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  1. Article ; Online: Risk-based prioritization of PFAS using phenotypic and transcriptomic data from human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes.

    Tsai, Han-Hsuan D / Ford, Lucie C / Chen, Zunwei / Dickey, Allison N / Wright, Fred A / Rusyn, Ivan

    ALTEX

    2024  

    Abstract: Per- and polyfluoroalkyl substances (PFAS) are chemicals with important applications; they are persistent in the environment and may pose human health hazards. Regulatory agencies are considering restrictions and bans of PFAS; however, little data exists ...

    Abstract Per- and polyfluoroalkyl substances (PFAS) are chemicals with important applications; they are persistent in the environment and may pose human health hazards. Regulatory agencies are considering restrictions and bans of PFAS; however, little data exists for informed decisions. Several prioritization strategies were proposed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite the selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist for PFAS requires confirmation. We tested 26 structurally diverse PFAS from 8 groups using human-induced pluripotent stem cell-derived hepatocytes and cardiomyocytes, and tested concentration-response effects on cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed for 8 of the 26 PFAS. Substance- and cell type-dependent transcriptomic changes were more prominent but lacked substantial group-specific effects. In hepatocytes, we found up-regulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractility-related pathways were most affected. We derived phenotypic and transcriptomic points of departure and compared them to predicted PFAS exposures. The conservative estimates for bioactivity and exposure were used to derive bioactivity-to-exposure ratio (BER) for each PFAS, most (23 of 26) PFAS had BER > 1. Overall, these data suggests that structure-based grouping of PFAS may not be sufficient to predict their biological effects. Testing of individual PFAS may be needed for scientific-based decision-making. Our proposed strategy of using two human cell types and considering phenotypic and transcriptomic effects, combined with dose-response analysis and calculation of BER, may be used for PFAS prioritization.
    Language English
    Publishing date 2024-02-22
    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.2311031
    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:
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    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Comparative Analysis of the Physiological and Transport Functions of Various Sources of Renal Proximal Tubule Cells Under Static and Fluidic Conditions in PhysioMimix{trade mark, serif} T12 Platform.

    Sakolish, Courtney / Moyer, Haley L / Tsai, Han-Hsuan D / Ford, Lucie C / Dickey, Allison N / Bajaj, Piyush / Villenave, Remi / Hewitt, Philip / Ferguson, Stephen S / Stanko, Jason / Rusyn, Ivan

    Drug metabolism and disposition: the biological fate of chemicals

    2024  

    Abstract: ... In ... ...

    Abstract In vitro
    Language English
    Publishing date 2024-04-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 186795-7
    ISSN 1521-009X ; 0090-9556
    ISSN (online) 1521-009X
    ISSN 0090-9556
    DOI 10.1124/dmd.124.001488
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1014: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  3. Article ; Online: Hazard and risk characterization of 56 structurally diverse PFAS using a targeted battery of broad coverage assays using six human cell types.

    Ford, Lucie C / Lin, Hsing-Chieh / Tsai, Han-Hsuan D / Zhou, Yi-Hui / Wright, Fred A / Sedykh, Alexander / Shah, Ruchir R / Chiu, Weihsueh A / Rusyn, Ivan

    Toxicology

    2024  Volume 503, Page(s) 153763

    Abstract: Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both ... ...

    Abstract Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both the environment and humans. Because of this, PFAS as a class (composed of hundreds to thousands of chemicals) are contaminants of very high concern. Little information is available for the vast majority of PFAS, and regulatory agencies lack safety data to determine whether exposure limits or restrictions are needed. Cell-based assays are a pragmatic approach to inform decision-makers on potential health hazards; therefore, we hypothesized that a targeted battery of human in vitro assays can be used to determine whether there are structure-bioactivity relationships for PFAS, and to characterize potential risks by comparing bioactivity (points of departure) to exposure estimates. We tested 56 PFAS from 8 structure-based subclasses in concentration response (0.1-100 μM) using six human cell types selected from target organs with suggested adverse effects of PFAS - human induced pluripotent stem cell (iPSC)-derived hepatocytes, neurons, and cardiomyocytes, primary human hepatocytes, endothelial and HepG2 cells. While many compounds were without effect; certain PFAS demonstrated cell-specific activity highlighting the necessity of using a compendium of in vitro models to identify potential hazards. No class-specific groupings were evident except for some chain length- and structure-related trends. In addition, margins of exposure (MOE) were derived using empirical and predicted exposure data. Conservative MOE calculations showed that most tested PFAS had a MOE in the 1-100 range; ∼20% of PFAS had MOE<1, providing tiered priorities for further studies. Overall, we show that a compendium of human cell-based models can be used to derive bioactivity estimates for a range of PFAS, enabling comparisons with human biomonitoring data. Furthermore, we emphasize that establishing structure-bioactivity relationships may be challenging for the tested PFAS.
    MeSH term(s) Humans ; Induced Pluripotent Stem Cells ; Biological Monitoring ; Fluorocarbons/chemistry
    Chemical Substances Fluorocarbons
    Language English
    Publishing date 2024-02-27
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 184557-3
    ISSN 1879-3185 ; 0300-483X
    ISSN (online) 1879-3185
    ISSN 0300-483X
    DOI 10.1016/j.tox.2024.153763
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 888: Show issues Location:
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  4. Article ; Online: Analysis of reproducibility and robustness of a renal proximal tubule microphysiological system OrganoPlate 3-lane 40 for in vitro studies of drug transport and toxicity.

