2007), stating that traditional toxicity testing was too slow and expensive to develop information on the potential toxicity of the large number of untested chemicals already used in commerce. In addition, new technologies have compounded the problem as new materials, such as engineered nanomaterials, are introduced at a rate exceeding traditional testing capacity. There is currently much effort to develop higher throughput neurotoxicity testing capabilities, especially for developmental neurotoxicity, but there is no general consensus regarding how alternative testing data should be interpreted for neurotoxicity risk assessment. The dependence of critical functions, such as learning, memory or sensory perception, on the operation of integrated neural systems makes the interpretation of data from simple test assays particularly difficult. The concept of Adverse Outcome Pathways (AOP), in which molecular initiating events (MIE) trigger a sequence of steps leading to an adverse outcome, may provide a conceptual framework in which simple alternative testing data indicative of MIEs can be used to predict neur

  13. The magnitude of neurotoxicity in patients with multiple myeloma and the impact of dose modifications: results from the population-based PROFILES registry.

    PubMed

    Beijers, Antoinetta J M; Oerlemans, Simone; Mols, Floortje; Eurelings, Marijke; Minnema, Monique C; Vreugdenhil, Art; van de Poll-Franse, Lonneke V

    2017-04-01

    The aim of this analysis is to assess (1) self-reported chemotherapy-induced peripheral neuropathy (CIPN) symptoms; (2) its association with sociodemographic and clinical characteristics; and (3) treatment dose modifications and its influence on the magnitude of neurotoxicity in a population-based cohort of patients with multiple myeloma (MM). MM patients (n = 156), diagnosed between 2000 and 2014, filled out the EORTC QLQ-CIPN20 (65% response). Data on treatment, outcomes, and dose modifications were extracted from the medical files. Fifty-three percent of patients reported at least one and on average three neuropathy symptoms that bothered them the most during the past week, with tingling toes/feet as most reported. In multivariate analysis, thalidomide, especially higher cumulative dose, was associated with neuropathy (β = 0.26, CI 95% 0.27-15.34, p = 0.04) and CIPN was not associated with age, sex, time since last course of therapy, number of prior therapies, osteoarthritis, or diabetes. Dose modifications were often applied (65%). Although not statistically significant, a trend towards higher sensory (22 vs. 15 vs. 12, p = 0.22) and motor neuropathy scores (21 vs. 15 vs. 11, p = 0.36) was observed among patients receiving dose modification because of CIPN (31%) compared to those receiving a dose modification for another reason or no dose modification, without altering treatment response. CIPN is a common dose limiting side effect in patients with MM. Severity of CIPN was mainly affected by treatment with thalidomide. In spite of dose modifications, patients still reported somewhat higher neuropathy scores without altered response rates. Early dose modification based on a more reliable tool for CIPN measurements may prove value.

  14. Study of lipid profile and parieto-temporal lipid peroxidation in AlCl3 mediated neurotoxicity. modulatory effect of fenugreek seeds

    PubMed Central

    2012-01-01

    Background Peroxidation of lipid (LPO) membrane and cholesterol metabolism have been involved in the physiopathology of many diseases of aging brain. Therefore, this prospective animal study was carried firstly to find out the correlation between LPO in posterior brain and plasmatic cholesterol along with lipoprotein levels after chronic intoxication by aluminium chloride (AlCl3). Chronic aluminum-induced neurotoxicity has been in fact related to enhanced brain lipid peroxidation together with hypercholesterolemia and hypertriglyceridemia, despite its controversial etiological role in neurodegenerative diseases. Secondly an evaluation of the effectiveness of fenugreek seeds in alleviating the engendered toxicity through these biochemical parameters was made. Results Oral administration of AlCl3 to rats during 5 months (500 mg/kg bw i.g for one month then 1600 ppm via the drinking water) enhanced the levels of LPO in posterior brain, liver and plasma together with lactate dehydrogenase (LDH) activities, total cholesterol (TC), triglycerides (TG) and LDL-C (Low Density Lipoproteins) levels. All these parameters were decreased following fenugreek seeds supplementation either as fenugreek seed powder (FSP) or fenugreek seed extract (FSE). A notable significant correlation was observed between LPObrain and LDL-C on one hand and LDHliver on the other hand. This latter was found to correlate positively with TC, TG and LDL-C. Furthermore, high significant correlations were observed between LDHbrain and TC, TG, LDL-C, LPObrain as well as LDHliver. Conclusion Aluminium-induced LPO in brain could arise from alteration of lipid metabolism particularly altered lipoprotein metabolism rather than a direct effect of cholesterol oxidation. Fenugreek seeds could play an anti-peroxidative role in brain which may be attributed in part to its modulatory effect on plasmatic lipid metabolism. PMID:22280491

  15. Study of lipid profile and parieto-temporal lipid peroxidation in AlCl₃ mediated neurotoxicity. Modulatory effect of fenugreek seeds.

    PubMed

    Belaïd-Nouira, Yosra; Bakhta, Hayfa; Bouaziz, Mohamed; Flehi-Slim, Imen; Haouas, Zohra; Ben Cheikh, Hassen

    2012-01-26

    Peroxidation of lipid (LPO) membrane and cholesterol metabolism have been involved in the physiopathology of many diseases of aging brain. Therefore, this prospective animal study was carried firstly to find out the correlation between LPO in posterior brain and plasmatic cholesterol along with lipoprotein levels after chronic intoxication by aluminium chloride (AlCl₃). Chronic aluminum-induced neurotoxicity has been in fact related to enhanced brain lipid peroxidation together with hypercholesterolemia and hypertriglyceridemia, despite its controversial etiological role in neurodegenerative diseases. Secondly an evaluation of the effectiveness of fenugreek seeds in alleviating the engendered toxicity through these biochemical parameters was made. Oral administration of AlCl₃ to rats during 5 months (500 mg/kg bw i.g for one month then 1600 ppm via the drinking water) enhanced the levels of LPO in posterior brain, liver and plasma together with lactate dehydrogenase (LDH) activities, total cholesterol (TC), triglycerides (TG) and LDL-C (Low Density Lipoproteins) levels. All these parameters were decreased following fenugreek seeds supplementation either as fenugreek seed powder (FSP) or fenugreek seed extract (FSE). A notable significant correlation was observed between LPObrain and LDL-C on one hand and LDHliver on the other hand. This latter was found to correlate positively with TC, TG and LDL-C. Furthermore, high significant correlations were observed between LDHbrain and TC, TG, LDL-C, LPObrain as well as LDHliver. Aluminium-induced LPO in brain could arise from alteration of lipid metabolism particularly altered lipoprotein metabolism rather than a direct effect of cholesterol oxidation. Fenugreek seeds could play an anti-peroxidative role in brain which may be attributed in part to its modulatory effect on plasmatic lipid metabolism.

  16. Biochemical and transcriptomic analyses reveal different metabolite biosynthesis profiles among three color and developmental stages in 'Anji Baicha' (Camellia sinensis).

    PubMed

    Li, Chun-Fang; Xu, Yan-Xia; Ma, Jian-Qiang; Jin, Ji-Qiang; Huang, Dan-Juan; Yao, Ming-Zhe; Ma, Chun-Lei; Chen, Liang

    2016-09-08

    The new shoots of the albino tea cultivar 'Anji Baicha' are yellow or white at low temperatures and turn green as the environmental temperatures increase during the early spring. 'Anji Baicha' metabolite profiles exhibit considerable variability over three color and developmental stages, especially regarding the carotenoid, chlorophyll, and theanine concentrations. Previous studies focused on physiological characteristics, gene expression differences, and variations in metabolite abundances in albino tea plant leaves at specific growth stages. However, the molecular mechanisms regulating metabolite biosynthesis in various color and developmental stages in albino tea leaves have not been fully characterized. We used RNA-sequencing to analyze 'Anji Baicha' leaves at the yellow-green, albescent, and re-greening stages. The leaf transcriptomes differed considerably among the three stages. Functional classifications based on Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that differentially expressed unigenes were mainly related to metabolic pathways, biosynthesis of secondary metabolites, phenylpropanoid biosynthesis, and carbon fixation in photosynthetic organisms. Chemical analyses revealed higher β-carotene and theanine levels, but lower chlorophyll a levels, in the albescent stage than in the green stage. Furthermore, unigenes involved in carotenoid, chlorophyll, and theanine biosyntheses were identified, and the expression patterns of the differentially expressed unigenes in these biosynthesis pathways were characterized. Through co-expression analyses, we identified the key genes in these pathways. These genes may be responsible for the metabolite biosynthesis differences among the different leaf color and developmental stages of 'Anji Baicha' tea plants. Our study presents the results of transcriptomic and biochemical analyses of 'Anji Baicha' tea plants at various stages. The distinct transcriptome profiles

  17. Putative adverse outcome pathways relevant to neurotoxicity

    PubMed Central

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  18. Clarithromycin-induced neurotoxicity in adults.

    PubMed

    Bandettini di Poggio, M; Anfosso, Sandra; Audenino, Daniela; Primavera, Alberto

    2011-03-01

    Clarithromycin is a relatively new antibiotic of the macrolide family heralded for an improved side effect profile, dosing schedule, and microbiological activity relative to its parent compound, erythromycin. We review the literature on clarithromycin-induced neurotoxicity in adults and present an illustrative case. A total of 38 patients with clarithromycin-induced neurotoxicity have been reported. The average age of patients was 51.3 years (range: 19-87 years) with females comprising 52.6% of patients. Psychiatric illness was the most common comorbidity, while only two patients had renal failure. Clarithromycin had been prescribed for respiratory infections in most patients, and only two patients were receiving more than 1000 mg/day of antibiotic. The symptoms started 1 day to 10 days after starting clarithromycin (mean: 5 days). A total of 71% of patients were under treatment with concomitant medication, and eight patients were undergoing treatment with psychoactive drugs. Patients had a very good outcome after clarithromycin was discontinued, but medication with neuroleptics or benzodiazepine was required for 58% of patients in the acute phase. Only four patients underwent an electroencephalogram (EEG). Our illustrative patient was a 74-year-old woman with clarithromycin-induced delirium due to non-convulsive status epilepticus (NCSE). Her clinical symptoms and electroencephalogram (EEG) readings dramatically improved after discontinuation of clarithromycin. The mechanism underlying the central nervous system side effects remains unclear. We suggest including an EEG in the diagnostic procedures of patients under treatment with clarithromycin who develop features of neurotoxicity because an EEG can help to differentiate patients with psychiatric illness from those with encephalopathy or epilepsy. Because of the widespread use of clarithromycin, clinicians should be aware of its neurotoxicity. Early detection of clarithromycin-induced neurotoxicity and

  19. Neurotoxicity of general anesthetics: an update.

    PubMed

    Vlisides, Phillip; Xie, Zhongcong

    2012-01-01

    Though general anesthetics have now been used clinically for well over a century, both their mechanisms of action as well as the nature of any potentially neurotoxic side effects remain elusive. With roughly 234 million people undergoing surgery each year worldwide, it remains imperative that any potentially deleterious effects of anesthetics be investigated and addressed. The issue of anesthetic- induced neurotoxicity in certain subsets of patients has continued to garner attention over the past decade, as more pre-clinical and clinical studies released are suggesting that inhalational and intravenous anesthetics may both cause and mitigate existing significant neuropathology. Pre-clinically, both cell-culture and animal studies suggest that anesthetics may cause neuroapoptosis, caspase activation, neurodegeneration, β-amyloid protein (Aβ) accumulation and oligomerization, and ultimately, deficits in neurocognition. Interestingly, however, newer data suggest that certain volatile anesthetics, such as desflurane, may have a less harmful neurotoxic profile compared to others in the pre-clinical and clinical settings. Continued pre-clinical investigation may have significant impact on clinical practice in the near future. Clinically, recent studies have raised awareness that exposure to general anesthetics during childhood may be associated with an increased risk for subsequent deficits in learning, memory, and cognition. Furthermore, retrospective studies continue to allude to the potential effects of surgery and anesthesia on cognitive trajectory, and more specifically, post-operative cognitive dysfunction (POCD) in the elderly. Studies to date regarding both of these clinical topics, however, are fraught with confounders, and many are underpowered statistically. The aim of this review is to examine the current data (both pre-clinical and clinical) on anesthetic-induced neurotoxicity and argue that further data are needed to either support or refute the potential

  20. Nitric oxide neurotoxicity.

    PubMed

    Dawson, V L; Dawson, T M

    1996-06-01

    Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.

  1. Cognitive Profiles of Adults with Asperger's Disorder, High-Functioning Autism, and Pervasive Developmental Disorder Not Otherwise Specified Based on the WAIS-III

    ERIC Educational Resources Information Center

    Kanai, Chieko; Tani, Masayuki; Hashimoto, Ryuichiro; Yamada, Takashi; Ota, Haruhisa; Watanabe, Hiromi; Iwanami, Akira; Kato, Nobumasa

    2012-01-01

    Little is known about the cognitive profiles of high-functioning Pervasive Developmental Disorders (PDD) in adults based on the Wechsler Intelligence Scale III (WAIS-III). We examined cognitive profiles of adults with no intellectual disability (IQ greater than 70), and in adults with Asperger's disorder (AS; n = 47), high-functioning autism (HFA;…

  2. Cognitive Profiles of Adults with Asperger's Disorder, High-Functioning Autism, and Pervasive Developmental Disorder Not Otherwise Specified Based on the WAIS-III

    ERIC Educational Resources Information Center

    Kanai, Chieko; Tani, Masayuki; Hashimoto, Ryuichiro; Yamada, Takashi; Ota, Haruhisa; Watanabe, Hiromi; Iwanami, Akira; Kato, Nobumasa

    2012-01-01

    Little is known about the cognitive profiles of high-functioning Pervasive Developmental Disorders (PDD) in adults based on the Wechsler Intelligence Scale III (WAIS-III). We examined cognitive profiles of adults with no intellectual disability (IQ greater than 70), and in adults with Asperger's disorder (AS; n = 47), high-functioning autism (HFA;…

  3. Developmental validation of the ParaDNA(®) Intelligence System-A novel approach to DNA profiling.

    PubMed

    Blackman, Stephen; Dawnay, Nick; Ball, Glyn; Stafford-Allen, Beccy; Tribble, Nicholas; Rendell, Paul; Neary, Kelsey; Hanson, Erin K; Ballantyne, Jack; Kallifatidis, Beatrice; Mendel, Julian; Mills, DeEtta K; Wells, Simon

    2015-07-01

    DNA profiling through the analysis of STRs remains one of the most widely used tools in human identification across the world. Current laboratory STR analysis is slow, costly and requires expert users and interpretation which can lead to instances of delayed investigations or non-testing of evidence on budget grounds. The ParaDNA(®) Intelligence System has been designed to provide a simple, fast and robust way to profile DNA samples in a lab or field-deployable manner. The system analyses 5-STRs plus amelogenin to deliver a DNA profile that enables users to gain rapid investigative leads and intelligent prioritisation of samples in human identity testing applications. Utilising an innovative sample collector, minimal training is required to enable both DNA analysts and nonspecialist personnel to analyse biological samples directly, without prior processing, in approximately 75min. The test uses direct PCR with fluorescent HyBeacon(®) detection of STR allele lengths to provide a DNA profile. The developmental validation study described here followed the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines and tested the sensitivity, reproducibility, accuracy, inhibitor tolerance, and performance of the ParaDNA Intelligence System on a range of mock evidence items. The data collected demonstrate that the ParaDNA Intelligence System displays useful DNA profiles when sampling a variety of evidence items including blood, saliva, semen and touch DNA items indicating the potential to benefit a number of applications in fields such as forensic, military and disaster victim identification (DVI).

  4. Statewide Advocacy Systems for the Developmentally Disabled-Profiles in Innovation. Executive Summary of Study Report.

