327 research outputs found
Advancing the Science of Developmental Neurotoxicity (DNT): Testing for Better Safety Evaluation
No full textBal-Price AK, Coecke S, Costa L, Crofton KM, Fritsche E, Goldberg A, Grandjean P, Lein PJ, Li A, Lucchini R, Mundy WR, Padilla S, Persico A, Seiler AEM, Kreysa J. Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation. Altex 2012: 29: 202-15
Biotechnology and Plant Breeding : Applications and Approaches for Developing Improved Cultivars /
No full textThis book discusses applications of biotechnology in plant breeding. It covers key topics such as biometry applied to molecular analysis of genetic diversity and genetically modified plants, and goes beyond recombinant DNA technology to bring together key information and references on new biotech tools for cultivar development.Online resource; title from PDF title page (ScienceDirect, viewed Feb. 12, 2014).Includes bibliographical references and index.1. Plant breeding and biotechnological advances / Aluizio Borem, Valdir Diola, and Roberto Fritsche-Neto -- 2. Molecular markers / Eveline Teixeira Caixeta [and three others] -- 3. Biometrics applied to molecular analysis in genetic diversity / Cosme Damiao Cruz, Caio Cesio Salgado, and Leonardo Lopes Bhering -- 4. Genome-wide association studies (GWAS) / Marcos Deon Vilela de Resende [and three others] -- 5. Genome-wide selection (GWS) / Marcos Deon Vilela de Resende [and three others] -- 6. Genes prospection / Valdir Diola and Roberto Fritsche-Neto -- 7. Tissue culture applications for the genetic improvement of plants / Moacir Pasqual, Joyce Doria Rodrigues Soares, and Filipe Almendagna Rodrigues -- 8. Transgenic plants / Francisco Murilo Zerbini [and three others] -- 9. Double haploids / Roberto Fritsche-Neto, Deoclecio Domingos Garbuglio, and Aluizio Borem -- 10. Tools for the future breeder / Valdir Diola, Aluizio Borem, and Natalia Arruda Sanglard.This book discusses applications of biotechnology in plant breeding. It covers key topics such as biometry applied to molecular analysis of genetic diversity and genetically modified plants, and goes beyond recombinant DNA technology to bring together key information and references on new biotech tools for cultivar development.Elsevie
Editorial: Developmental Neurotoxicity
No full textThe developing human brain is inherently more susceptible to damage caused by toxic agents than is the brain of an adult (Bondy and Campbell, 2005; Rodier, 1995). This is why many environmental chemicals, including heavy metals, pesticides, organic solvents, flame retardants and persistent organic pollutants, can cause neurodevelopmental damage (Grandjean and Landrigan, 2006; Martin et al., 2017). It is suggested that this damage is associated with the rise in children’s learning disabilities, autism, and ADHD (Bennett et al., 2016; Grandjean et al., 2017). However, the number of chemicals with sufficient information on their developmental neurotoxicity (DNT) is sparse (Fritsche et al., 2017). Based primarily on this lack of data, a clear consensus was generated by scientists across the world (Bennett et al., 2016), including co-authors of this special issue (Fritsche et al., 2018), that current DNT testing based on the in vivo OECD 426 (OECD, 2007) or EPA OPPTS 870.630 (EPA, 1996) test guidelines are not sufficient to adequately screen and characterize compounds potentially toxic for the developing brain. Consequently, a new testing paradigm is urgently needed that uses time- and cost‐efficient methods to screen large numbers of chemicals for their DNT potential, providing adequate experimental data that allow regulatory decisions.
As stated in this special issue, the DNT scientists recommend developing a standardised in vitro testing battery using mixed neuronal/glial cultures, preferably derived from human pluripotent stem cells (illustrated on the cover picture; Fig. 1 from Bal-Price et al., 2018) to generate data on the effects of chemicals on key neurodevelopmental processes that represent different stages of human brain development (Fritsche et al., 2017). In addition, the use of alternative species, such as zebrafish or C. elegans could complement such an in vitro battery with behavioural studies due to the organisms’ intact developing nervous systems. The endpoints of these test methods should be anchored to key events identified in the existing DNT adverse outcome pathways (AOPs), increasing scientific confidence in the mechanistic understanding of the toxicity pathways involved (Bal-Price and Meek, 2017). Because the number of DNT AOPs is currently low, such data might also lead to new AOP development.
Furthermore, in silico models are needed to provide rapid chemical structure‐based screening. Finally, these test methods ought to be used in an integrated fashion using an IATA (Integrated Approaches to Testing and Assessment) platform. Such a platform allows designed fit-for-purpose data generation for various regulatory purposes with different problem formulations (Bal-Price et al., 2018). This joint effort that is currently performed under the coordinating roof of the OECD in collaboration with the European Food Safety Authority and the US as well as the Danish Environmental Protection Agency will result in an OECD DNT guidance document on the use and data interpretation of an alternative DNT testing battery (Bal-Price et al., 2018). Such a guidance will be extremely helpful for a faster evaluation of compounds regarding their DNT potential and thus aiding in the closure of data gaps.
