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  1. Article ; Online: Review of the state of science and evaluation of currently available in silico prediction models for reproductive and developmental toxicity: A case study on pesticides.

    Weyrich, Anastasia / Joel, Madeleine / Lewin, Geertje / Hofmann, Thomas / Frericks, Markus

    Birth defects research

    2022  Volume 114, Issue 14, Page(s) 812–842

    Abstract: Background: In silico methods for toxicity prediction have increased significantly in recent years due to the 3Rs principle. This also applies to predicting reproductive toxicology, which is one of the most critical factors in pesticide approval. The ... ...

    Abstract Background: In silico methods for toxicity prediction have increased significantly in recent years due to the 3Rs principle. This also applies to predicting reproductive toxicology, which is one of the most critical factors in pesticide approval. The widely used quantitative structure-activity relationship (QSAR) models use experimental toxicity data to create a model that relates experimentally observed toxicity to molecular structures to predict toxicity. Aim of the study was to evaluate the available prediction models for developmental and reproductive toxicity regarding their strengths and weaknesses in a pesticide database.
    Methods: The reproductive toxicity of 315 pesticides, which have a GHS classification by ECHA, was compared with the prediction of different in silico models: VEGA, OECD (Q)SAR Toolbox, Leadscope Model Applier, and CASE Ultra by MultiCASE.
    Results: In all models, a large proportion (up to 77%) of all pesticides were outside the chemical space of the model. Analysis of the prediction of remaining pesticides revealed a balanced accuracy of the models between 0.48 and 0.66.
    Conclusion: Overall, predictions were only meaningful in rare cases and therefore always require evaluation by an expert. The critical factors were the underlying data and determination of molecular similarity, which offer great potential for improvement.
    MeSH term(s) Computer Simulation ; Databases, Factual ; Pesticides/toxicity ; Quantitative Structure-Activity Relationship ; Reproduction
    Chemical Substances Pesticides
    Language English
    Publishing date 2022-06-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2104792-3
    ISSN 2472-1727
    ISSN (online) 2472-1727
    DOI 10.1002/bdr2.2062
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 749: Show issues Location:
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  2. Article ; Online: Food grade safflower concentrate: No evidence for reproduction and early developmental toxicity.

    Lewin, Geertje / Joel, Madeleine / Peter, Birgit / Lützow, Manfred

    Reproductive toxicology (Elmsford, N.Y.)

    2021  Volume 104, Page(s) 155–165

    Abstract: Safflower (Carthamus tinctorius) petals have been used for centuries as a spice, in tea blends and in traditional Asian medicine. Aqueous extracts of Safflower petals have been used as a colouring food over the last 30 years due to their bright colour. ... ...

    Abstract Safflower (Carthamus tinctorius) petals have been used for centuries as a spice, in tea blends and in traditional Asian medicine. Aqueous extracts of Safflower petals have been used as a colouring food over the last 30 years due to their bright colour. Publications in the past raised concerns about fertility impairing, maternal toxicity, fetotoxic and teratogenic properties in rodents. As the tested extracts were poorly characterized and the studies were not performed according to guidelines, a need for further evaluation was seen. In silico predictions for the main pigments provided negative results for bacterial mutagenicity. Further, in vitro genotoxicity and in vivo reproductive toxicity studies of a well-characterized aqueous safflower concentrate generated more relevant data for risk assessment of its use in food. In vitro AMES tests and a mouse lymphoma cell assay were negative. An OECD guideline 421 screening study was performed in rats with oral daily doses of up to 1000 mg/kg bodyweight, applied via gavage to simulate a bolus effect. The highest dose reflected a toxicological limit test. The study did not give indications of general toxicity, did not show any effect on fertility and reproduction nor any effect on prenatal development and, also in contrast to previous results, treatment did not affect estradiol and FSH levels. Furthermore, pups raised until PND 14-16, developed normally with no adverse effects observed. With the established NOAEL of at least 1000 mg/kg/d, a considerable margin of exposure is achieved when compared with human intake estimates.
    MeSH term(s) Animal Feed ; Animals ; Carthamus tinctorius ; Female ; Male ; Mice ; No-Observed-Adverse-Effect Level ; Plant Extracts/toxicity ; Pregnancy ; Rats ; Reproduction
    Chemical Substances Plant Extracts
    Language English
    Publishing date 2021-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639342-1
    ISSN 1873-1708 ; 0890-6238
    ISSN (online) 1873-1708
    ISSN 0890-6238
    DOI 10.1016/j.reprotox.2021.01.009
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  3. Article ; Online: A Compendium of Mutational Signatures of Environmental Agents.