    ERIC Educational Resources Information Center

    Weisberg, Susan

    The booklet provides information on the early implementation of state protection and advocacy (P and A) systems as provided for and funded by Public Law 94-103 (Developmentally Disabled Assistance and Bill of Rights Act). The P and A implementing agencies are described in terms of the following characteristics: budget, staffing, use of resources,…

  5. Health Profile of Aging Family Caregivers Supporting Adults with Intellectual and Developmental Disabilities at Home

    ERIC Educational Resources Information Center

    Yamaki, Kiyoshi; Hsieh, Kelly; Heller, Tamar

    2009-01-01

    The health status of 206 female caregivers supporting adults with intellectual and developmental disabilities at home was investigated using objective (i.e., presence of chronic health conditions and activity limitations) and subjective (i.e., self-perceived health status) health measures compared with those of women in the general population in 2…

  6. Sex Differences in WISC-III Profiles of Children with High-Functioning Pervasive Developmental Disorders

    ERIC Educational Resources Information Center

    Koyama, Tomonori; Kamio, Yoko; Inada, Naoko; Kurita, Hiroshi

    2009-01-01

    Using the Japanese version of the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), 26 girls with high-functioning (IQ greater than or equal to 70) pervasive developmental disorders (HFPDD) (mean age, 8.2 years) were compared with 116 boys with HFPDD (mean age, 9.0 years). Compared with the boys, the girls scored significantly…

  7. Sex Differences in WISC-III Profiles of Children with High-Functioning Pervasive Developmental Disorders

    ERIC Educational Resources Information Center

    Koyama, Tomonori; Kamio, Yoko; Inada, Naoko; Kurita, Hiroshi

    2009-01-01

    Using the Japanese version of the Wechsler Intelligence Scale for Children-Third Edition (WISC-III), 26 girls with high-functioning (IQ greater than or equal to 70) pervasive developmental disorders (HFPDD) (mean age, 8.2 years) were compared with 116 boys with HFPDD (mean age, 9.0 years). Compared with the boys, the girls scored significantly…

  8. Developmental Profiles in Preschool Children with Autism Spectrum Disorders Referred for Intervention

    ERIC Educational Resources Information Center

    Fernell, Elisabeth; Hedvall, Asa; Norrelgen, Fritiof; Eriksson, Mats; Hoglund-Carlsson, Lotta; Barnevik-Olsson, Martina; Svensson, Liselotte; Holm, Annette; Westerlund, Joakim; Gillberg, Christopher

    2010-01-01

    The aim was to characterize the panorama of developmental disorders in 208 preschool children with a clinical diagnosis of autism spectrum disorder (ASD), referred to a specialized centre, the Autism Centre for Young Children (ACYC), for intervention. At the centre, a research team examined all children according to structured protocols and…

  9. Health Profile of Aging Family Caregivers Supporting Adults with Intellectual and Developmental Disabilities at Home

    ERIC Educational Resources Information Center

    Yamaki, Kiyoshi; Hsieh, Kelly; Heller, Tamar

    2009-01-01

    The health status of 206 female caregivers supporting adults with intellectual and developmental disabilities at home was investigated using objective (i.e., presence of chronic health conditions and activity limitations) and subjective (i.e., self-perceived health status) health measures compared with those of women in the general population in 2…

  10. Integration of tomato reproductive developmental landmarks and expression profiles, and the effect of SUN on fruit shape

    PubMed Central

    Xiao, Han; Radovich, Cheryll; Welty, Nicholas; Hsu, Jason; Li, Dongmei; Meulia, Tea; van der Knaap, Esther

    2009-01-01

    Background Universally accepted landmark stages are necessary to highlight key events in plant reproductive development and to facilitate comparisons among species. Domestication and selection of tomato resulted in many varieties that differ in fruit shape and size. This diversity is useful to unravel underlying molecular and developmental mechanisms that control organ morphology and patterning. The tomato fruit shape gene SUN controls fruit elongation. The most dramatic effect of SUN on fruit shape occurs after pollination and fertilization although a detailed investigation into the timing of the fruit shape change as well as gene expression profiles during critical developmental stages has not been conducted. Results We provide a description of floral and fruit development in a red-fruited closely related wild relative of tomato, Solanum pimpinellifolium accession LA1589. We use established and propose new floral and fruit landmarks to present a framework for tomato developmental studies. In addition, gene expression profiles of three key stages in floral and fruit development are presented, namely floral buds 10 days before anthesis (floral landmark 7), anthesis-stage flowers (floral landmark 10 and fruit landmark 1), and 5 days post anthesis fruit (fruit landmark 3). To demonstrate the utility of the landmarks, we characterize the tomato shape gene SUN in fruit development. SUN controls fruit shape predominantly after fertilization and its effect reaches a maximum at 8 days post-anthesis coinciding with fruit landmark 4 representing the globular embryo stage of seed development. The expression profiles of the NILs that differ at sun show that only 34 genes were differentially expressed and most of them at a less than 2-fold difference. Conclusion The landmarks for flower and fruit development in tomato were outlined and integrated with the effect of SUN on fruit shape. Although we did not identify many genes differentially expressed in the NILs that differ at

  11. Transcriptome profiling of individual larvae of two different developmental modes in the poecilogonous polychaete Streblospio benedicti (Spionidae).

    PubMed

    Marsh, Adam G; Fielman, Kevin T

    2005-05-15

    Understanding the range of biochemical and physiological phenotypes in a cohort of embryos or larvae is crucial to understanding the lifespan, dispersal potential, and recruitment success of the early life history stages of a species. In this study, a novel kinetic assay has been employed to profile the transcriptome pool complexity in individual larvae of both planktotrophic and lecithotrophic developmental modes in the poecilogonous polycheate Streblospio benedicti. Using a nano-scale synthesis strategy, the mRNA pool in a single embryo or larva can be amplified into cDNA for quantitative characterization in a high-throughput, kinetic reannealing assay in a 96-well, microtiterplate format. This assay generates transcript-pool complexity estimates at 1 degrees C temperature increments for each sample producing 3,360 quantitative measurements per 96-well plate. Measuring transcriptome complexity on 8 individual planktotrophic and 8 individual lecithotrophic larvae (with 4 duplicate assays for each individual) reveals a more complex gene expression profile in planktotrophic larvae and a lower level of interindividual variation in expression patterns in lecithotrophic larvae. Although differences in these gene expression patterns are more likely due to physiological differences between feeding and non-feeding larval types in these late-stage individuals, this is one of the first assessments of inter-individual variation in gene expression patterns in marine invertebrate larvae and indicates a large potential for developmental variability.

  12. High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression

    PubMed Central

    Batut, Philippe; Dobin, Alexander; Plessy, Charles; Carninci, Piero; Gingeras, Thomas R.

    2013-01-01

    Many eukaryotic genes possess multiple alternative promoters with distinct expression specificities. Therefore, comprehensively annotating promoters and deciphering their individual regulatory dynamics is critical for gene expression profiling applications and for our understanding of regulatory complexity. We introduce RAMPAGE, a novel promoter activity profiling approach that combines extremely specific 5′-complete cDNA sequencing with an integrated data analysis workflow, to address the limitations of current techniques. RAMPAGE features a streamlined protocol for fast and easy generation of highly multiplexed sequencing libraries, offers very high transcription start site specificity, generates accurate and reproducible promoter expression measurements, and yields extensive transcript connectivity information through paired-end cDNA sequencing. We used RAMPAGE in a genome-wide study of promoter activity throughout 36 stages of the life cycle of Drosophila melanogaster, and describe here a comprehensive data set that represents the first available developmental time-course of promoter usage. We found that >40% of developmentally expressed genes have at least two promoters and that alternative promoters generally implement distinct regulatory programs. Transposable elements, long proposed to play a central role in the evolution of their host genomes through their ability to regulate gene expression, contribute at least 1300 promoters shaping the developmental transcriptome of D. melanogaster. Hundreds of these promoters drive the expression of annotated genes, and transposons often impart their own expression specificity upon the genes they regulate. These observations provide support for the theory that transposons may drive regulatory innovation through the distribution of stereotyped cis-regulatory modules throughout their host genomes. PMID:22936248

  13. High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression.

    PubMed

    Batut, Philippe; Dobin, Alexander; Plessy, Charles; Carninci, Piero; Gingeras, Thomas R

    2013-01-01

    Many eukaryotic genes possess multiple alternative promoters with distinct expression specificities. Therefore, comprehensively annotating promoters and deciphering their individual regulatory dynamics is critical for gene expression profiling applications and for our understanding of regulatory complexity. We introduce RAMPAGE, a novel promoter activity profiling approach that combines extremely specific 5'-complete cDNA sequencing with an integrated data analysis workflow, to address the limitations of current techniques. RAMPAGE features a streamlined protocol for fast and easy generation of highly multiplexed sequencing libraries, offers very high transcription start site specificity, generates accurate and reproducible promoter expression measurements, and yields extensive transcript connectivity information through paired-end cDNA sequencing. We used RAMPAGE in a genome-wide study of promoter activity throughout 36 stages of the life cycle of Drosophila melanogaster, and describe here a comprehensive data set that represents the first available developmental time-course of promoter usage. We found that >40% of developmentally expressed genes have at least two promoters and that alternative promoters generally implement distinct regulatory programs. Transposable elements, long proposed to play a central role in the evolution of their host genomes through their ability to regulate gene expression, contribute at least 1300 promoters shaping the developmental transcriptome of D. melanogaster. Hundreds of these promoters drive the expression of annotated genes, and transposons often impart their own expression specificity upon the genes they regulate. These observations provide support for the theory that transposons may drive regulatory innovation through the distribution of stereotyped cis-regulatory modules throughout their host genomes.

  14. Chitosan nanoparticles and their Tween 80 modified counterparts disrupt the developmental profile of zebrafish embryos.

    PubMed

    Yuan, Zhongyue; Li, Ying; Hu, Yulan; You, Jian; Higashisaka, Kazuma; Nagano, Kazuya; Tsutsumi, Yasuo; Gao, Jianqing

    2016-12-30

    Chitosan nanoparticles (CS-NPs) and their Tween 80 modified counterparts (TmCS-NPs) are among the most commonly used brain-targeted vehicles. However, their potential developmental toxicity is poorly understood. In this study, zebrafish embryos are introduced as an in vivo platform. Both NPs showed a dose-dependent increase in developmental toxicity (decreased hatching rate, increased mortality and incidences of malformation). Neurobehavioral changes included decreased spontaneous movement in TmCS-NP treated embryos and hyperactive effect in CS-NP treated larvae. Both NPs remarkably inhibited axonal development of primary and secondary motor neurons, and affected the muscle structure. Overall, this study demonstrated that CS-NPs and TmCS-NPs could affect embryonic development, disrupt neurobehavior of zebrafish larvae and affect muscle and neuron development, suggesting more attention on biodegradable chitosan nanoparticles.

  15. Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish.

    PubMed

    Haggard, Derik E; Noyes, Pamela D; Waters, Katrina M; Tanguay, Robert L

    2016-10-01

    Triclosan (TCS) is an antimicrobial agent commonly found in a variety of personal care products and cosmetics. TCS readily enters the environment through wastewater and is detected in human plasma, urine, and breast milk due to its widespread use. Studies have implicated TCS as a disruptor of thyroid and estrogen signaling; therefore, research examining the developmental effects of TCS is warranted. In this study, we used embryonic zebrafish to investigate the developmental toxicity and potential mechanism of action of TCS. Embryos were exposed to graded concentrations of TCS from 6 to 120hours post-fertilization (hpf) and the concentration where 80% of the animals had mortality or morbidity at 120hpf (EC80) was calculated. Transcriptomic profiling was conducted on embryos exposed to the EC80 (7.37μM). We identified a total of 922 significant differentially expressed transcripts (FDR adjusted P-value≤0.05; fold change ≥2). Pathway and gene ontology enrichment analyses identified biological networks and transcriptional hubs involving normal liver functioning, suggesting TCS may be hepatotoxic in zebrafish. Tissue-specific gene enrichment analysis further supported the role of the liver as a target organ for TCS toxicity. We also examined the in vitro bioactivity profile of TCS reported by the ToxCast screening program. TCS had a diverse bioactivity profile and was a hit in 217 of the 385 assay endpoints we identified. We observed similarities in gene expression and hepatic steatosis assays; however, hit data for TCS were more concordant with the hypothesized CAR/PXR activity of TCS from rodent and human in vitro studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Transcriptome profiling of the C. elegans Rb ortholog reveals diverse developmental roles.

    PubMed

    Kirienko, Natalia V; Fay, David S

    2007-05-15

    LIN-35 is the single C. elegans ortholog of the mammalian pocket protein family members, pRb, p107, and p130. To gain insight into the roles of pocket proteins during development, a microarray analysis was performed with lin-35 mutants. Stage-specific regulation patterns were revealed, indicating that LIN-35 plays diverse roles at distinct developmental stages. LIN-35 was found to repress the expression of many genes involved in cell proliferation in larvae, an activity that is carried out in conjunction with E2F. In addition, LIN-35 was found to regulate neuronal genes during embryogenesis and targets of the intestinal-specific GATA transcription factor, ELT-2, at multiple developmental stages. Additional findings suggest that LIN-35 functions in cell cycle regulation in embryos in a manner that is independent of E2F. A comparison of LIN-35-regulated genes with known fly and mammalian pocket protein targets revealed a high degree of overlap, indicating strong conservation of pocket protein functions in diverse phyla. Based on microarray results and our refinement of the C. elegans E2F consensus sequence, we were able to generate a comprehensive list of putative E2F-regulated genes in C. elegans. These results implicate a large number of genes previously unconnected to cell cycle control as having potential roles in this process.

  17. Describing and Predicting Developmental Profiles of Externalizing Problems from Childhood to Adulthood

    PubMed Central

    Petersen, Isaac T.; Bates, John E.; Dodge, Kenneth A.; Lansford, Jennifer E.; Pettit, Gregory S.

    2014-01-01

    This longitudinal study considers externalizing behavior problems from ages 5 to 27 (N = 585). Externalizing problem ratings by mothers, fathers, teachers, peers, and self-report were modeled with growth curves. Risk and protective factors across many different domains and time frames were included as predictors of the trajectories. A major contribution of the study is in demonstrating how heterotypic continuity and changing measures can be handled in modeling changes in externalizing behavior over long developmental periods. On average, externalizing problems decreased from early childhood to preadolescence, increased during adolescence, and decreased from late adolescence to adulthood. There was strong nonlinear continuity in externalizing problems over time. Family process, peer process, stress, and individual characteristics predicted externalizing problems beyond the strong continuity of externalizing problems. The model accounted for 70% of the variability in the development of externalizing problems. The model’s predicted values showed moderate sensitivity and specificity in prediction of arrests, illegal drug use, and drunk driving. Overall, the study showed that by using changing, developmentally-relevant measures and simultaneously taking into account numerous characteristics of children and their living situations, research can model lengthy spans of development and improve predictions of the development of later, severe externalizing problems. PMID:25166430

  18. Safety profile of Hoodia gordonii extract: rabbit prenatal developmental toxicity study.

    PubMed

    Dent, M P; Wolterbeek, A P M; Russell, P J; Bradford, R

    2012-01-01

    Hoodia gordonii extract was orally administered by gavage to groups of 22 female New Zealand white rabbits from day 3-28 after mating at doses of 0 (control), 3, 6 or 12 mg/kg bodyweight/day. These doses were reached by a dose escalation phase between days 3 and 7 after mating. As well as a vehicle control group, a control group pair-fed to the high dose was also included. On day 29 after mating the females were euthanized and examined. Treatment at 6 or 12 mg/kg/day was associated with a dose-related reduction in feed intake and bodyweight gain. Feed consumption and bodyweight gain was unaffected at 3mg/kg/day. In spite of marked maternal effects at 12 mg/kg/day, reproductive indices were unaffected at all doses and there were no effects on fetal or placental weights and no morphological changes in the fetuses. The no-observed-effect level (NOEL) for developmental effects was therefore 12 mg/kg/day, and the maternal NOEL was 3mg/kg/day. At doses that caused marked maternal effects, H. gordonii extract did not affect embryonic or fetal development in a species that is considered predictive of developmental toxicity in man.

  19. Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex

    PubMed Central

    Iafrati, Jillian; Malvache, Arnaud; Gonzalez Campo, Cecilia; Orejarena, M. Juliana; Lassalle, Olivier; Bouamrane, Lamine; Chavis, Pascale

    2016-01-01

    The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders. PMID:27765946

  20. ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties.

    PubMed

    St Pourcain, B; Robinson, E B; Anttila, V; Sullivan, B B; Maller, J; Golding, J; Skuse, D; Ring, S; Evans, D M; Zammit, S; Fisher, S E; Neale, B M; Anney, R J L; Ripke, S; Hollegaard, M V; Werge, T; Ronald, A; Grove, J; Hougaard, D M; Børglum, A D; Mortensen, P B; Daly, M J; Davey Smith, G

    2017-01-03

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.Molecular Psychiatry advance online

  1. ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties

    PubMed Central

    St Pourcain, Beate; Robinson, Elise B.; Anttila, Verneri; Sullivan, Brendan Bulik; Maller, Julian; Golding, Jean; Skuse, David; Ring, Susan; Evans, David M.; Zammit, Stanley; Fisher, Simon E.; Neale, Benjamin M.; Anney, Richard; Ripke, Stephan; Hollegaard, Mads V.; Werge, Thomas; Ronald, Angelica; Grove, Jakob; Hougaard, David M.; Børglum, Anders D.; Mortensen, Preben Bo; Daly, Mark; Smith, George Davey

    2016-01-01

    Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social-communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N≤5,553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social-Communication Disorder Checklist (SCDC). Data on clinical ASD (PGC-ASD: 5,305 cases, 5,305 pseudo-controls; iPSYCH-ASD: 7,783 cases, 11,359 controls) and schizophrenia (PGC-SCZ2: 34,241 cases, 45,604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social-communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social-communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social-communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms. PMID:28044064

  2. Brief report: Assessing youth well-being in global emergency settings: Early results from the Emergency Developmental Assets Profile.

