Using nuclear receptor activity to stratify hepatocarcinogens
Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vit...
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| description | Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.
The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).
The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity. |
| doi_str_mv | 10.1371/journal.pone.0014584 |
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The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).
The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0014584</identifier><identifier>PMID: 21339822</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Algorithms ; Animals ; Aromatic compounds ; Biocompatibility ; Biological activity ; Cancer ; Carcinogens ; Carcinogens - classification ; Carcinogens - toxicity ; Carcinoma, Hepatocellular - chemically induced ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - metabolism ; Cell Biology/Chemical Biology of the Cell ; Cells, Cultured ; Chemicals ; Cluster analysis ; Clustering ; Contaminants ; Development and progression ; Disease Progression ; DNA binding proteins ; Drug Evaluation, Preclinical - methods ; Environmental effects ; Environmental protection ; Gastroenterology and Hepatology/Hepatology ; Gene expression ; Gene Expression - drug effects ; Gene Expression Profiling ; Gene Regulatory Networks - drug effects ; Genotoxicity ; High-Throughput Screening Assays - methods ; Histopathology ; Humans ; Kinases ; Lesions ; Ligands ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Liver cancer ; Liver Neoplasms - chemically induced ; Liver Neoplasms - genetics ; Liver Neoplasms - metabolism ; liver X receptors ; