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  1. Article ; Online: Unlocking the Power of Transcriptomic Biomarkers in Qualitative and Quantitative Genotoxicity Assessment of Chemicals.

    Thienpont, Anouck / Cho, Eunnara / Williams, Andrew / Meier, Matthew J / Yauk, Carole L / Rogiers, Vera / Vanhaecke, Tamara / Mertens, Birgit

    Chemical research in toxicology

    2024  Volume 37, Issue 3, Page(s) 465–475

    Abstract: To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high ... ...

    Abstract To modernize genotoxicity assessment and reduce reliance on experimental animals, new approach methodologies (NAMs) that provide human-relevant dose-response data are needed. Two transcriptomic biomarkers, GENOMARK and TGx-DDI, have shown a high classification accuracy for genotoxicity. As these biomarkers were extracted from different training sets, we investigated whether combining the two biomarkers in a human-derived metabolically competent cell line (i.e., HepaRG) provides complementary information for the classification of genotoxic hazard identification and potency ranking. First, the applicability of GENOMARK to TempO-Seq, a high-throughput transcriptomic technology, was evaluated. HepaRG cells were exposed for 72 h to increasing concentrations of 10 chemicals (i.e., eight known
    MeSH term(s) Animals ; Humans ; Gene Expression Profiling/methods ; Transcriptome ; Biomarkers ; Cell Line ; DNA Damage
    Chemical Substances Biomarkers
    Language English
    Publishing date 2024-02-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639353-6
    ISSN 1520-5010 ; 0893-228X
    ISSN (online) 1520-5010
    ISSN 0893-228X
    DOI 10.1021/acs.chemrestox.3c00318
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2320: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Impact of experimental design factors on the potency of genotoxicants in in vitro tests.

    Sanders, Julie / Thienpont, Anouck / Anthonissen, Roel / Vanhaecke, Tamara / Mertens, Birgit

    Mutagenesis

    2022  Volume 37, Issue 5-6, Page(s) 248–258

    Abstract: Previous studies have shown that differences in experimental design factors may alter the potency of genotoxic compounds in in vitro genotoxicity tests. Most of these studies used traditional statistical methods based on the lowest observed genotoxic ... ...

    Abstract Previous studies have shown that differences in experimental design factors may alter the potency of genotoxic compounds in in vitro genotoxicity tests. Most of these studies used traditional statistical methods based on the lowest observed genotoxic effect levels, whereas more appropriate methods, such as the benchmark dose (BMD) approach, are now available to compare genotoxic potencies under different test conditions. We therefore investigated the influence of two parameters, i.e. cell type and exposure duration, on the potencies of two known genotoxicants [aflatoxin B1 and ethyl methanesulfonate (EMS)] in the in vitro micronucleus (MN) assay and comet assay (CA). Both compounds were tested in the two assays using two cell types (i.e. CHO-K1 and TK6 cells). To evaluate the effect of exposure duration, the genotoxicity of EMS was assessed after 3 and 24 h of exposure. Results were analyzed using the BMD covariate approach, also referred to as BMD potency ranking, and the outcome was compared with that of more traditional statistical methods based on lowest observed genotoxic effect levels. When comparing the in vitro MN results obtained in both cell lines with the BMD covariate approach, a difference in potency was detected only when EMS exposures were conducted for 24 h, with TK6 cells being more sensitive. No difference was observed in the potency of both EMS and aflatoxin B1 in the in vitro CA using both cell lines. In contrast, EMS was more potent after 24 h exposure compared with a 3 h exposure under all tested conditions, i.e. in the in vitro MN assay and CA in both cell lines. Importantly, for several of the investigated factors, the BMD covariate method could not be used to confirm the differences in potencies detected with the traditional statistical methods, thus highlighting the need to evaluate the impact of experimental design factors with adequate approaches.
    MeSH term(s) Aflatoxin B1/toxicity ; Research Design ; In Vitro Techniques
    Chemical Substances Aflatoxin B1 (9N2N2Y55MH)
    Language English
    Publishing date 2022-11-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 632903-2
    ISSN 1464-3804 ; 0267-8357
    ISSN (online) 1464-3804
    ISSN 0267-8357
    DOI 10.1093/mutage/geac025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2189: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Novel prediction models for genotoxicity based on biomarker genes in human HepaRG™ cells.

    Thienpont, Anouck / Verhulst, Stefaan / Van Grunsven, Leo A / Rogiers, Vera / Vanhaecke, Tamara / Mertens, Birgit

    ALTEX

    2022  Volume 40, Issue 2, Page(s) 271–286

    Abstract: Transcriptomics-based biomarkers are promising new approach methodologies (NAMs) to identify molecular events underlying the genotoxic mode of action of chemicals. Previously, we developed the GENOMARK biomarker, consisting of 84 genes selected based on ... ...

    Abstract Transcriptomics-based biomarkers are promising new approach methodologies (NAMs) to identify molecular events underlying the genotoxic mode of action of chemicals. Previously, we developed the GENOMARK biomarker, consisting of 84 genes selected based on whole genomics DNA microarray profiles of 24 (non-)genotoxic reference chemicals covering different modes of action in metabolically competent human HepaRG™ cells. In the present study, new prediction models for genotoxicity were developed based on an extended reference dataset of 38 chemicals including existing as well as newly generated gene expression data. Both unsupervised and supervised machine learning algorithms were used, but as unsupervised machine learning did not clearly distinguish between groups, the performance of two supervised machine learning algorithms, i.e., support vector machine (SVM) and random forest (RF), was evaluated. More specifically, the predictive accuracy was compared, the sensitivity to outliers for one or more biomarker genes was assessed, and the prediction performance for 10 misleading positive chemicals exposed at their IC10 concentration was determined. In addition, the applicability of both prediction models on a publicly available gene expression dataset, generated with RNA-sequencing, was investigated. Overall, the RF and SVM models were complementary in their classification of chemicals for genotoxicity. To facilitate data analysis, an online application was developed, combining the outcomes of both prediction models. This research demonstrates that the combination of gene expression data with supervised machine learning algorithms can contribute to the ongoing paradigm shift towards a more human-relevant in vitro genotoxicity testing strategy without the use of experimental animals.
    MeSH term(s) Animals ; Humans ; Algorithms ; Biomarkers ; Gene Expression Profiling/methods ; Supervised Machine Learning ; DNA Damage
    Chemical Substances Biomarkers
    Language English
    Publishing date 2022-11-04
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 165707-0
    ISSN 1868-8551 ; 1018-4562 ; 0946-7785
    ISSN (online) 1868-8551
    ISSN 1018-4562 ; 0946-7785
    DOI 10.14573/altex.2206201
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 2971: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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