    PubMed

    Scales, Peter C; Roehlkepartain, Eugene C; Wallace, Teresa; Inselman, Ashley; Stephenson, Paul; Rodriguez, Michael

    2015-12-01

    The 13-item Emergency Developmental Assets Profile measures the well-being of children and youth in emergency settings such as refugee camps and armed conflict zones, assessing whether young people are experiencing adequate positive relationships and opportunities, and developing positive values, skills, and self-perceptions, despite being in crisis circumstances. The instrument was found to have acceptable and nearly identical internal consistency reliability in 22 administrations in non-emergency samples in 15 countries (.75), and in 4 samples of youth ages 10-18 (n = 1550) in the emergency settings (war refugees and typhoon victims, .74) that are the measure's focus, and evidence of convergent validity. Confirmatory Factor Analysis showed acceptable model fit among those youth in emergency settings. Measures of model fit showed that the Em-DAP has configural and metric invariance across all emergency contexts and scalar invariance across some. The Em-DAP is a promising brief cross-cultural tool for assessing the developmental quality of life as reported by samples of youth in a current humanitarian crisis situation. The results can help to inform international relief program decisions about services and activities to be provided for children, youth, and families in emergency settings. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  3. Early-postnatal changes in adiposity and lipids profile by transgenerational developmental programming in swine with obesity/leptin resistance.

    PubMed

    Gonzalez-Bulnes, Antonio; Astiz, Susana; Ovilo, Cristina; Lopez-Bote, Clemente J; Sanchez-Sanchez, Raul; Perez-Solana, Maria L; Torres-Rovira, Laura; Ayuso, Miriam; Gonzalez, Jorge

    2014-10-01

    Maternal malnutrition during pregnancy, both deficiency and excess, induces changes in the intrauterine environment and the metabolic status of the offspring, playing a key role in the growth, status of fitness/obesity and appearance of metabolic disorders during postnatal life. There is increasing evidence that these effects may not be only limited to the first generation of descendants, the offspring directly exposed to metabolic challenges, but to subsequent generations. This study evaluated, in a swine model of obesity/leptin resistance, the existence and extent of transgenerational developmental programming effects. Pre- and postnatal development, adiposity and metabolic features were assessed in the second generation of piglets, descendant of sows exposed to either undernutrition or overnutrition during pregnancy. The results indicated that these piglets exhibited early-postnatal increases in adiposity and disturbances in lipid profiles compatible with the early prodrome of metabolic syndrome, with liver tissue also displaying evidence of paediatric liver disease. These features indicative of early-life metabolic disorders were more evident in the males that were descended from overfed grandmothers and during the transition from milk to solid feeding. Thus, this study provides evidence supporting transgenerational developmental programming and supports the necessity for the development of strategies for avoiding the current epidemics of childhood overweight and obesity.

  4. Empathy in Children with Autism and Conduct Disorder: Group-Specific Profiles and Developmental Aspects

    ERIC Educational Resources Information Center

    Schwenck, Christina; Mergenthaler, Julia; Keller, Katharina; Zech, Julie; Salehi, Sarah; Taurines, Regina; Romanos, Marcel; Schecklmann, Martin; Schneider, Wolfgang; Warnke, Andreas; Freitag, Christine M.

    2012-01-01

    Background: A deficit in empathy is discussed to underlie difficulties in social interaction of children with autism spectrum disorder (ASD) and conduct disorder (CD). To date, no study has compared children with ASD and different subtypes of CD to describe disorder-specific empathy profiles in clinical samples. Furthermore, little is known about…

  5. Empathy in Children with Autism and Conduct Disorder: Group-Specific Profiles and Developmental Aspects

    ERIC Educational Resources Information Center

    Schwenck, Christina; Mergenthaler, Julia; Keller, Katharina; Zech, Julie; Salehi, Sarah; Taurines, Regina; Romanos, Marcel; Schecklmann, Martin; Schneider, Wolfgang; Warnke, Andreas; Freitag, Christine M.

    2012-01-01

    Background: A deficit in empathy is discussed to underlie difficulties in social interaction of children with autism spectrum disorder (ASD) and conduct disorder (CD). To date, no study has compared children with ASD and different subtypes of CD to describe disorder-specific empathy profiles in clinical samples. Furthermore, little is known about…

  6. Developmental functioning and medical Co-morbidity profile of children with complex and essential autism.

    PubMed

    Flor, Jaimie; Bellando, Jayne; Lopez, Maya; Shui, Amy

    2017-08-01

    Children with Autism Spectrum Disorders (ASD) may be characterized as "complex" (those with microcephaly and/or dysmorphology) or "essential" (those with neither of these two). Previous studies found subjects in the complex group exhibited lower IQ scores, poorer response to behavioral intervention, more seizures and more abnormal EEGs and brain MRIs compared to the essential group. The objective of this study was to determine if there are differences in complex versus essential subjects based on several developmental/psychological measures as well as certain medical comorbidities. This study utilized data from 1,347 individuals (2-17 years old) well-characterized subjects enrolled in Autism Treatment Network (ATN) Registry. Head circumference measurement and the Autism Dysmorphology Measure (ADM) were used by trained physicians to classify subjects as complex or essential. Significantly lower scores were seen for complex subjects in cognitive level, adaptive behavior and quality of life. Complex subjects showed significantly increased physician-documented GI symptoms and were on a higher number of medications. No significant differences in autism severity scores, behavioral ratings and parent-reported sleep problems were found. After adjusting for multiple comparisons made, adaptive scores remained significantly lower for the complex group, and the complex group used a significantly higher number of medications and had increased GI symptoms. Complex and essential autism subtypes may have distinct developmental and medical correlates and thus underlines the importance of looking for microcephaly and dysmorphology, when evaluating a child with autism. Determining this distinction in autism may have implications in prognosis, identifying medical co-morbidities, directing diagnostic evaluations and treatment interventions. Autism Res 2017, 10: 1344-1352. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. © 2017 International Society for Autism

  7. Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional diversification, and novel developmental profiles.

    PubMed

    Wang, Jianbin; Czech, Benjamin; Crunk, Amanda; Wallace, Adam; Mitreva, Makedonka; Hannon, Gregory J; Davis, Richard E

    2011-09-01

    Eukaryotic cells express several classes of small RNAs that regulate gene expression and ensure genome maintenance. Endogenous siRNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs) mainly control gene and transposon expression in the germline, while microRNAs (miRNAs) generally function in post-transcriptional gene silencing in both somatic and germline cells. To provide an evolutionary and developmental perspective on small RNA pathways in nematodes, we identified and characterized known and novel small RNA classes through gametogenesis and embryo development in the parasitic nematode Ascaris suum and compared them with known small RNAs of Caenorhabditis elegans. piRNAs, Piwi-clade Argonautes, and other proteins associated with the piRNA pathway have been lost in Ascaris. miRNAs are synthesized immediately after fertilization in utero, before pronuclear fusion, and before the first cleavage of the zygote. This is the earliest expression of small RNAs ever described at a developmental stage long thought to be transcriptionally quiescent. A comparison of the two classes of Ascaris endo-siRNAs, 22G-RNAs and 26G-RNAs, to those in C. elegans, suggests great diversification and plasticity in the use of small RNA pathways during spermatogenesis in different nematodes. Our data reveal conserved characteristics of nematode small RNAs as well as features unique to Ascaris that illustrate significant flexibility in the use of small RNAs pathways, some of which are likely an adaptation to Ascaris' life cycle and parasitism. The transcriptome assembly has been submitted to NCBI Transcriptome Shotgun Assembly Sequence Database(http://www.ncbi.nlm.nih.gov/genbank/TSA.html) under accession numbers JI163767–JI182837 and JI210738–JI257410.

  8. Chemotherapy-Related Neurotoxicity.

    PubMed

    Taillibert, Sophie; Le Rhun, Emilie; Chamberlain, Marc C

    2016-09-01

    Chemotherapy may have detrimental effects on either the central or peripheral nervous system. Central nervous system neurotoxicity resulting from chemotherapy manifests as a wide range of clinical syndromes including acute, subacute, and chronic encephalopathies, posterior reversible encephalopathy, acute cerebellar dysfunction, chronic cognitive impairment, myelopathy, meningitis, and neurovascular syndromes. These clinical entities vary by causative agent, degree of severity, evolution, and timing of occurrence. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) and myopathy are the two main complications of chemotherapy. CIPN is the most common complication, and the majority manifest as a dose-dependent length-dependent sensory axonopathy. In severe cases of CIPN, the dose of chemotherapy is reduced, the administration delayed, or the treatment discontinued. Few treatments are available for CIPN and based on meta-analysis, duloxetine is the preferred symptomatic treatment. Myopathy due to corticosteroid use is the most frequent cause of muscle disorders in patients with cancer.

  9. Neurotoxicity of metals.

    PubMed

    Caito, Samuel; Aschner, Michael

    2015-01-01

    Metals are frequently used in industry and represent a major source of toxin exposure for workers. For this reason governmental agencies regulate the amount of metal exposure permissible for worker safety. While essential metals serve physiologic roles, metals pose significant health risks upon acute and chronic exposure to high levels. The central nervous system is particularly vulnerable to metals. The brain readily accumulates metals, which under physiologic conditions are incorporated into essential metalloproteins required for neuronal health and energy homeostasis. Severe consequences can arise from circumstances of excess essential metals or exposure to toxic nonessential metal. Herein, we discuss sources of occupational metal exposure, metal homeostasis in the human body, susceptibility of the nervous system to metals, detoxification, detection of metals in biologic samples, and chelation therapeutic strategies. The neurologic pathology and physiology following aluminum, arsenic, lead, manganese, mercury, and trimethyltin exposures are highlighted as classic examples of metal-induced neurotoxicity.

  10. Neurotoxicity of organomercurial compounds.

    PubMed

    Sanfeliu, Coral; Sebastià, Jordi; Cristòfol, Rosa; Rodríguez-Farré, Eduard

    2003-01-01

    Mercury is a ubiquitous contaminant, and a range of chemical species is generated by human activity and natural environmental change. Elemental mercury and its inorganic and organic compounds have different toxic properties, but all them are considered hazardous in human exposure. In an equimolecular exposure basis, organomercurials with a short aliphatic chain are the most harmful compounds and they may cause irreversible damage to the nervous system. Methylmercury (CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified as Minamata disease and the Iraq poisoning. The first description of the CNS pathology dates from 1954. Since then, the clinical neurology, the neuropathology and the mechanisms of neurotoxicity of organomercurials have been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all mercury compounds, has been suggested to be the basis of their harmful biological effects. However, there is clear selectivity of CH(3)Hg(+) for specific cell types and brain structures, which is not yet fully understood. The main mechanisms involved are inhibition of protein synthesis, microtubule disruption, increase of intracellular Ca(2+) with disturbance of neurotransmitter function, oxidative stress and triggering of excitotoxicity mechanisms. The effects are more damaging during CNS development, leading to alterations of the structure and functionality of the nervous system. The major source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its intake is practically unavoidable. The present concern is on the study of the effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these levels are easily attained with few meals of fish per week, depending on the source of the fish and its position in the

  11. Expression Profile of Developmentally Important Genes in preand peri-Implantation Goat Embryos Produced In Vitro

    PubMed Central

    Tahmoorespur, Mojtaba; Hosseini, Sayyed Morteza; Ostadhosseini, Somayyeh; Nasiri, Mohammad Reza; Nasr-Esfahani, Mohammad Hossein

    2016-01-01

    Background: Little is understood about the regulation of gene expression during early goat embryo development. This study investigated the expression profile of 19 genes, known to be critical for early embryo development in mouse and human, at five different stages of goat in vitro embryo development (oocyte, 8-16 cell, morula, day-7 blastocyst, and day 14 blastocyst). Materials and Methods: In this experimental study, stage-specific profiling using real time-quantitative polymerase chain reaction (RT-qPCR) revealed robust and dynamic patterns of stage-specific gene activity that fall into four major clusters depending on their respective mRNA profiles. Results: The gradual pattern of reduction in the maternally stored transcripts without renewal thereafter (cluster-1: Lifr1, Bmpr1, Alk4, Id3, Ctnnb, Akt, Oct4, Rex1, Erk1, Smad1 and 5) implies that their protein products are essential during early cleavages when the goat embryo is silent and reliant to the maternal legacy of mRNA. The potential importance of transcription augment at day-3 (cluster-2: Fzd, c-Myc, Cdc25a, Sox2) or day- 14 (cluster-3: Fgfr4, Nanog) suggests that they are nascent embryonic mRNAs which intimately involved in the overriding of MET or regulation of blastocyst formation, respectively. The observation of two expression peaks at both day-3 and day-14 (cluster-4: Gata4, Cdx2) would imply their potential importance during these two critical stages of preand periimplantation development. Conclusion: Evolutionary comparison revealed that the selected subset of genes has been rewired in goat and human/goat similarity is greater than the mouse/goat or bovine/goat similarities. The developed profiles provide a resource for comprehensive understanding of goat preimplantation development and pluripotent stem cell engineering as well. PMID:27695614

  12. Cardiovascular regulation profile predicts developmental trajectory of BMI and pediatric obesity.

    PubMed

    Graziano, Paulo A; Calkins, Susan D; Keane, Susan P; O'Brien, Marion

    2011-09-01

    The present study examined the role of cardiovascular regulation in predicting pediatric obesity. Participants for this study included 268 children (141 girls) obtained from a larger ongoing longitudinal study. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (vagal withdrawal) to three cognitively challenging tasks were derived when children were 5.5 years of age. Heart period (HP) and HP change (heart rate (HR) acceleration) were also examined. Height and weight measures were collected when children were 5.5, 7.5, and 10.5 years of age. Results indicated that physiological regulation at age 5.5 was predictive of both normal variations in BMI development and pediatric obesity at age 10.5. Specifically, children with a cardiovascular regulation profile characterized by lower levels of RSA suppression and HP change experienced significantly greater levels of BMI growth and were more likely to be classified as overweight/at-risk for overweight at age 10.5 compared to children with a cardiovascular regulation profile characterized by high levels of RSA suppression and HP change. However, a significant interaction with racial status was found suggesting that the association between cardiovascular regulation profile and BMI growth and pediatric obesity was only significant for African-American children. An autonomic cardiovascular regulation profile consisting of low parasympathetic activity represents a significant individual risk factor for the development of pediatric obesity, but only for African-American children. Mechanisms by which early physiological regulation difficulties may contribute to the development of pediatric obesity are discussed.

  13. Developmental Profile of Ion Channel Specializations in the Avian Nucleus Magnocellularis

    PubMed Central

    Hong, Hui; Rollman, Lisia; Feinstein, Brooke; Sanchez, Jason Tait

    2016-01-01

    Ultrafast and temporally precise action potentials (APs) are biophysical specializations of auditory brainstem neurons; properties necessary for encoding sound localization and communication cues. Fundamental to these specializations are voltage dependent potassium (KV) and sodium (NaV) ion channels. Here, we characterized the functional development of these ion channels and quantified how they shape AP properties in the avian cochlear nucleus magnocellularis (NM). We report that late developing NM neurons (embryonic [E] days 19–21) generate fast APs that reliably phase lock to sinusoidal inputs at 75 Hz. In contrast, early developing neurons (developmental upregulation of low-voltage activated potassium (K+LVA) channels. Indeed, blockade of K+LVA eliminated remaining current and increased neural excitability for late developing neurons. We also report developmental changes in the amplitude, kinetics and voltage dependence of NaV currents. For early developing neurons, increase in NaV current amplitude was due to channel density while channel conductance dominated for late developing neurons. From E10 to E21, NaV channel currents became faster but differed in their voltage dependence; early developing neurons (E19) contained NaV channels that inactivate at more

  14. Developmental profile and hormonal regulation of the transcription factors broad and Krüppel homolog 1 in hemimetabolous thrips.

    PubMed

    Minakuchi, Chieka; Tanaka, Miho; Miura, Ken; Tanaka, Toshiharu

    2011-02-01

    In holometabolous insects, Krüppel homolog 1 (Kr-h1) and broad (br) are key players in the juvenile hormone (JH) regulation of metamorphosis: Kr-h1 is an early JH-response gene, while br is a transcription factor that directs pupal development. Thrips (Thysanoptera) are classified as hemimetabolous insects that develop directly from nymph to adult, but they have quiescent and non-feeding stages called propupa and pupa. We analyzed the developmental profiles of br and Kr-h1 in the western flower thrips Frankliniella occidentalis (Thripidae) that has one propupal instar and one pupal instar, and Haplothrips brevitubus (Phlaeothripidae) that has one propupal instar and two pupal instars, i.e. pupa I and pupa II. In F. occidentalis, the br mRNA levels were moderate in the embryonic stage, high at the larva-propupa transition, and low in the pre-final larval instar and the pupal stage, while Kr-h1 mRNA levels were high in the embryonic stage, remained at a moderate level in the larval and propupal stages, and low in the pupal stage. The expression profiles in H. brevitubus were very similar to those in F. occidentalis, except that the increase of br expression in the final larval stage occurs more slowly in H. brevitubus, and that the mRNA levels of br and Kr-h1 remained high in pupa I of H. brevitubus and then decreased. These profiles of br and Kr-h1 were comparable to those in holometabolous insects, although br expression found in thrips' embryogenesis is reminiscent of several hemimetabolous species. Treatment with an exogenous JH mimic (JHM) in distinct developmental stages consistently resulted in lethality as pupa of F. occidentalis or pupa II of H. brevitubus. Treatment with JHM to newly molted propupae caused prolonged expression of Kr-h1 and br in both species, suggesting that Kr-h1 and br could be involved in mediating anti-metamorphic signals of JHM.