Summing up, this special issue of Toxicology and Applied Pharmacology contains several articles outlining novel concepts (i.e., AOP, IATA, ontology-driven animal-free testing) as well as a range of alternative approaches (i.e., in vitro, zebrafish, C. elegans, in silico, a systems biology approach), which are the flagships for more effective DNT testing for better protection of pregnant women, infants and children exposed to environmental chemicals.JRC.F.3 - Chemicals Safety and Alternative Method
Identification of an amino acid determinant of pH regiospecificity in a seed lipoxygenase from Momordica charantia
No full textLipoxygenases (LOX) form a heterogeneous family of lipid peroxidizing enzymes, which catalyze specific dioxygenation of polyunsaturated fatty acids. According to their positional specificity of linoleic acid oxygenation plant LOX have been classified into linoleate 9- and linoleate 13-LOX and recent reports identified a critical valine at the active site of 9-LOX. In contrast, more bulky phenylalanine or histidine residues were found at this position in 13-LOX. We have recently cloned a LOX-isoform from Momordica charantia and multiple amino acid alignments indicated the existence of a glutamine (Gln599) at the position were 13-LOX usually carry histidine or phenylalanine residues. Analyzing the pH-dependence of the positional specificity of linoleic acid oxygenation we observed that at pH-values higher than 7.5 this enzyme constitutes a linoleate 13-LOX whereas at lower pH, 9-H(P)ODE was the major reaction product. Site-directed mutagenesis of glutamine 599 to histidine (Gln599His) converted the enzyme to a pure 13-LOX. These data confirm previous observation suggesting that reaction specificity of certain LOX-isoforms is not an absolute enzyme property but may be impacted by reaction conditions such as pH of the reaction mixture. We extended this concept by identifying glutamine 599 as sequence determinant for such pH-dependence of the reaction specificity. Although the biological relevance for this alteration switch remains to be investigated it is of particular interest that it occurs at near physiological conditions in the pH-range between 7 and 8. (C) 2008 Elsevier Ltd. All rights reserved.Fachagentur fur Nachwachsende Rohstoffe; BASF Plant Science Gmb
Correction to: female reproductive organs of Brassica napus are more sensitive than male to transient heat stress
No full textThe article Female reproductive organs of Brassica napus are more sensitive than male to transient heat stress, written by Sheng Chen, Renu Saradadevi, Miriam S. Vidotti, Roberto Fritsche-Neto, Jose Crossa, Kadambot H. M. Siddique, Wallace A. Cowling, was originally published Online First without Open Access. After publication in volume 217: 117 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed t
Neural In Vitro Models for Studying Substances Acting on the Central Nervous System
No full textAnimal models have been greatly contributing to our understanding of physiology, mechanisms of diseases, and toxicity. Yet, their limitations due to, e.g., interspecies variation are reflected in the high number of drug attrition rates, especially in central nervous system (CNS) diseases. Therefore, human-based neural in vitro models for studying safety and efficacy of substances acting on the CNS are needed. Human iPSC-derived cells offer such a platform with the unique advantage of reproducing the "human context" in vitro by preserving the genetic and molecular phenotype of their donors. Guiding the differentiation of hiPSC into cells of the nervous system and combining them in a 2D or 3D format allows to obtain complex models suitable for investigating neurotoxicity or brain-related diseases with patient-derived cells. This chapter will give an overview over stem cell-based human 2D neuronal and mixed neuronal/astrocyte models, in vitro cultures of microglia, as well as CNS disease models and considers new developments in the field, more specifically the use of brain organoids and 3D bioprinted in vitro models for safety and efficacy evaluation
Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research
No full textAbstractInfant leukaemia (Acknowledgementson behalf of the EFSA WG EPI1 and its other members:Karine Angeli, ANSES, France, Ellen Fritsche, IUF, Leibniz Research Institute for Environmental Medicine, Dusseldorf, Germany, Marcel Leist, University of Konstanz, Germany, Alberto Mantovani, Istituto Superiore di Sanità, Rome, Italy,Anna Price, EU JRC, Ispra, Italy, Barbara Viviani, University of Milan, ItalyAbstract
Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease—secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide—and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.Acknowledgements
on behalf of the EFSA WG EPI1 and its other members:
Karine Angeli, ANSES, France, Ellen Fritsche, IUF, Leibniz Research Institute for Environmental Medicine, Dusseldorf, Germany, Marcel Leist, University of Konstanz, Germany, Alberto Mantovani, Istituto Superiore di Sanità, Rome, Italy,Anna Price, EU JRC, Ispra, Italy, Barbara Viviani, University of Milan, Ital
OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes
No full textOECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes
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