    Sakolish, Courtney / Moyer, Haley L / Tsai, Han-Hsuan D / Ford, Lucie C / Dickey, Allison N / Wright, Fred A / Han, Gang / Bajaj, Piyush / Baltazar, Maria T / Carmichael, Paul L / Stanko, Jason P / Ferguson, Stephen S / Rusyn, Ivan

    Toxicological sciences : an official journal of the Society of Toxicology

    2023  Volume 196, Issue 1, Page(s) 52–70

    Abstract: Microphysiological systems are an emerging area of in vitro drug development, and their independent evaluation is important for wide adoption and use. The primary goal of this study was to test reproducibility and robustness of a renal proximal tubule ... ...

    Abstract Microphysiological systems are an emerging area of in vitro drug development, and their independent evaluation is important for wide adoption and use. The primary goal of this study was to test reproducibility and robustness of a renal proximal tubule microphysiological system, OrganoPlate 3-lane 40, as an in vitro model for drug transport and toxicity studies. This microfluidic model was compared with static multiwell cultures and tested using several human renal proximal tubule epithelial cell (RPTEC) types. The model was characterized in terms of the functional transport for various tubule-specific proteins, epithelial permeability of small molecules (cisplatin, tenofovir, and perfluorooctanoic acid) versus large molecules (fluorescent dextrans, 60-150 kDa), and gene expression response to a nephrotoxic xenobiotic. The advantages offered by OrganoPlate 3-lane 40 as compared with multiwell cultures are the presence of media flow, albeit intermittent, and increased throughput compared with other microfluidic models. However, OrganoPlate 3-lane 40 model appeared to offer only limited (eg, MRP-mediated transport) advantages in terms of either gene expression or functional transport when compared with the multiwell plate culture conditions. Although OrganoPlate 3-lane 40 can be used to study cellular uptake and direct toxic effects of small molecules, it may have limited utility for drug transport studies. Overall, this study offers refined experimental protocols and comprehensive comparative data on the function of RPETCs in traditional multiwell culture and microfluidic OrganoPlate 3-lane 40, information that will be invaluable for the prospective end-users of in vitro models of the human proximal tubule.
    MeSH term(s) Humans ; Microphysiological Systems ; Reproducibility of Results ; Prospective Studies ; Kidney Tubules, Proximal ; Kidney
    Language English
    Publishing date 2023-08-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfad080
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1709: Show issues Location:
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  5. Article ; Online: Application of Ion Mobility Spectrometry-Mass Spectrometry for Compositional Characterization and Fingerprinting of a Library of Diverse Crude Oil Samples.

    Cordova, Alexandra C / Dodds, James N / Tsai, Han-Hsuan D / Lloyd, Dillon T / Roman-Hubers, Alina T / Wright, Fred A / Chiu, Weihsueh A / McDonald, Thomas J / Zhu, Rui / Newman, Galen / Rusyn, Ivan

    Environmental toxicology and chemistry

    2023  Volume 42, Issue 11, Page(s) 2336–2349

    Abstract: Exposure characterization of crude oils, especially in time-sensitive circumstances such as spills and disasters, is a well-known analytical chemistry challenge. Gas chromatography-mass spectrometry is commonly used for "fingerprinting" and origin ... ...

    Abstract Exposure characterization of crude oils, especially in time-sensitive circumstances such as spills and disasters, is a well-known analytical chemistry challenge. Gas chromatography-mass spectrometry is commonly used for "fingerprinting" and origin tracing in oil spills; however, this method is both time-consuming and lacks the resolving power to separate co-eluting compounds. Recent advances in methodologies to analyze petroleum substances using high-resolution analytical techniques have demonstrated both improved resolving power and higher throughput. One such method, ion mobility spectrometry-mass spectrometry (IMS-MS), is especially promising because it is both rapid and high-throughput, with the ability to discern among highly homologous hydrocarbon molecules. Previous applications of IMS-MS to crude oil analyses included a limited number of samples and did not provide detailed characterization of chemical constituents. We analyzed a diverse library of 195 crude oil samples using IMS-MS and applied a computational workflow to assign molecular formulas to individual features. The oils were from 12 groups based on geographical and geological origins: non-US (1 group), US onshore (3), and US Gulf of Mexico offshore (8). We hypothesized that information acquired through IMS-MS data would provide a more confident grouping and yield additional fingerprint information. Chemical composition data from IMS-MS was used for unsupervised hierarchical clustering, as well as machine learning-based supervised analysis to predict geographic and source rock categories for each sample; the latter also yielded several novel prospective biomarkers for fingerprinting of crude oils. We found that IMS-MS data have complementary advantages for fingerprinting and characterization of diverse crude oils and that proposed polycyclic aromatic hydrocarbon biomarkers can be used for rapid exposure characterization. Environ Toxicol Chem 2023;42:2336-2349. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
    MeSH term(s) Petroleum/analysis ; Ion Mobility Spectrometry ; Mass Spectrometry ; Gas Chromatography-Mass Spectrometry/methods ; Biomarkers
    Chemical Substances Petroleum ; Biomarkers
    Language English
    Publishing date 2023-08-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 46234-2
    ISSN 1552-8618 ; 0730-7268
    ISSN (online) 1552-8618
    ISSN 0730-7268
    DOI 10.1002/etc.5727
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    Zs.A 2312: Show issues Location:
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