  15. Developmental profile of SK2 channel expression and function in CA1 neurons

    PubMed Central

    Ballesteros-Merino, Carmen; Lin, Mike; Wu, Wendy W.; Ferrandiz-Huertas, Clotilde; Cabañero, María J.; Watanabe, Masahiko; Fukazawa, Yugo; Shigemoto, Ryuichi; Maylie, James; Adelman, John P.; Luján, Rafael

    2012-01-01

    We investigated the temporal and spatial expression of SK2 in the developing mouse hippocampus using molecular and biochemical techniques, quantitative immunogold electron microscopy and electrophysiology. The mRNA encoding SK2 was expressed in the developing and adult hippocampus. Western blotting and immunohistochemistry showed that SK2 protein increased with age. This was accompanied by a shift in subcellular localization. Early in development (P5), SK2 was predominantly localized to the endoplasmic reticulum in the pyramidal cell layer. But by P30 SK2 was almost exclusively expressed in the dendrites and spines. The level of SK2 at the postsynaptic density (PSD) also increased during development. In the adult, SK2 expression on the spine plasma membrane showed a proximal-to-distal gradient. Consistent with this redistribution and gradient of SK2, the selective SK channel blocker apamin increased evoked excitatory postsynaptic potentials (EPSPs) only in CA1 pyramidal neurons from mice older than P15. However, the effect of apamin on EPSPs was not different between synapses in proximal or distal stratum radiatum or stratum lacunosum-moleculare in adult. These results show a developmental increase and gradient in SK2-containing channel surface expression that underlie their influence on neurotransmission, and that may contribute to increased memory acquisition during early development. PMID:22072564

  16. Neonatal anesthetic neurotoxicity: Insight into the molecular mechanisms of long-term neurocognitive deficits.

    PubMed

    Yu, Deshui; Li, Linji; Yuan, Weiguo

    2017-03-01

    Mounting animal studies have demonstrated that almost all the clinically used general anesthetics could induce widespread neuroapoptosis in the immature brain. Alarmingly, some published findings have reported long-term neurocognitive deficits in response to early anesthesia exposure which deeply stresses the potential seriousness of developmental anesthetic neurotoxicity. However, the connection between anesthesia induced neuroapoptosis and subsequent neurocognitive deficits remains controversial. It should be noted that developmental anesthesia related neurotoxicity is not limited to neuroapoptosis. Early anesthesia exposure caused transient suppression of neurogenesis, ultrastructural abnormalities in synapse and alteration in the development of neuronal networks also could contribute to the long-term neurocognitive dysfunction. Understanding the mechanisms of developmental anesthetic neurotoxicity, especially by which anesthesia impairs brain function months after exposure, may lead to development of rational preventive and therapeutic strategies. The focus of present review is on some of those potential mechanisms that have been proposed for anesthesia induced cognitive decline. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Guidelines for Neurotoxicity Risk Assessment

    EPA Pesticide Factsheets

    These Guidelines set forth principles and procedures to guide EPA scientists in evaluating environmental contaminants that may pose neurotoxic risks, and inform Agency decision makers and the public about these procedures.

  18. Comparison of Small RNA Profiles of Glycine max and Glycine soja at Early Developmental Stages

    PubMed Central

    Sun, Yuzhe; Mui, Zeta; Liu, Xuan; Yim, Aldrin Kay-Yuen; Qin, Hao; Wong, Fuk-Ling; Chan, Ting-Fung; Yiu, Siu-Ming; Lam, Hon-Ming; Lim, Boon Leong

    2016-01-01

    Small RNAs, including microRNAs (miRNAs) and phased small interfering RNAs (phasiRNAs; from PHAS loci), play key roles in plant development. Cultivated soybean, Glycine max, contributes a great deal to food production, but, compared to its wild kin, Glycine soja, it may lose some genetic information during domestication. In this work, we analyzed the sRNA profiles of different tissues in both cultivated (C08) and wild soybeans (W05) at three stages of development. A total of 443 known miRNAs and 15 novel miRNAs showed varying abundances between different samples, but the miRNA profiles were generally similar in both accessions. Based on a sliding window analysis workflow that we developed, 50 PHAS loci generating 55 21-nucleotide phasiRNAs were identified in C08, and 46 phasiRNAs from 41 PHAS loci were identified in W05. In germinated seedlings, phasiRNAs were more abundant in C08 than in W05. Disease resistant TIR-NB-LRR genes constitute a very large family of PHAS loci. PhasiRNAs were also generated from several loci that encode for NAC transcription factors, Dicer-like 2 (DCL2), Pentatricopeptide Repeat (PPR), and Auxin Signaling F-box 3 (AFB3) proteins. To investigate the possible involvement of miRNAs in initiating the PHAS-phasiRNA pathway, miRNA target predictions were performed and 17 C08 miRNAs and 15 W05 miRNAs were predicted to trigger phasiRNAs biogenesis. In summary, we provide a comprehensive description of the sRNA profiles of wild versus cultivated soybeans, and discuss the possible roles of sRNAs during soybean germination. PMID:27929436

  19. Comparison of Small RNA Profiles of Glycine max and Glycine soja at Early Developmental Stages.

    PubMed

    Sun, Yuzhe; Mui, Zeta; Liu, Xuan; Yim, Aldrin Kay-Yuen; Qin, Hao; Wong, Fuk-Ling; Chan, Ting-Fung; Yiu, Siu-Ming; Lam, Hon-Ming; Lim, Boon Leong

    2016-12-06

    Small RNAs, including microRNAs (miRNAs) and phased small interfering RNAs (phasiRNAs; from PHAS loci), play key roles in plant development. Cultivated soybean, Glycine max, contributes a great deal to food production, but, compared to its wild kin, Glycine soja, it may lose some genetic information during domestication. In this work, we analyzed the sRNA profiles of different tissues in both cultivated (C08) and wild soybeans (W05) at three stages of development. A total of 443 known miRNAs and 15 novel miRNAs showed varying abundances between different samples, but the miRNA profiles were generally similar in both accessions. Based on a sliding window analysis workflow that we developed, 50 PHAS loci generating 55 21-nucleotide phasiRNAs were identified in C08, and 46 phasiRNAs from 41 PHAS loci were identified in W05. In germinated seedlings, phasiRNAs were more abundant in C08 than in W05. Disease resistant TIR-NB-LRR genes constitute a very large family of PHAS loci. PhasiRNAs were also generated from several loci that encode for NAC transcription factors, Dicer-like 2 (DCL2), Pentatricopeptide Repeat (PPR), and Auxin Signaling F-box 3 (AFB3) proteins. To investigate the possible involvement of miRNAs in initiating the PHAS-phasiRNA pathway, miRNA target predictions were performed and 17 C08 miRNAs and 15 W05 miRNAs were predicted to trigger phasiRNAs biogenesis. In summary, we provide a comprehensive description of the sRNA profiles of wild versus cultivated soybeans, and discuss the possible roles of sRNAs during soybean germination.

  20. Guidelines for neurotoxicity risk assessment

    SciTech Connect

    1998-04-01

    These Guidelines describe the principles, concepts, and procedures that the US Environmental Protection Agency (EPA) will follow in evaluating data on potential neurotoxicity associated with exposure to environmental toxicants. The procedures outlined are intended to help develop a sound scientific basis for neurotoxicity risk assessment, promote consistency in the Agency`s assessment of toxic effects on the nervous system, and inform others of the approaches used by the Agency in those assessments.

  1. Building a Database of Developmental Neurotoxitants: Evidence from Human and Animal Studies

    EPA Science Inventory

    EPA’s program for the screening and prioritization of chemicals for developmental neurotoxicity (DNT) necessitates the generation of a list of chemicals that are known mammalian developmental neurotoxicants. This chemical list will be used to evaluate the sensitivity, reliability...

  2. Building a Database of Developmental Neurotoxitants: Evidence from Human and Animal Studies

    EPA Science Inventory

    EPA’s program for the screening and prioritization of chemicals for developmental neurotoxicity (DNT) necessitates the generation of a list of chemicals that are known mammalian developmental neurotoxicants. This chemical list will be used to evaluate the sensitivity, reliability...

  3. Developmental validation of DogFiler, a novel multiplex for canine DNA profiling in forensic casework.

    PubMed

    Wictum, Elizabeth; Kun, Teri; Lindquist, Christina; Malvick, Julia; Vankan, Dianne; Sacks, Benjamin

    2013-01-01

    While the analysis of human DNA has been the focus of large-scale collaborative endeavors, non-human forensic DNA analysis has not benefited from the same funding streams and coordination of effort. Consequently, the development of standard marker panels, allelic ladders and allele-specific sequence data comparable to those established for human forensic genetics has lagged. To meet that need for domestic dogs, we investigated sequence data provided by the published 7.6X dog genome for novel short tandem repeat markers that met our criteria for sensitivity, stability, robustness, polymorphic information content, and ease of scoring. Fifteen unlinked tetranucleotide repeat markers were selected from a pool of 3113 candidate markers and assembled with a sex-linked marker into a multiplex capable of generating a full profile with as little as 60pg of nuclear DNA. An accompanying allelic ladder was assembled and sequenced to obtain detailed repeat motif data. Validation was carried out according to SWGDAM guidelines, and the DogFiler panel has been integrated into forensic casework and accepted in courts across the U.S. Applying various formulae for calculating random match probabilities for inbred populations, estimates for this panel of markers have proven to be comparable to those obtained in human forensic genetics. The DogFiler panel and the associated allelic ladder represent the first published non-human profiling system to fully address all SWGDAM recommendations.

  4. Functional characterization and developmental expression profiling of gibberellin signalling components in Vitis vinifera

    PubMed Central

    Acheampong, Atiako Kwame; Hu, Jianhong; Rotman, Ariel; Zheng, Chuanlin; Halaly, Tamar; Takebayashi, Yumiko; Jikumaru, Yusuke; Kamiya, Yuji; Lichter, Amnon; Sun, Tai-Ping; Or, Etti

    2015-01-01

    Gibberellins (GAs) regulate numerous developmental processes in grapevine (Vitis vinifera) such as rachis elongation, fruit set, and fruitlet abscission. The ability of GA to promote berry enlargement has led to its indispensable use in the sternospermocarpic (‘seedless’) table grape industry worldwide. However, apart from VvGAI1 (VvDELLA1), which regulates internode elongation and fruitfulness, but not berry size of seeded cultivars, little was known about GA signalling in grapevine. We have identified and characterized two additional DELLAs (VvDELLA2 and VvDELLA3), two GA receptors (VvGID1a and VvGID1b), and two GA-specific F-box proteins (VvSLY1a and VvSLY1b), in cv. Thompson seedless. With the exception of VvDELLA3-VvGID1b, all VvDELLAs interacted with the VvGID1s in a GA-dependent manner in yeast two-hybrid assays. Additionally, expression of these grape genes in corresponding Arabidopsis mutants confirmed their functions in planta. Spatiotemporal analysis of VvDELLAs showed that both VvDELLA1 and VvDELLA2 are abundant in most tissues, except in developing fruit where VvDELLA2 is uniquely expressed at high levels, suggesting a key role in fruit development. Our results further suggest that differential organ responses to exogenous GA depend on the levels of VvDELLA proteins and endogenous bioactive GAs. Understanding this interaction will allow better manipulation of GA signalling in grapevine. PMID:25588745

  5. Functional characterization and developmental expression profiling of gibberellin signalling components in Vitis vinifera.

    PubMed

    Acheampong, Atiako Kwame; Hu, Jianhong; Rotman, Ariel; Zheng, Chuanlin; Halaly, Tamar; Takebayashi, Yumiko; Jikumaru, Yusuke; Kamiya, Yuji; Lichter, Amnon; Sun, Tai-Ping; Or, Etti

    2015-03-01

    Gibberellins (GAs) regulate numerous developmental processes in grapevine (Vitis vinifera) such as rachis elongation, fruit set, and fruitlet abscission. The ability of GA to promote berry enlargement has led to its indispensable use in the sternospermocarpic ('seedless') table grape industry worldwide. However, apart from VvGAI1 (VvDELLA1), which regulates internode elongation and fruitfulness, but not berry size of seeded cultivars, little was known about GA signalling in grapevine. We have identified and characterized two additional DELLAs (VvDELLA2 and VvDELLA3), two GA receptors (VvGID1a and VvGID1b), and two GA-specific F-box proteins (VvSLY1a and VvSLY1b), in cv. Thompson seedless. With the exception of VvDELLA3-VvGID1b, all VvDELLAs interacted with the VvGID1s in a GA-dependent manner in yeast two-hybrid assays. Additionally, expression of these grape genes in corresponding Arabidopsis mutants confirmed their functions in planta. Spatiotemporal analysis of VvDELLAs showed that both VvDELLA1 and VvDELLA2 are abundant in most tissues, except in developing fruit where VvDELLA2 is uniquely expressed at high levels, suggesting a key role in fruit development. Our results further suggest that differential organ responses to exogenous GA depend on the levels of VvDELLA proteins and endogenous bioactive GAs. Understanding this interaction will allow better manipulation of GA signalling in grapevine. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  6. [Hyperhomocysteinemia: atherothrombosis and neurotoxicity].

    PubMed

    Fridman, O

    1999-01-01

    The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation

  7. Pyruvate-kinase isoenzymes from zygotic and microspore-derived embryos of Brassica napus : Developmental profiles and subunit composition.

    PubMed

    Sangwan, R S; Gauthier, D A; Turpin, D H; Pomeroy, M K; Plaxton, W C

    1992-05-01

    Polyclonal antibodies against castor-oil seed cytosolic and leucoplastic pyruvate kinases (PKc and PKp, respectively; EC 2.7.1.40) were utilized to examine the subunit compositions and developmental profiles of canola (Brassica napus L. cv. Topas) PKc and PKp over 6 d of seed germination and 35 d of culture of microspore-derived embryos. The PKc from germinating seeds appears to be composed of a single type of 56-kDa subunit, whereas the enzyme from cultured embryos contains equal proportions of immunologically related 57- and 56-kDa subunits. The PKp was immunologically undetectable in germinating seeds, while the enzyme from cultured embryos consisted of immunologically related 64- and 58-kDa subunits in a ratio of about 1∶2, respectively. The large increase in PK activity that occurs between the second and fourth days of seed gemination is based upon de-novo synthesis of PKc. Between 7 and 14 d of culture of microspore-derived embryos, the levels of PKp and PK maximal activity increased approx. 3- and 2.5-fold, respectively. These increases were coincident with an approximately fourfold rise in the in-vivo pyruvate: phosphoenolpyruvate concentration ratio. Conversely, PKc was not only far less abundant relative to PKp, but its level remained constant over 35 d of microspore-embryo culture. Developing non-zygotic (microspore-derived) embryos strongly resembled ripening zygotic (seed) embryos in terms of PK specific activity as well as relative amounts and subunit compositions of PKc and PKp. The results indicate that the synthesis of PK isoenzymes in B. napus seeds is highly regulated and that this regulation follows a preset developmental program.