    Kucab, Jill E / Zou, Xueqing / Morganella, Sandro / Joel, Madeleine / Nanda, A Scott / Nagy, Eszter / Gomez, Celine / Degasperi, Andrea / Harris, Rebecca / Jackson, Stephen P / Arlt, Volker M / Phillips, David H / Nik-Zainal, Serena

    Cell

    2019  Volume 177, Issue 4, Page(s) 821–836.e16

    Abstract: Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected ... ...

    Abstract Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. VIDEO ABSTRACT.
    MeSH term(s) Carcinogens, Environmental/adverse effects ; Carcinogens, Environmental/classification ; DNA Damage/genetics ; DNA Mutational Analysis/methods ; DNA Repair/genetics ; DNA Replication ; Genetic Profile ; Genome, Human/genetics ; Humans ; INDEL Mutation/genetics ; Mutagenesis ; Mutation/genetics ; Neoplasms/genetics ; Pluripotent Stem Cells/metabolism ; Whole Genome Sequencing/methods
    Chemical Substances Carcinogens, Environmental
    Language English
    Publishing date 2019-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2019.03.001
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  4. Article: A Compendium of Mutational Signatures of Environmental Agents

    Kucab, Jill E / Zou, Xueqing / Morganella, Sandro / Joel, Madeleine / Nanda, A. Scott / Nagy, Eszter / Gomez, Celine / Degasperi, Andrea / Harris, Rebecca / Jackson, Stephen P / Arlt, Volker M / Phillips, David H / Nik-Zainal, Serena

    Cell. 2019 May 02, v. 177, no. 4

    2019  

    Abstract: Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected ... ...

    Abstract Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents.[Display omitted]
    Keywords DNA ; DNA damage ; carcinogens ; etiology ; genome ; humans ; mutagens ; mutation ; neoplasms ; stem cells ; topography
    Language English
    Dates of publication 2019-0502
    Size p. 821-836.e16.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2019.03.001
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Differentiation-associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic-metabolizing activity of "luminal" muscle-invasive bladder cancers.

    Baker, Simon C / Arlt, Volker M / Indra, Radek / Joel, Madeleine / Stiborová, Marie / Eardley, Ian / Ahmad, Niaz / Otto, Wolfgang / Burger, Maximilian / Rubenwolf, Peter / Phillips, David H / Southgate, Jennifer

    Molecular carcinogenesis

    2018  Volume 57, Issue 5, Page(s) 606–618

    Abstract: Extra-hepatic metabolism of xenobiotics by epithelial tissues has evolved as a self-defence mechanism but has potential to contribute to the local activation of carcinogens. Bladder epithelium (urothelium) is bathed in excreted urinary toxicants and pro- ... ...

    Abstract Extra-hepatic metabolism of xenobiotics by epithelial tissues has evolved as a self-defence mechanism but has potential to contribute to the local activation of carcinogens. Bladder epithelium (urothelium) is bathed in excreted urinary toxicants and pro-carcinogens. This study reveals how differentiation affects cytochrome P450 (CYP) activity and the role of NADPH:P450 oxidoreductase (POR). CYP1A1 and CYP1B1 transcripts were inducible in normal human urothelial (NHU) cells maintained in both undifferentiated and functional barrier-forming differentiated states in vitro. However, ethoxyresorufin O-deethylation (EROD) activity, the generation of reactive BaP metabolites and BaP-DNA adducts, were predominantly detected in differentiated NHU cell cultures. This gain-of-function was attributable to the expression of POR, an essential electron donor for all CYPs, which was significantly upregulated as part of urothelial differentiation. Immunohistology of muscle-invasive bladder cancer (MIBC) revealed significant overall suppression of POR expression. Stratification of MIBC biopsies into "luminal" and "basal" groups, based on GATA3 and cytokeratin 5/6 labeling, showed POR over-expression by a subgroup of the differentiated luminal tumors. In bladder cancer cell lines, CYP1-activity was undetectable/low in basal POR
    MeSH term(s) Aged ; Aged, 80 and over ; Cell Differentiation ; Cell Line, Tumor ; Cytochrome P-450 CYP1A1/genetics ; Cytochrome P-450 CYP1B1/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Down-Regulation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Middle Aged ; Tissue Array Analysis ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/metabolism ; Urothelium/cytology ; Urothelium/metabolism ; Xenobiotics/pharmacology
    Chemical Substances POR protein, human ; Xenobiotics ; Cytochrome P-450 Enzyme System (9035-51-2) ; CYP1A1 protein, human (EC 1.14.14.1) ; CYP1B1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1)
    Language English
    Publishing date 2018-02-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1004029-8
    ISSN 1098-2744 ; 0899-1987
    ISSN (online) 1098-2744
    ISSN 0899-1987
    DOI 10.1002/mc.22784
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    Zs.A 2664: Show issues Location:
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