  8. Developmental profiling of gene expression in soybean trifoliate leaves and cotyledons.

    PubMed

    Brown, Anne V; Hudson, Karen A

    2015-07-03

    Immediately following germination, the developing soybean seedling relies on the nutrient reserves stored in the cotyledons to sustain heterotrophic growth. During the seed filling period, developing seeds rely on the transport of nutrients from the trifoliate leaves. In soybean, both cotyledons and leaves develop the capacity for photosynthesis, and subsequently senesce and abscise once their function has ended. Before this occurs, the nutrients they contain are mobilized and transported to other parts of the plant. These processes are carefully orchestrated by genetic regulation throughout the development of the leaf or cotyledon. To identify genes involved in the processes of leaf or cotyledon development and senescence in soybean, we used RNA-seq to profile multiple stages of cotyledon and leaf tissues. Differentially expressed genes between stages of leaf or cotyledon development were determined, major patterns of gene expression were defined, and shared genes were identified. Over 38,000 transcripts were expressed during the course of leaf and cotyledon development. Of those transcripts, 5,000 were expressed in a tissue specific pattern. Of the genes that were differentially expressed between both later stage tissues, 90 % had the same direction of change, suggesting that the mechanisms of senescence are conserved between tissues. Analysis of the enrichment of biological functions within genes sharing common expression profiles highlights the main processes occurring within these defined temporal windows of leaf and cotyledon development. Over 1,000 genes were identified with predicted regulatory functions that may have a role in control of leaf or cotyledon senescence. The process of leaf and cotyledon development can be divided into distinct stages characterized by the expression of specific gene sets. The importance of the WRKY, NAC, and GRAS family transcription factors as major regulators of plant senescence is confirmed for both soybean leaf and

  9. Neurobehavioural effects of developmental toxicity

    PubMed Central

    Grandjean, Philippe; Landrigan, Philip J

    2015-01-01

    Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children worldwide, and some diagnoses seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence. In 2006, we did a systematic review and identified five industrial chemicals as developmental neurotoxicants: lead, methylmercury, polychlorinated biphenyls, arsenic, and toluene. Since 2006, epidemiological studies have documented six additional developmental neurotoxicants—manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane, tetrachloroethylene, and the polybrominated diphenyl ethers. We postulate that even more neurotoxicants remain undiscovered. To control the pandemic of developmental neurotoxicity, we propose a global prevention strategy. Untested chemicals should not be presumed to be safe to brain development, and chemicals in existing use and all new chemicals must therefore be tested for developmental neurotoxicity. To coordinate these efforts and to accelerate translation of science into prevention, we propose the urgent formation of a new international clearinghouse. PMID:24556010

  10. Carotenoid profiling, in silico analysis and transcript profiling of miRNAs targeting carotenoid biosynthetic pathway genes in different developmental tissues of tomato.

    PubMed

    Koul, Archana; Yogindran, Sneha; Sharma, Deepak; Kaul, Sanjana; Rajam, Manchikatla Venkat; Dhar, Manoj K

    2016-11-01

    Carotenoid biosynthetic pathway is one of the highly significant and very well elucidated secondary metabolic pathways in plants. microRNAs are the potential regulators, widely known for playing a pivotal role in the regulation of various biological as well as metabolic processes. miRNAs may assist in the metabolic engineering of the secondary metabolites for the production of elite genotypes with increased biomass and content of various metabolites. miRNA mediated regulation of carotenoid biosynthetic genes has not been elucidated so far. To illustrate the potential regulatory role of miRNAs in carotenoid biosynthesis, transcript profiling of the known miRNAs and their possible target carotenoid genes was undertaken at eight different developmental stages of tomato, using stem-loop PCR approach combined with quantitative RT-PCR. The inter-relationship amongst carotenoid content, biosynthetic genes and miRNAs was studied in depth. Comparative expression profiles of miRNA and target genes showed variable expression in different tissues studied. The expression level of miRNAs and their target carotenoid genes displayed similar pattern in the vegetative tissues as compared to the reproductive ones, viz. fruit (different stages), indicating the possibility of regulation of carotenoid biosynthesis at various stages of fruit development. This was later confirmed by the HPLC analysis of the carotenoids. The present study has further enhanced the understanding of regulation of carotenoid biosynthetic pathway in plants. The identified miRNAs can be employed to manipulate the biosynthesis of different carotenoids, through metabolic engineering for the production of lycopene rich tomatoes.

  11. Neurotoxicity and risk assessment of brominated and alternative flame retardants.

    PubMed

    Hendriks, Hester S; Westerink, Remco H S

    2015-01-01

    Brominated flame retardants (BFRs) are widely used chemicals that prevent or slow the onset and spreading of fire. Unfortunately, many of these compounds pose serious threats for human health and the environment, indicating an urgent need for safe(r) and less persistent alternative flame retardants (AFRs). As previous research identified the nervous system as a sensitive target organ, the neurotoxicity of past and present flame retardants is reviewed. First, an overview of the neurotoxicity of BFRs in humans and experimental animals is provided, and some common in vitro neurotoxic mechanisms of action are discussed. The combined epidemiological and toxicological studies clearly underline the need for replacing BFRs. Many potentially suitable AFRs are already in use, despite the absence of a full profile of their environmental behavior and toxicological properties. To prioritize the suitability of some selected halogenated and non-halogenated organophosphorous flame retardants and inorganic halogen-free flame retardants, the available neurotoxic data of these AFRs are discussed. The suitability of the AFRs is rank-ordered and combined with human exposure data (serum concentrations, breast milk concentrations and house dust concentrations) and physicochemical properties (useful to predict e.g. bioavailability and persistence in the environment) for a first semi-quantitative risk assessment of the AFRs. As can be concluded from the reviewed data, several BFRs and AFRs share some neurotoxic effects and modes of action. Moreover, the available neurotoxicity data indicate that some AFRs may be suitable substitutes for BFRs. However, proper risk assessment is hampered by an overall scarcity of data, particularly regarding environmental persistence, human exposure levels, and the formation of breakdown products and possible metabolites as well as their toxicity. Until these data gaps in environmental behavioral and toxicological profiles are filled, large scale use of

  12. Neurotoxic Shellfish Poisoning

    PubMed Central

    Watkins, Sharon M.; Reich, Andrew; Fleming, Lora E.; Hammond, Roberta

    2008-01-01

    Neurotoxic shellfish poisoning (NSP) is caused by consumption of molluscan shellfish contaminated with brevetoxins primarily produced by the dinoflagellate, Karenia brevis. Blooms of K. brevis, called Florida red tide, occur frequently along the Gulf of Mexico. Many shellfish beds in the US (and other nations) are routinely monitored for presence of K. brevis and other brevetoxin-producing organisms. As a result, few NSP cases are reported annually from the US. However, infrequent larger outbreaks do occur. Cases are usually associated with recreationally-harvested shellfish collected during or post red tide blooms. Brevetoxins are neurotoxins which activate voltage-sensitive sodium channels causing sodium influx and nerve membrane depolarization. No fatalities have been reported, but hospitalizations occur. NSP involves a cluster of gastrointestinal and neurological symptoms: nausea and vomiting, paresthesias of the mouth, lips and tongue as well as distal paresthesias, ataxia, slurred speech and dizziness. Neurological symptoms can progress to partial paralysis; respiratory distress has been recorded. Recent research has implicated new species of harmful algal bloom organisms which produce brevetoxins, identified additional marine species which accumulate brevetoxins, and has provided additional information on the toxicity and analysis of brevetoxins. A review of the known epidemiology and recommendations for improved NSP prevention are presented. PMID:19005578

  13. NEUROTOXICITY OF TETRACHLOROETHYLENE ...

    EPA Pesticide Factsheets

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleaning facilities and on people living near dry cleaning facilities. It also reviews the neurobehavioral studies of laboratory animals exposed to perc via inhalation. The reports describe impairment of visual information processing and other adverse neurobehavioral effects in several studies of employees working in dry cleaning facilities using perc. Two studies of people living near dry cleaning facilities have also shown neurological effects, and their exposures have been at lower concentrations than the workers and the specific neurological tests used in the residential studies have been different. The expert panel will discuss issues centering on the question of whether this limited information at lower exposures is strong enough to infer that low concentrations of perc is a hazard to the general population. Discussion paper.

  14. Age-dependent alterations of the NMDA receptor developmental profile and adult behavior in postnatally ketamine-treated mice.

    PubMed

    Lecointre, Maryline; Vézier, Claire; Bénard, Magalie; Ramdani, Yasmina; Dupré, Nicolas; Brasse-Lagnel, Carole; Henry, Vincent J; Roy, Vincent; Marret, Stéphane; Gonzalez, Bruno J; Jégou, Sylvie; Leroux-Nicollet, Isabelle

    2015-03-01

    Ketamine is a NMDA receptor (NMDAR) antagonist used in pediatric anesthesia. Given the role of glutamatergic signaling during brain maturation, we studied the effects of a single ketamine injection (40 mg/kg s.c) in mouse neonates depending on postnatal age at injection (P2, P5, or P10) on cortical NMDAR subunits expression and association with Membrane-Associated Guanylate Kinases PSD95 and SAP102. The effects of ketamine injection at P2, P5, or P10 on motor activity were compared in adulthood. Ketamine increased GluN2A and GluN2B mRNA levels in P2-treated mice without change in proteins, while it decreased GluN2B protein in P10-treated mice without change in mRNA. Ketamine reduced GluN2A mRNA and protein levels in P5-treated mice without change in GluN2B and GluN1. Ketamine affected the GluN2A/PSD95 association regardless of the age at injection, while GluN2B/PSD95 association was enhanced only in P5-treated mice. Microdissection of ketamine-treated mouse cortex showed a decrease in GluN2A mRNA level in superficial layers (I-IV) and an increase in all subunit expressions in deep layers (V-VI) in P5- and P10-treated mice, respectively. Our data suggest that ketamine impairs cortical NMDAR subunit developmental profile and delays the synaptic targeting of GluN2A-enriched NMDAR. Ketamine injection at P2 or P10 resulted in hyperlocomotion in adult male mice in an open field, without change in females. Voluntary running-wheel exercise showed age- and sex-dependent alterations of the mouse activity, especially during the dark phase. Overall, a single neonatal ketamine exposure led to short-term NMDAR cortical developmental profile impairments and long-term motor activity alterations persisting in adulthood. © 2014 Wiley Periodicals, Inc.

  15. Developmental Validation of Short Tandem Repeat Reagent Kit for Forensic DNA Profiling of Canine Biological Materials

    PubMed Central

    Dayton, Melody; Koskinen, Mikko T; Tom, Bradley K; Mattila, Anna-Maria; Johnston, Eric; Halverson, Joy; Fantin, Dennis; DeNise, Sue; Budowle, Bruce; Smith, David Glenn; Kanthaswamy, Sree

    2009-01-01

    Aim To develop a reagent kit that enables multiplex polymerase chain reaction (PCR) amplification of 18 short tandem repeats (STR) and the canine sex-determining Zinc Finger marker. Methods Validation studies to determine the robustness and reliability in forensic DNA typing of this multiplex assay included sensitivity testing, reproducibility studies, intra- and inter-locus color balance studies, annealing temperature and cycle number studies, peak height ratio determination, characterization of artifacts such as stutter percentages and dye blobs, mixture analyses, species-specificity, case type samples analyses and population studies. Results The kit robustly amplified domesticated dog samples and consistently generated full 19-locus profiles from as little as 125 pg of dog DNA. In addition, wolf DNA samples could be analyzed with the kit. Conclusion The kit, which produces robust, reliable, and reproducible results, will be made available for the forensic research community after modifications based on this study’s evaluation to comply with the quality standards expected for forensic casework. PMID:19480022

  16. In Situ-Synthesized Novel Microarray Optimized for Mouse Stem Cell and Early Developmental Expression Profiling

    PubMed Central

    Carter, Mark G.; Hamatani, Toshio; Sharov, Alexei A.; Carmack, Condie E.; Qian, Yong; Aiba, Kazuhiro; Ko, Naomi T.; Dudekula, Dawood B.; Brzoska, Pius M.; Hwang, S. Stuart; Ko, Minoru S.H.

    2003-01-01

    Applications of microarray technologies to mouse embryology/genetics have been limited, due to the nonavailability of microarrays containing large numbers of embryonic genes and the gap between microgram quantities of RNA required by typical microarray methods and the miniscule amounts of tissue available to researchers. To overcome these problems, we have developed a microarray platform containing in situ-synthesized 60-mer oligonucleotide probes representing approximately 22,000 unique mouse transcripts, assembled primarily from sequences of stem cell and embryo cDNA libraries. We have optimized RNA labeling protocols and experimental designs to use as little as 2 ng total RNA reliably and reproducibly. At least 98% of the probes contained in the microarray correspond to clones in our publicly available collections, making cDNAs readily available for further experimentation on genes of interest. These characteristics, combined with the ability to profile very small samples, make this system a resource for stem cell and embryogenomics research. [Supplemental material is available online at www.genome.org and at the NIA Mouse cDNA Project Web site, http://lgsun.grc.nia.nih.gov/cDNA/cDNA.html.] PMID:12727912

  17. Expression Profiling Reveals Developmentally Regulated lncRNA Repertoire in the Mouse Male Germline1

    PubMed Central

    Bao, Jianqiang; Wu, Jingwen; Schuster, Andrew S.; Hennig, Grant W.; Yan, Wei

    2013-01-01

    ABSTRACT In mammals, the transcriptome of large noncoding RNAs (lncRNAs) is believed to be greater than that of messenger RNAs (mRNAs). Some lncRNAs, especially large intergenic noncoding RNAs (lincRNAs), participate in epigenetic regulation by binding chromatin-modifying protein complexes and regulating protein-coding gene expression. Given that epigenetic regulation plays a critical role in male germline development, we embarked on expression profiling of both lncRNAs and mRNAs during male germline reprogramming and postnatal development using microarray analyses. We identified thousands of lncRNAs and hundreds of lincRNAs that are either up- or downregulated at six critical time points during male germ cell development. In addition, highly regulated lncRNAs were correlated with nearby (<30 kb) mRNA gene clusters, which were also significantly up- or downregulated. Large ncRNAs can be localized to both the nucleus and cytoplasm, with nuclear lncRNAs mostly associated with key components of the chromatin-remodeling protein complexes. Our data indicate that expression of lncRNAs is dynamically regulated during male germline development and that lncRNAs may function to regulate gene expression at both transcriptional and posttranscriptional levels via genetic and epigenetic mechanisms. PMID:24048575

  18. Comprehensive developmental profiles of gene activity in regions and subregions of the Arabidopsis seed

    PubMed Central

    Belmonte, Mark F.; Kirkbride, Ryan C.; Stone, Sandra L.; Pelletier, Julie M.; Bui, Anhthu Q.; Yeung, Edward C.; Hashimoto, Meryl; Fei, Jiong; Harada, Corey M.; Munoz, Matthew D.; Le, Brandon H.; Drews, Gary N.; Brady, Siobhan M.; Goldberg, Robert B.; Harada, John J.

    2013-01-01

    Seeds are complex structures that consist of the embryo, endosperm, and seed-coat regions that are of different ontogenetic origins, and each region can be further divided into morphologically distinct subregions. Despite the importance of seeds for food, fiber, and fuel globally, little is known of the cellular processes that characterize each subregion or how these processes are integrated to permit the coordinated development of the seed. We profiled gene activity genome-wide in every organ, tissue, and cell type of Arabidopsis seeds from fertilization through maturity. The resulting mRNA datasets offer the most comprehensive description of gene activity in seeds with high spatial and temporal resolution, providing unique insights into the function of understudied seed regions. Global comparisons of mRNA populations reveal unexpected overlaps in the functional identities of seed subregions. Analyses of coexpressed gene sets suggest that processes that regulate seed size and filling are coordinated across several subregions. Predictions of gene regulatory networks based on the association of transcription factors with enriched DNA sequence motifs upstream of coexpressed genes identify regulators of seed development. These studies emphasize the utility of these datasets as an essential resource for the study of seed biology. PMID:23319655

  19. Developmental transcript profiling of cyst nematode feeding cells in soybean roots.

    PubMed

    Ithal, Nagabhushana; Recknor, Justin; Nettleton, Dan; Maier, Tom; Baum, Thomas J; Mitchum, Melissa G

    2007-05-01

    Cyst nematodes of the genus Heterodera are obligate, sedentary endoparasites that have developed highly evolved relationships with specific host plant species. Successful parasitism involves significant physiological and morphological changes to plant root cells for the formation of specialized feeding cells called syncytia. To better understand the molecular mechanisms that lead to the development of nematode feeding cells, transcript profiling was conducted on developing syncytia induced by the soybean cyst nematode Heterodera glycines in soybean roots by coupling laser capture microdissection with high-density oligonucleotide microarray analysis. This approach has identified pathways that may play intrinsic roles in syncytium induction, formation, and function. Our data suggest interplay among phytohormones that likely regulates synchronized changes in the expression of genes encoding cell-wall-modifying proteins. This process appears to be tightly controlled and coordinately regulated with cell wall rigidification processes that may involve lignification of feeding cell walls. Our data also show local downregulation of jasmonic acid biosynthesis and responses in developing syncytia, which suggest a local suppression of plant defense mechanisms. Moreover, we identified genes encoding putative transcription factors and components of signal transduction pathways that may be important in the regulatory processes governing syncytium formation and function. Our analysis provides a broad mechanistic picture that forms the basis for future hypothesis-driven research to understand cyst nematode parasitism and to develop effective management tools against these pathogens.

  20. MAIZEWALL. Database and Developmental Gene Expression Profiling of Cell Wall Biosynthesis and Assembly in Maize 1[W

    PubMed Central

    Guillaumie, Sabine; San-Clemente, Hélène; Deswarte, Caroline; Martinez, Yves; Lapierre, Catherine; Murigneux, Alain; Barrière, Yves; Pichon, Magalie; Goffner, Deborah

    2007-01-01

    An extensive search for maize (Zea mays) genes involved in cell wall biosynthesis and assembly has been performed and 735 sequences have been centralized in a database, MAIZEWALL (http://www.polebio.scsv.ups-tlse.fr/MAIZEWALL). MAIZEWALL contains a bioinformatic analysis for each entry and gene expression data that are accessible via a user-friendly interface. A maize cell wall macroarray composed of a gene-specific tag for each entry was also constructed to monitor global cell wall-related gene expression in different organs and during internode development. By using this macroarray, we identified sets of genes that exhibit organ and internode-stage preferential expression profiles. These data provide a comprehensive fingerprint of cell wall-related gene expression throughout the maize plant. Moreover, an in-depth examination of genes involved in lignin biosynthesis coupled to biochemical and cytological data from different organs and stages of internode development has also been undertaken. These results allow us to trace spatially and developmentally regulated, putative preferential routes of monolignol biosynthesis involving specific gene family members and suggest that, although all of the gene families of the currently accepted monolignol biosynthetic pathway are conserved in maize, there are subtle differences in family size and a high degree of complexity in spatial expression patterns. These differences are in keeping with the diversity of lignified cell types throughout the maize plant. PMID:17098859

  1. A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies.

    PubMed

    Zanghi, Christine N; Jevtovic-Todorovic, Vesna

    The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Folate metabolite profiling of different cell types and embryos suggests variation in folate one-carbon metabolism, including developmental changes in human embryonic brain.

    PubMed

    Leung, Kit-Yi; De Castro, Sandra C P; Cabreiro, Filipe; Gustavsson, Peter; Copp, Andrew J; Greene, Nicholas D E

    2013-06-01

    Folates act as co-factors for transfer of one-carbon units for nucleotide production, methylation and other biosynthetic reactions. Comprehensive profiling of multiple folates can be achieved using liquid chromatography tandem mass spectrometry, enabling determination of their relative abundance that may provide an indication of metabolic differences between cell types. For example, cell lines exposed to methotrexate showed a dose-dependent elevation of dihydrofolate, consistent with inhibition of dihydrofolate reductase. We analysed the folate profile of E. coli sub-types as well as cell lines and embryonic tissue from both human and mouse. The folate profile of bacteria differed markedly from those of all the mammalian samples, most notably in the greater abundance of formyl tetrahydrofolate. The overall profiles of mouse and human fibroblasts and mid-gestation mouse embryos were broadly similar, with specific differences. The major folate species in these cell types was 5-methyl tetrahydrofolate, in contrast to lymphoblastoid cell lines in which the predominant form was tetrahydrofolate. Analysis of embryonic human brain revealed a shift in folate profile with increasing developmental stage, with a decline in relative abundance of dihydrofolate and increase in 5-methyl tetrahydrofolate. These cell type-specific and developmental changes in folate profile may indicate differential requirements for the various outputs of folate metabolism.

  3. Developmental histories of perceived racial discrimination and diurnal cortisol profiles in adulthood: A 20-year prospective study

    PubMed Central

    Adam, Emma K.; Heissel, Jennifer A.; Zeiders, Katharine H.; Richeson, Jennifer A.; Ross, Emily C.; Ehrlich, Katherine B.; Levy, Dorainne J.; Kemeny, Margaret; Brodish, Amanda B.; Malanchuk, Oksana; Peck, Stephen C.; Fuller-Rowell, Thomas E.; Eccles, Jacquelynne S.

    2015-01-01

    Perceived racial discrimination (PRD) has been associated with altered diurnal cortisol rhythms in past cross-sectional research. We investigate whether developmental histories of PRD, assessed prospectively, are associated with adult diurnal cortisol profiles. One-hundred and twelve (N = 50 Black, N = 62 White) adults from the Maryland Adolescent Development in Context Study provided saliva samples in adulthood (at approximately age 32 years) at waking, 30 min after waking, and at bedtime for 7 days. Diurnal cortisol measures were calculated, including waking cortisol levels, diurnal cortisol slopes, the cortisol awakening response (CAR), and average daily cortisol (AUC). These cortisol outcomes were predicted from measures of PRD obtained over a 20-year period beginning when individuals were in 7th grade (approximately age 12). Greater average PRD measured across the 20-year period predicted flatter adult diurnal cortisol slopes for both Black and White adults, and a lower CAR. Greater average PRD also predicted lower waking cortisol for Black, but not White adults. PRD experiences in adolescence accounted for many of these effects. When adolescent and young adult PRD are entered together predicting cortisol outcomes, PRD experiences in adolescence (but not young adulthood) significantly predicted flatter diurnal cortisol slopes for both Black and White adults. Adolescent, but not young adult PRD, also significantly predicted lower waking and lower average cortisol for Black adults. Young adult PRD was, however, a stronger predictor of the CAR, predicting a marginally lower CAR for Whites, and a significantly larger CAR for Blacks. Effects were robust to controlling for covariates including health behaviors, depression, income and parent education levels. PRD experiences interacted with parent education and income to predict aspects of the diurnal cortisol rhythm. Although these results suggest PRD influences on cortisol for both Blacks and Whites, the key

  4. Developmental histories of perceived racial discrimination and diurnal cortisol profiles in adulthood: A 20-year prospective study.

    PubMed

    Adam, Emma K; Heissel, Jennifer A; Zeiders, Katharine H; Richeson, Jennifer A; Ross, Emily C; Ehrlich, Katherine B; Levy, Dorainne J; Kemeny, Margaret; Brodish, Amanda B; Malanchuk, Oksana; Peck, Stephen C; Fuller-Rowell, Thomas E; Eccles, Jacquelynne S

    2015-12-01

    Perceived racial discrimination (PRD) has been associated with altered diurnal cortisol rhythms in past cross-sectional research. We investigate whether developmental histories of PRD, assessed prospectively, are associated with adult diurnal cortisol profiles. One-hundred and twelve (N=50 Black, N=62 White) adults from the Maryland Adolescent Development in Context Study provided saliva samples in adulthood (at approximately age 32 years) at waking, 30min after waking, and at bedtime for 7 days. Diurnal cortisol measures were calculated, including waking cortisol levels, diurnal cortisol slopes, the cortisol awakening response (CAR), and average daily cortisol (AUC). These cortisol outcomes were predicted from measures of PRD obtained over a 20-year period beginning when individuals were in 7th grade (approximately age 12). Greater average PRD measured across the 20-year period predicted flatter adult diurnal cortisol slopes for both Black and White adults, and a lower CAR. Greater average PRD also predicted lower waking cortisol for Black, but not White adults. PRD experiences in adolescence accounted for many of these effects. When adolescent and young adult PRD are entered together predicting cortisol outcomes, PRD experiences in adolescence (but not young adulthood) significantly predicted flatter diurnal cortisol slopes for both Black and White adults. Adolescent, but not young adult PRD, also significantly predicted lower waking and lower average cortisol for Black adults. Young adult PRD was, however, a stronger predictor of the CAR, predicting a marginally lower CAR for Whites, and a significantly larger CAR for Blacks. Effects were robust to controlling for covariates including health behaviors, depression, income and parent education levels. PRD experiences interacted with parent education and income to predict aspects of the diurnal cortisol rhythm. Although these results suggest PRD influences on cortisol for both Blacks and Whites, the key findings

  5. Psychometrics and utility of Psycho-Educational Profile-Revised as a developmental quotient measure among children with the dual disability of intellectual disability and autism.

    PubMed

    Alwinesh, Merlin Thanka Jemi; Joseph, Rachel Beulah Jansirani; Daniel, Anna; Abel, Julie Sandra; Shankar, Satya Raj; Mammen, Priya; Russell, Sushila; Russell, Paul Swamidhas Sudhakar

    2012-09-01

    There is no agreement about the measure to quantify the intellectual/developmental level in children with the dual disability of intellectual disability and autism. Therefore, we studied the psychometric properties and utility of Psycho-Educational Profile-Revised (PEP-R) as a developmental test in this population. We identified 116 children with dual disability from the day care and inpatient database of a specialised Autism Clinic. Scale and domain level scores of PEP-R were collected and analyzed. We examined the internal consistency, domain-total correlation of PEP-R and concurrent validity of PEP-R against Gesell's Developmental Schedule, inter-rater and test-retest reliability and utility of PEP-R among children with dual disability in different ages, functional level and severity of autism. Besides the adequate face and content validity, PEP-R demonstrates a good internal consistency (Cronbach's α ranging from 0.91 to 0.93) and domain-total correlation (ranging from 0.75 to 0.90). The inter-rater reliability (intraclass correlation coefficient, ICC = 0.96) and test-retest reliability (ICC = 0.87) for PEP-R is good. There is moderate-to-high concurrent validity with GDS (r ranging from 0.61 to 0.82; all Ps = 0.001). The utility of PEP-R as a developmental measure was good with infants, toddlers, pre-school and primary school children. The ability of PEP-R to measure the developmental age was good, irrespective of the severity of autism but was better with high-functioning children. The PEP-R as an intellectual/developmental test has strong psychometric properties in children with dual disability. It could be used in children with different age groups and severity of autism. PEP-R should be used with caution as a developmental test in children with dual disability who are low functioning.

  6. Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies

    PubMed Central

    Farina, Marcelo; Rocha, João B. T.; Aschner, Michael

    2011-01-01

    Neurological disorders are common, costly, and can cause enduring disability. Although mostly unknown, a few environmental toxicants are recognized causes of neurological disorders and subclinical brain dysfunction. One of the best known neurotoxins is methylmercury (MeHg), a ubiquitous environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. In the aquatic environment, MeHg is accumulated in fish, which represent a major source of human exposure. Although several episodes of MeHg poisoning have contributed to the understanding of the clinical symptoms and histological changes elicited by this neurotoxicant in humans, experimental studies have been pivotal in elucidating the molecular mechanisms that mediate MeHg-induced neurotoxicity. The objective of this mini-review is to summarize data from experimental studies on molecular mechanisms of MeHg-induced neurotoxicity. While the full picture has yet to be unmasked, in vitro approaches based on cultured cells, isolated mitochondria and tissue slices, as well as in vivo studies based mainly on the use of rodents, point to impairment in intracellular calcium homeostasis, alteration of glutamate homeostasis and oxidative stress as important events in MeHg-induced neurotoxicity. The potential relationship among these events is discussed, with particular emphasis on the neurotoxic cycle triggered by MeHg-induced excitotoxicity and oxidative stress. The particular sensitivity of the developing brain to MeHg toxicity, the critical role of selenoproteins and the potential protective role of selenocompounds are also discussed. These concepts provide the biochemical bases to the understanding of MeHg neurotoxicity, contributing to the discovery of endogenous and exogenous molecules that counteract such toxicity and provide efficacious means for ablating this vicious cycle. PMID:21683713

  7. Developmental profile and synaptic origin of early network oscillations in the CA1 region of rat neonatal hippocampus

    PubMed Central

    Garaschuk, Olga; Hanse, Eric; Konnerth, Arthur

    1998-01-01

    with the gradual disappearance of the ENOs. The developmental decrease in the amplitude of ENO-associated Ca2+ transients occurred in parallel with the transformation of the excitatory synaptic transmission in the hippocampus from the immature GABAergic to the mature glutamatergic form. Thus, at the beginning of the first postnatal week single-shock synaptic stimulation produced Ca2+ transients that were completely blocked by bicuculline. At the end of the second postnatal week the same type of evoked synaptic stimulation produced a Ca2+ transient that was little affected by bicuculline but was abolished by the combined application of d,l-APV and CNQX. These results demonstrate the presence of periodic and spontaneous Ca2+ transients in the majority of pyramidal cells and interneurones of the neonatal CA1 hippocampal network. These ENOs exhibit a highly region-specific developmental profile and may control the activity-dependent wiring of the synaptic connectivity during early postnatal development. PMID:9490842

  8. Developmental neurotoxicity of 3,3’,4,4’-tetrachloroazobenzene with thyroxine deficit: Sensitivity of glia and dentate granule neurons in the absence of behavioral changes

    PubMed Central

    Harry, G. Jean; Hooth, Michelle J.; Vallant, Molly; Behl, Mamta; Travlos, Gregory S.; Howard, James L.; Price, Catherine J.; McBride, Sandra; Mervis, Ron; Mouton, Peter R.

    2015-01-01

    Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3’,4,4’-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3’- triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND)4-21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations. PMID:26029700

  9. Transcript Profiling Reveals the Presence of Abiotic Stress and Developmental Stage Specific Ascorbate Oxidase Genes in Plants

    PubMed Central

    Batth, Rituraj; Singh, Kapil; Kumari, Sumita; Mustafiz, Ananda

    2017-01-01

    Abiotic stress and climate change is the major concern for plant growth and crop yield. Abiotic stresses lead to enhanced accumulation of reactive oxygen species (ROS) consequently resulting in cellular damage and major losses in crop yield. One of the major scavengers of ROS is ascorbate (AA) which acts as first line of defense against external oxidants. An enzyme named ascorbate oxidase (AAO) is known to oxidize AA and deleteriously affect the plant system in response to stress. Genome-wide analysis of AAO gene family has led to the identification of five, three, seven, four, and six AAO genes in Oryza sativa, Arabidopsis, Glycine max, Zea mays, and Sorghum bicolor genomes, respectively. Expression profiling of these genes was carried out in response to various abiotic stresses and during various stages of vegetative and reproductive development using publicly available microarray database. Expression analysis in Oryza sativa revealed tissue specific expression of AAO genes wherein few members were exclusively expressed in either root or shoot. These genes were found to be regulated by both developmental cues as well as diverse stress conditions. The qRT-PCR analysis in response to salinity and drought stress in rice shoots revealed OsAAO2 to be the most stress responsive gene. On the other hand, OsAAO3 and OsAAO4 genes showed enhanced expression in roots under salinity/drought stresses. This study provides lead about important stress responsive AAO genes in various crop plants, which could be used to engineer climate resilient crop plants. PMID:28261251

  10. Transcriptional Profiling of Coxiella burnetii Reveals Extensive Cell Wall Remodeling in the Small Cell Variant Developmental Form.

    PubMed

    Sandoz, Kelsi M; Popham, David L; Beare, Paul A; Sturdevant, Daniel E; Hansen, Bryan; Nair, Vinod; Heinzen, Robert A

    2016-01-01

    A hallmark of Coxiella burnetii, the bacterial cause of human Q fever, is a biphasic developmental cycle that generates biologically, ultrastructurally, and compositionally distinct large cell variant (LCV) and small cell variant (SCV) forms. LCVs are replicating, exponential phase forms while SCVs are non-replicating, stationary phase forms. The SCV has several properties, such as a condensed nucleoid and an unusual cell envelope, suspected of conferring enhanced environmental stability. To identify genetic determinants of the LCV to SCV transition, we profiled the C. burnetii transcriptome at 3 (early LCV), 5 (late LCV), 7 (intermediate forms), 14 (early SCV), and 21 days (late SCV) post-infection of Vero epithelial cells. Relative to early LCV, genes downregulated in the SCV were primarily involved in intermediary metabolism. Upregulated SCV genes included those involved in oxidative stress responses, arginine acquisition, and cell wall remodeling. A striking transcriptional signature of the SCV was induction (>7-fold) of five genes encoding predicted L,D transpeptidases that catalyze nonclassical 3-3 peptide cross-links in peptidoglycan (PG), a modification that can influence several biological traits in bacteria. Accordingly, of cross-links identified, muropeptide analysis showed PG of SCV with 46% 3-3 cross-links as opposed to 16% 3-3 cross-links for LCV. Moreover, electron microscopy revealed SCV with an unusually dense cell wall/outer membrane complex as compared to LCV with its clearly distinguishable periplasm and inner and outer membranes. Collectively, these results indicate the SCV produces a unique transcriptome with a major component directed towards remodeling a PG layer that likely contributes to Coxiella's environmental resistance.

  11. An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD

    SciTech Connect

    Mustafa, A.; Holladay, S.D.; Goff, M.; Witonsky, S.G.; Kerr, R.; Reilly, C.M.; Sponenberg, D.P.; Gogal, R.M.

    2008-10-01

    Developmental exposure of mice to the environmental contaminant and AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes persistent postnatal suppression of T cell-mediated immune responses. The extent to which prenatal TCDD may induce or exacerbate postnatal autoimmune disease remains unknown. In the present study, time-pregnant high affinity AhR C57BL/6 mice received a single oral administration of 0, 2.5, or 5 {mu}g/kg TCDD on gestation day (gd) 12. Offspring of these mice (n = 5/gender/treatment) were evaluated at 24 weeks-of-age and showed considerable immune dysregulation that was often gender-specific. Decreased thymic weight and percentages of CD4{sup +}CD8{sup +} thymocytes, and increased CD4{sup +}CD8{sup -} thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4{sup -}CD8{sup +} T cells, and increased V{beta}3{sup +} and V{beta}17a{sup +} T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24{sup -}B220{sup +} B cell progenitors. Antibody titers to dsDNA, ssDNA and cardiolipin displayed increasing trends in both male and female mice, reaching significance for anti-dsDNA in both genders and for ssDNA in males at 5 {mu}g/kg TCDD. Immunofluorescent staining of IgG and C3 deposition in kidney glomeruli increased in both genders of prenatal TCDD-exposed mice, suggestive of early stages of autoimmune glomerulonephritis. Collectively, these results show that exposure to TCDD during immune system development causes persistent humoral immune dysregulation as well as altered cell-mediated responses, and induces an adult profile of changes suggestive of increased risk for autoimmune disease.

  12. Transcriptional Profiling of Coxiella burnetii Reveals Extensive Cell Wall Remodeling in the Small Cell Variant Developmental Form

    PubMed Central

    Sandoz, Kelsi M.; Popham, David L.; Beare, Paul A.; Sturdevant, Daniel E.; Hansen, Bryan; Nair, Vinod; Heinzen, Robert A.

    2016-01-01

    A hallmark of Coxiella burnetii, the bacterial cause of human Q fever, is a biphasic developmental cycle that generates biologically, ultrastructurally, and compositionally distinct large cell variant (LCV) and small cell variant (SCV) forms. LCVs are replicating, exponential phase forms while SCVs are non-replicating, stationary phase forms. The SCV has several properties, such as a condensed nucleoid and an unusual cell envelope, suspected of conferring enhanced environmental stability. To identify genetic determinants of the LCV to SCV transition, we profiled the C. burnetii transcriptome at 3 (early LCV), 5 (late LCV), 7 (intermediate forms), 14 (early SCV), and 21 days (late SCV) post-infection of Vero epithelial cells. Relative to early LCV, genes downregulated in the SCV were primarily involved in intermediary metabolism. Upregulated SCV genes included those involved in oxidative stress responses, arginine acquisition, and cell wall remodeling. A striking transcriptional signature of the SCV was induction (>7-fold) of five genes encoding predicted L,D transpeptidases that catalyze nonclassical 3–3 peptide cross-links in peptidoglycan (PG), a modification that can influence several biological traits in bacteria. Accordingly, of cross-links identified, muropeptide analysis showed PG of SCV with 46% 3–3 cross-links as opposed to 16% 3–3 cross-links for LCV. Moreover, electron microscopy revealed SCV with an unusually dense cell wall/outer membrane complex as compared to LCV with its clearly distinguishable periplasm and inner and outer membranes. Collectively, these results indicate the SCV produces a unique transcriptome with a major component directed towards remodeling a PG layer that likely contributes to Coxiella’s environmental resistance. PMID:26909555

  13. Transcript Profiling Reveals the Presence of Abiotic Stress and Developmental Stage Specific Ascorbate Oxidase Genes in Plants.

    PubMed

    Batth, Rituraj; Singh, Kapil; Kumari, Sumita; Mustafiz, Ananda

    2017-01-01

    Abiotic stress and climate change is the major concern for plant growth and crop yield. Abiotic stresses lead to enhanced accumulation of reactive oxygen species (ROS) consequently resulting in cellular damage and major losses in crop yield. One of the major scavengers of ROS is ascorbate (AA) which acts as first line of defense against external oxidants. An enzyme named ascorbate oxidase (AAO) is known to oxidize AA and deleteriously affect the plant system in response to stress. Genome-wide analysis of AAO gene family has led to the identification of five, three, seven, four, and six AAO genes in Oryza sativa, Arabidopsis, Glycine max, Zea mays, and Sorghum bicolor genomes, respectively. Expression profiling of these genes was carried out in response to various abiotic stresses and during various stages of vegetative and reproductive development using publicly available microarray database. Expression analysis in Oryza sativa revealed tissue specific expression of AAO genes wherein few members were exclusively expressed in either root or shoot. These genes were found to be regulated by both developmental cues as well as diverse stress conditions. The qRT-PCR analysis in response to salinity and drought stress in rice shoots revealed OsAAO2 to be the most stress responsive gene. On the other hand, OsAAO3 and OsAAO4 genes showed enhanced expression in roots under salinity/drought stresses. This study provides lead about important stress responsive AAO genes in various crop plants, which could be used to engineer climate resilient crop plants.

  14. Developmental Trajectories in Syndromes with Intellectual Disability, with a Focus on Wolf-Hirschhorn and Its Cognitive-Behavioral Profile

    ERIC Educational Resources Information Center

    Fisch, Gene S.; Carpenter, Nancy; Howard-Peebles, Patricia N.; Holden, Jeanette J. A.; Tarleton, Jack; Simensen, Richard; Battaglia, Agatino

    2012-01-01

    Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn…

  15. Developmental Trajectories in Syndromes with Intellectual Disability, with a Focus on Wolf-Hirschhorn and Its Cognitive-Behavioral Profile

    ERIC Educational Resources Information Center

    Fisch, Gene S.; Carpenter, Nancy; Howard-Peebles, Patricia N.; Holden, Jeanette J. A.; Tarleton, Jack; Simensen, Richard; Battaglia, Agatino

    2012-01-01

    Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn…

  16. Cadmium and Its Neurotoxic Effects

    PubMed Central

    Wang, Bo; Du, Yanli

    2013-01-01

    Cadmium (Cd) is a heavy metal that has received considerable concern environmentally and occupationally. Cd has a long biological half-life mainly due to its low rate of excretion from the body. Thus, prolonged exposure to Cd will cause toxic effect due to its accumulation over time in a variety of tissues, including kidneys, liver, central nervous system (CNS), and peripheral neuronal systems. Cd can be uptaken from the nasal mucosa or olfactory pathways into the peripheral and central neurons; for the latter, Cd can increase the blood brain barrier (BBB) permeability. However, mechanisms underlying Cd neurotoxicity remain not completely understood. Effect of Cd neurotransmitter, oxidative damage, interaction with other metals such as cobalt and zinc, estrogen-like, effect and epigenetic modification may all be the underlying mechanisms. Here, we review the in vitro and in vivo evidence of neurotoxic effects of Cd. The available finding indicates the neurotoxic effects of Cd that was associated with both biochemical changes of the cell and functional changes of central nervous system, suggesting that neurotoxic effects may play a role in the systemic toxic effects of the exposure to Cd, particularly the long-term exposure. PMID:23997854

  17. Enhancing the value of psychiatric mouse models; differential expression of developmental behavioral and cognitive profiles in four inbred strains of mice.

    PubMed

    Molenhuis, Remco T; de Visser, Leonie; Bruining, Hilgo; Kas, Martien J

    2014-06-01

    The behavioral characterization of animal models of psychiatric disorders is often based upon independent traits measured at adult age. To model the neurodevelopmental aspects of psychiatric pathogenesis, we introduce a novel approach for a developmental behavioral analysis in mice. C57BL/6J (C57) mice were used as a reference strain and compared with 129S1/SvImJ (129Sv), BTBR T+tf/J (BTBR) and A/J (AJ) strains as marker strains for aberrant development. Mice were assessed at pre-adolescence (4 weeks), adolescence (6 weeks), early adulthood (8 weeks) and in adulthood (10-12 weeks) on a series of behavioral tasks measuring general health, neurological reflexes, locomotor activity, anxiety, short- and long-term memory and cognitive flexibility. Developmental delays in short-term object memory were associated with either a hypo-reactive profile in 129Sv mice or a hyper-reactive profile in BTBR mice. Furthermore, BTBR mice showed persistent high levels of repetitive grooming behavior during all developmental stages that was associated with the adult expression of cognitive rigidity. In addition, strain differences in development were observed in puberty onset, touch escape, and body position. These data showed that this longitudinal testing battery provides sufficient behavioral and cognitive resolution during different development stages and offers the opportunity to address the behavioral developmental trajectory in genetic mouse models for neurodevelopmental disorders. Furthermore, the data revealed that the assessment of multiple behavioral and cognitive domains at different developmental stages is critical to determine confounding factors (e.g., impaired motor behavior) that may interfere with the behavioral testing performance in mouse models for brain disorders. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  18. ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP)

    EPA Science Inventory

    Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are...

  19. Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: Developmental effects.

    EPA Science Inventory

    The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive developm...

  20. Gene expression profiles in the cerebellum and hippocampus following exposure to a neurotoxicant, Aroclor 1254: Developmental effects.

    EPA Science Inventory

    The developmental consequences of exposure to the polychlorinated biphenyls (PCBs) have been widely studied, making PCBs a unique model to understand issues related to environmental mixture of persistent chemicals. PCB exposure in humans adversely affects neurocognitive developm...

  1. General Anesthetics and Neurotoxicity: How Much Do We Know?

    PubMed

    Jevtovic-Todorovic, Vesna

    2016-09-01

    Over a decade ago, alarming findings were reported that exposure of the very young and very old animals to clinically used general anesthetics could be detrimental to their brains. The evidence presented suggested that the exposure to commonly used gaseous and intravenous general anesthetics induces the biochemical and morphologic changes in the immature and aging neurons ultimately resulting in their demise. More alarming was the demonstration of significant cognitive and behavioral impairments noted long after the initial anesthesia exposure. This article provides an overview of anesthesia-induced developmental neurotoxicity and commentary on the effects of general anesthesia on the aging brain. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Multiple mechanisms of PCB neurotoxicity

    SciTech Connect

    Carpenter, D.O.; Stoner, C.T.; Lawrence, D.A.

    1996-12-31

    Polychlorinated biphenyls (PCBs) have been implicated in cancer, but many of the symptoms in humans exposed to PCBs are related to the nervous system and behavior. We demonstrated three different direct mechanisms whereby PCBs are neurotoxic in rats. By using flow cytometry, we demonstrated that the orthosubstituted PCB congener 2,4,4{prime}, but neither TCDD nor the coplanar PCB congener 3,4,5,3{prime},4{prime}, causes rapid death of cerebellar granule cells. The ortho-substituted congener 2,4,4{prime} reduced long-term potentiation, an indicator of cognitive potential, in hippocampal brain slices, but a similar effect was observed for the coplanar congener 3,4,3{prime},4{prime}, indicating that this effect may be caused by both ortho- and coplanar congeners by mechanisms presumably not mediated via the Ah receptor. It was previously shown that some ortho-substituted PCB congeners cause a reduction in levels of the neurotransmitter dopamine, and we present in vitro and in vivo evidence that this is due to reduction of synthesis of dopamine via inhibition of the enzyme tyrosine hydroxylase. Thus, PCBs have a variety of mechanisms of primary neurotoxicity, and neurotoxicity is a characteristic of ortho-substituted, non-dioxin-like congeners as well as some coplanar congeners. The relative contribution of each of these mechanisms to the loss of cognitive function in humans exposed to PCBs remains to be determined. 42 refs., 3 figs., 1 tab.

  3. Local Anesthetic-Induced Neurotoxicity

    PubMed Central

    Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

    2016-01-01

    This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID:26959012

  4. Occupational neurotoxic diseases in taiwan.

    PubMed

    Liu, Chi-Hung; Huang, Chu-Yun; Huang, Chin-Chang

    2012-12-01

    Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization.

  5. Occupational Neurotoxic Diseases in Taiwan

    PubMed Central

    Liu, Chi-Hung; Huang, Chu-Yun

    2012-01-01

    Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization. PMID:23251841

  6. Transcriptome profiles of embryos before and after cleavage in Eriocheir sinensis: identification of developmental genes at the earliest stages

    NASA Astrophysics Data System (ADS)

    Hui, Min; Cui, Zhaoxia; Liu, Yuan; Song, Chengwen

    2017-07-01

    In crab, embryogenesis is a complicated developmental program marked by a series of critical events. RNA-Sequencing technology offers developmental biologists a way to identify many more developmental genes than ever before. Here, we present a comprehensive analysis of the transcriptomes of Eriocheir sinensis oosperms (Os) and embryos at the 2-4 cell stage (Cs), which are separated by a cleavage event. A total of 18 923 unigenes were identified, and 403 genes matched with gene ontology (GO) terms related to developmental processes. In total, 432 differentially expressed genes (DEGs) were detected between the two stages. Nine DEGs were specifically expressed at only one stage. These DEGs may be relevant to stage-specific molecular events during development. A number of DEGs related to `hedgehog signaling pathway', `Wnt signaling pathway' `germplasm', `nervous system', `sensory perception' and `segment polarity' were identified as being up-regulated at the Cs stage. The results suggest that these embryonic developmental events begin before the early cleavage event in crabs, and that many of the genes expressed in the two transcriptomes might be maternal genes. Our study provides ample information for further research on the molecular mechanisms underlying crab development.

  7. Transcriptome profiles of embryos before and after cleavage in Eriocheir sinensis: identification of developmental genes at the earliest stages

    NASA Astrophysics Data System (ADS)

    Hui, Min; Cui, Zhaoxia; Liu, Yuan; Song, Chengwen

    2016-09-01

    In crab, embryogenesis is a complicated developmental program marked by a series of critical events. RNA-Sequencing technology offers developmental biologists a way to identify many more developmental genes than ever before. Here, we present a comprehensive analysis of the transcriptomes of Eriocheir sinensis oosperms (Os) and embryos at the 2-4 cell stage (Cs), which are separated by a cleavage event. A total of 18 923 unigenes were identified, and 403 genes matched with gene ontology (GO) terms related to developmental processes. In total, 432 differentially expressed genes (DEGs) were detected between the two stages. Nine DEGs were specifically expressed at only one stage. These DEGs may be relevant to stage-specific molecular events during development. A number of DEGs related to `hedgehog signaling pathway', `wnt signaling pathway' `germplasm', `nervous system', `sensory perception' and `segment polarity' were identified as being up-regulated at the Cs stage. The results suggest that these embryonic developmental events begin before the early cleavage event in crabs, and that many of the genes expressed in the two transcriptomes might be maternal genes. Our study provides ample information for further research on the molecular mechanisms underlying crab development.

  8. Evaluating the human-health effects of hazardous wastes: Reproduction and development, neurotoxicity, genetic toxicity, and cancer

    SciTech Connect

    Dyer, R.S.; Houk, V.S.; Reiter, L.W.

    1991-01-01

    Several approaches are available for characterizing potential toxicity of wastes. The paper describes biological tests which are appropriate for identifying waste as neurotoxic, genotoxic, or likely to produce developmental or reproductive effects. The tests recommended are, for neurotoxicity a functional observational battery, coupled with a measure of motor (bodily movement) activity; for genetic toxicity, the 'Ames' test of mutagenicity in Salmonella and a test of clastogenicity (DNA damage); and for developmental and reproductive toxicity, the Chernoff-Kavlock assay and a multigenerational reproductive assay. In addition, the paper identifies several generic factors which must be considered in performing any evaluations of hazardous wastes.

  9. Gene Expression Profiling in Human Fetal Liver and Identification of Tissue- and Developmental-Stage-Specific Genes through Compiled Expression Profiles and Efficient Cloning of Full-Length cDNAs

    PubMed Central

    Yu, Yongtao; Zhang, Chenggang; Zhou, Gangqiao; Wu, Songfeng; Qu, Xianghu; Wei, Handong; Xing, Guichun; Dong, Chunna; Zhai, Yun; Wan, Jinghong; Ouyang, Shuguang; Li, Li; Zhang, Shaowen; Zhou, Kaixin; Zhang, Yinan; Wu, Chutse; He, Fuchu

    2001-01-01

    Fetal liver intriguingly consists of hepatic parenchymal cells and hematopoietic stem/progenitor cells. Human fetal liver aged 22 wk of gestation (HFL22w) corresponds to the turning point between immigration and emigration of the hematopoietic system. To gain further molecular insight into its developmental and functional characteristics, HFL22w was studied by generating expressed sequence tags (ESTs) and by analyzing the compiled expression profiles of liver at different developmental stages. A total of 13,077 ESTs were sequenced from a 3′-directed cDNA library of HFL22w, and classified as follows: 5819 (44.5%) matched to known genes; 5460 (41.8%) exhibited no significant homology to known genes; and the remaining 1798 (13.7%) were genomic sequences of unknown function, mitochondrial genomic sequences, or repetitive sequences. Integration of ESTs of known human genes generated a profile including 1660 genes that could be divided into 15 gene categories according to their functions. Genes related to general housekeeping, ESTs associated with hematopoiesis, and liver-specific genes were highly expressed. Genes for signal transduction and those associated with diseases, abnormalities, or transcription regulation were also noticeably active. By comparing the expression profiles, we identified six gene groups that were associated with different developmental stages of human fetal liver, tumorigenesis, different physiological functions of Itoh cells against the other types of hepatic cells, and fetal hematopoiesis. The gene expression profile therefore reflected the unique functional characteristics of HFL22w remarkably. Meanwhile, 110 full-length cDNAs of novel genes were cloned and sequenced. These novel genes might contribute to our understanding of the unique functional characteristics of the human fetal liver at 22 wk. [The sequence data described in this paper have been submitted to the GenBank data library under the accession nos. listed in Table 6 herein] PMID

  10. Identification and profiling of microRNAs in two developmental stages of the model cestode parasite Mesocestoides corti.

    PubMed

    Basika, Tatiana; Macchiaroli, Natalia; Cucher, Marcela; Espínola, Sergio; Kamenetzky, Laura; Zaha, Arnaldo; Rosenzvit, Mara; Ferreira, Henrique B

    MicroRNAs (miRNAs), a class of small non-coding RNAs, are key regulators of gene expression at post-transcriptional level and play essential roles in fundamental biological processes such as metabolism and development. The particular developmental characteristics of cestode parasites highlight the importance of studying miRNA gene regulation in these organisms. Here, we performed a comprehensive analysis of miRNAs in two developmental stages of the model cestode Mesocestoides corti. Using a high-throughput sequencing approach, we found transcriptional evidence of 42 miRNA loci in tetrathyridia larvae and strobilated worms. Tetrathyridium and strobilated worm-specific miRNAs were found, as well as differentialy expressed miRNAs between these developmental stages, suggesting miRNA regulation of stage-specific features. Moreover, it was shown that uridylation is a differential mechanism of post-transcriptional modification of M. corti miRNAs. The whole set of M. corti miRNAs represent 33 unique miRNA families, and confirm the remarkable loss of conserved miRNA families within platyhelminth parasites, reflecting their relatively low morphological complexity and high adaptation to parasitism. Overall, the presented results provide a valuable platform to studies aiming to identify and characterize novel miRNA-based molecular mechanisms of post-transcriptional gene regulation in cestodes, necessary for the elucidation of developmental aspects of the complex biology of these parasites.

  11. The Profile of Performance Skills and Emotional Factors in the Context of Participation among Young Children with Developmental Coordination Disorder

    ERIC Educational Resources Information Center

    Liberman, Lihi; Ratzon, Navah; Bart, Orit

    2013-01-01

    Participation is a person's involvement in daily activities in a variety of environments, roles and life situations. Children with Developmental Coordination Disorder (DCD) experience difficulties in gaining academic achievements or in their engagement in activity of daily living. Motor difficulties have a negative effect on the ability to…

  12. The Profile of Performance Skills and Emotional Factors in the Context of Participation among Young Children with Developmental Coordination Disorder

    ERIC Educational Resources Information Center

    Liberman, Lihi; Ratzon, Navah; Bart, Orit

    2013-01-01

    Participation is a person's involvement in daily activities in a variety of environments, roles and life situations. Children with Developmental Coordination Disorder (DCD) experience difficulties in gaining academic achievements or in their engagement in activity of daily living. Motor difficulties have a negative effect on the ability to…

  13. Special Issue: Environmental Chemicals and Neurotoxicity Oxidative stress in MeHg-induced neurotoxicity

    PubMed Central

    Farina, Marcelo; Aschner, Michael; Rocha, João B. T.

    2011-01-01

    Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically

  14. Mechanistic insights into neurotoxicity induced by anesthetics in the developing brain.

    PubMed

    Lei, Xi; Guo, Qihao; Zhang, Jun

    2012-01-01

    Compelling evidence has shown that exposure to anesthetics used in the clinic can cause neurodegeneration in the mammalian developing brain, but the basis of this is not clear. Neurotoxicity induced by exposure to anesthestics in early life involves neuroapoptosis and impairment of neurodevelopmental processes such as neurogenesis, synaptogenesis and immature glial development. These effects may subsequently contribute to behavior abnormalities in later life. In this paper, we reviewed the possible mechanisms of anesthetic-induced neurotoxicity based on new in vitro and in vivo findings. Also, we discussed ways to protect against anesthetic-induced neurotoxicity and their implications for exploring cellular and molecular mechanisms of neuroprotection. These findings help in improving our understanding of developmental neurotoxicology and in avoiding adverse neurological outcomes in anesthesia practice.

  15. Large-scale gene expression profiling data for the model moss Physcomitrella patens aid understanding of developmental progression, culture and stress conditions.

    PubMed

    Hiss, Manuel; Laule, Oliver; Meskauskiene, Rasa M; Arif, Muhammad A; Decker, Eva L; Erxleben, Anika; Frank, Wolfgang; Hanke, Sebastian T; Lang, Daniel; Martin, Anja; Neu, Christina; Reski, Ralf; Richardt, Sandra; Schallenberg-Rüdinger, Mareike; Szövényi, Peter; Tiko, Theodhor; Wiedemann, Gertrud; Wolf, Luise; Zimmermann, Philip; Rensing, Stefan A

    2014-08-01

    The moss Physcomitrella patens is an important model organism for studying plant evolution, development, physiology and biotechnology. Here we have generated microarray gene expression data covering the principal developmental stages, culture forms and some environmental/stress conditions. Example analyses of developmental stages and growth conditions as well as abiotic stress treatments demonstrate that (i) growth stage is dominant over culture conditions, (ii) liquid culture is not stressful for the plant, (iii) low pH might aid protoplastation by reduced expression of cell wall structure genes, (iv) largely the same gene pool mediates response to dehydration and rehydration, and (v) AP2/EREBP transcription factors play important roles in stress response reactions. With regard to the AP2 gene family, phylogenetic analysis and comparison with Arabidopsis thaliana shows commonalities as well as uniquely expressed family members under drought, light perturbations and protoplastation. Gene expression profiles for P. patens are available for the scientific community via the easy-to-use tool at https://www.genevestigator.com. By providing large-scale expression profiles, the usability of this model organism is further enhanced, for example by enabling selection of control genes for quantitative real-time PCR. Now, gene expression levels across a broad range of conditions can be accessed online for P. patens.

  16. BDE-47 causes developmental retardation with down-regulated expression profiles of ecdysteroid signaling pathway-involved nuclear receptor (NR) genes in the copepod Tigriopus japonicus.

    PubMed

    Hwang, Dae-Sik; Han, Jeonghoon; Won, Eun-Ji; Kim, Duck-Hyun; Jeong, Chang-Bum; Hwang, Un-Ki; Zhou, Bingsheng; Choe, Joonho; Lee, Jae-Seong

    2016-08-01

    2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) is a persistent organic pollutant (POP) in marine environments. Despite its adverse effects (e.g. developmental retardation) in ecdysozoa, the effects of BDE-47 on transcription of ecdysteroid signaling pathway-involved-nuclear receptor (NR) genes and metamorphosis-related genes have not been examined in copepods. To examine the deleterious effect of BDE-47 on copepod molting and metamorphosis, BDE-47 was exposed to the harpacticoid copepod Tigriopus japonicus, followed by monitoring developmental retardation and transcriptional alteration of NR genes. The developmental rate was significantly inhibited (P<0.05) in response to BDE-47 and the agricultural insecticide gamma-hexachlorocyclohexane. Conversely, the ecdysteroid agonist ponasterone A (PoA) led to decreased molting and metamorphosis time (P<0.05) from the nauplius stage to the adult stage. In particular, expression profiles of all NR genes were the highest at naupliar stages 5-6 except for SVP, FTZ-F1, and HR96 genes. Nuclear receptor USP, HR96, and FTZ-F1 genes also showed significant sex differences (P<0.05) in gene expression levels over different developmental stages, indicating that these genes may be involved in vitellogenesis. NR gene expression patterns showed significant decreases (P<0.05) in response to BDE-47 exposure, implying that molting and metamorphosis retardation is likely associated with NR gene expression. In summary, BDE-47 leads to molting and metamorphosis retardation and suppresses transcription of NR genes. This information will be helpful in understanding the molting and metamorphosis delay mechanism in response to BDE-47 exposure.

  17. Detecting Developmental Neurotoxicants Using Zebrafish Embryos

    EPA Science Inventory

    As part of EPA’s program on the screening and prioritization of chemicals for developmental neurotoxicity, a rapid, cost-effective in vivo vertebrate screen is being developed using an alternative species approach. Zebrafish (Danio rerio), a small freshwater fish with external f...

  18. Detecting Developmental Neurotoxicants Using Zebrafish Embryos

    EPA Science Inventory

    As part of EPA’s program on the screening and prioritization of chemicals for developmental neurotoxicity, a rapid, cost-effective in vivo vertebrate screen is being developed using an alternative species approach. Zebrafish (Danio rerio), a small freshwater fish with external f...

  19. Developmental Changes in the Profiles of Dyscalculia: An Explanation Based on a Double Exact-and-Approximate Number Representation Model

    PubMed Central

    Noël, Marie-Pascale; Rousselle, Laurence

    2011-01-01

    Studies on developmental dyscalculia (DD) have tried to identify a basic numerical deficit that could account for this specific learning disability. The first proposition was that the number magnitude representation of these children was impaired. However, Rousselle and Noël (2007) brought data showing that this was not the case but rather that these children were impaired when processing the magnitude of symbolic numbers only. Since then, incongruent results have been published. In this paper, we will propose a developmental perspective on this issue. We will argue that the first deficit shown in DD regards the building of an exact representation of numerical value, thanks to the learning of symbolic numbers, and that the reduced acuity of the approximate number magnitude system appears only later and is secondary to the first deficit. PMID:22203797

  20. Developmental Changes in the Profiles of Dyscalculia: An Explanation Based on a Double Exact-and-Approximate Number Representation Model.

    PubMed

    Noël, Marie-Pascale; Rousselle, Laurence

    2011-01-01

    Studies on developmental dyscalculia (DD) have tried to identify a basic numerical deficit that could account for this specific learning disability. The first proposition was that the number magnitude representation of these children was impaired. However, Rousselle and Noël (2007) brought data showing that this was not the case but rather that these children were impaired when processing the magnitude of symbolic numbers only. Since then, incongruent results have been published. In this paper, we will propose a developmental perspective on this issue. We will argue that the first deficit shown in DD regards the building of an exact representation of numerical value, thanks to the learning of symbolic numbers, and that the reduced acuity of the approximate number magnitude system appears only later and is secondary to the first deficit.

  1. Profiles.

    ERIC Educational Resources Information Center

    Macintosh, Henry G.

    An introduction to profiles is presented with examples provided to permit an overall appraisal of the potential of profiles, of the principles upon which they might be based, and of the problems that will have to be overcome if their potential is to be realized in practice. The larger scale examples of profiles discussed are the Scottish Pupil…

  2. RISK CHARACTERIZATION OF PERSISTENT NEUROTOXIC CONTAMINANTS

    EPA Science Inventory

    Neurotoxicity is an adverse change in structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent. Thousands of chemicals have been estimated to have neurotoxic potential. Many persistent and bioaccumulat...

  3. RISK CHARACTERIZATION OF PERSISTENT NEUROTOXIC CONTAMINANTS

    EPA Science Inventory

    Neurotoxicity is an adverse change in structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent. Thousands of chemicals have been estimated to have neurotoxic potential. Many persistent and bioaccumulat...

  4. Use of HCI to screen for developmental neurotoxicity

    EPA Science Inventory

    The development of the nervous system is a prolonged process. It starts with the generation of neuroepithelial cells during embryogenesis and is not complete until the final stages of synaptic remodeling in the young adult. The outcome is a functionally connected neural network t...

  5. 40 CFR 799.9630 - TSCA developmental neurotoxicity.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...—(i) Species and strain. Testing must be performed in the rat. Because of its differences in timing of... motor activity are sound level, size and shape of the test cage, temperature, relative humidity, light... number of animals showing each abnormal sign at each observation time. (E) The percentage of...

  6. 40 CFR 795.250 - Developmental neurotoxicity screen.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... lumbar swelling; Gasserian ganglia, dorsal root ganglia, dorsal and ventral root fibers, proximal sciatic nerve (mid-thigh and sciatic notch), sural nerve (at knee), and tibial nerve (at knee). Tissue samples... and embedded in paraffin or paraplast except for the sural nerve which should be embedded in plastic...

  7. 40 CFR 795.250 - Developmental neurotoxicity screen.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... lumbar swelling; Gasserian ganglia, dorsal root ganglia, dorsal and ventral root fibers, proximal sciatic nerve (mid-thigh and sciatic notch), sural nerve (at knee), and tibial nerve (at knee). Tissue samples... and embedded in paraffin or paraplast except for the sural nerve which should be embedded in plastic...

  8. 40 CFR 795.250 - Developmental neurotoxicity screen.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... lumbar swelling; Gasserian ganglia, dorsal root ganglia, dorsal and ventral root fibers, proximal sciatic nerve (mid-thigh and sciatic notch), sural nerve (at knee), and tibial nerve (at knee). Tissue samples... and embedded in paraffin or paraplast except for the sural nerve which should be embedded in plastic...

  9. 40 CFR 795.250 - Developmental neurotoxicity screen.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... lumbar swelling; Gasserian ganglia, dorsal root ganglia, dorsal and ventral root fibers, proximal sciatic nerve (mid-thigh and sciatic notch), sural nerve (at knee), and tibial nerve (at knee). Tissue samples... and embedded in paraffin or paraplast except for the sural nerve which should be embedded in plastic...

  10. 40 CFR 795.250 - Developmental neurotoxicity screen.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... lumbar swelling; Gasserian ganglia, dorsal root ganglia, dorsal and ventral root fibers, proximal sciatic nerve (mid-thigh and sciatic notch), sural nerve (at knee), and tibial nerve (at knee). Tissue samples... and embedded in paraffin or paraplast except for the sural nerve which should be embedded in plastic...

  11. 40 CFR 799.9630 - TSCA developmental neurotoxicity.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... is administered to several groups of pregnant animals during gestation and early lactation, one dose... assessment of the offspring conducted on the second (F2) generation. (d) Test procedure—(1) Animal selection... selection must be provided. (ii) Age. Young adult (nulliparous females) animals must be used. (iii) Sex...

  12. Behavorial Screens for Detecting Developmental Neurotoxicity in Larval Zebrafish

    EPA Science Inventory

    As part of the EPA's effort to develop an in vivo, vertebrate screen for toxic chemicals, we have characterized basic behaviors of 6-day post-fertilization (dpf) zebrafish (Danio rerio) larvae in a microtiter plate format. Our main goal is to develop a convenient, reproducible me...

  13. 40 CFR 799.9630 - TSCA developmental neurotoxicity.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...., ptosis. (B) Description, incidence, and severity of any convulsions, tremors, or abnormal movements. (C...). (9) Green, R.J. and Stanton, M.E. Differential ontogeny of working memory and reference memory in...

  14. 40 CFR 799.9630 - TSCA developmental neurotoxicity.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...., ptosis. (B) Description, incidence, and severity of any convulsions, tremors, or abnormal movements. (C...-313, 326-351 (1975). (9) Green, R.J. and Stanton, M.E. Differential ontogeny of working memory...

  15. STANDARD EVALUATION PROCEDURES FOR SUBMITTED DEVELOPMENTAL NEUROTOXICITY DATA

    EPA Science Inventory

    As a NAFTA-inspired multi-governmental initiative, experts from the US EPA (Office of Research and Development, Office of Pesticide Program, or OPP) and the PMRA (Pest Management Regulatory Agency) of Health Canada formed a working group to create a document that would serve as a...

  16. Behavorial Screens for Detecting Developmental Neurotoxicity in Larval Zebrafish

    EPA Science Inventory

    As part of the EPA's effort to develop an in vivo, vertebrate screen for toxic chemicals, we have characterized basic behaviors of 6-day post-fertilization (dpf) zebrafish (Danio rerio) larvae in a microtiter plate format. Our main goal is to develop a convenient, reproducible me...

  17. Use of HCI to screen for developmental neurotoxicity

    EPA Science Inventory

    The development of the nervous system is a prolonged process. It starts with the generation of neuroepithelial cells during embryogenesis and is not complete until the final stages of synaptic remodeling in the young adult. The outcome is a functionally connected neural network t...

  18. 40 CFR 799.9630 - TSCA developmental neurotoxicity.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... is administered to several groups of pregnant animals during gestation and early lactation, one dose... assessment of the offspring conducted on the second (F2) generation. (d) Test procedure—(1) Animal selection... selection must be provided. (ii) Age. Young adult (nulliparous females) animals must be used. (iii) Sex...

  19. STANDARD EVALUATION PROCEDURES FOR SUBMITTED DEVELOPMENTAL NEUROTOXICITY DATA

    EPA Science Inventory

    As a NAFTA-inspired multi-governmental initiative, experts from the US EPA (Office of Research and Development, Office of Pesticide Program, or OPP) and the PMRA (Pest Management Regulatory Agency) of Health Canada formed a working group to create a document that would serve as a...

  20. Screening for Developmental Neurotoxicants using In Vitro "Brain on a Chip" Cultures

    EPA Science Inventory

    Currently there are thousands of chemicals in the environment that have not been screened for their potential to cause developmental neurotoxicity (DNT). The use of microelectrode array (MEA) technology allows for simultaneous extracellular measurement of action potential (spike)...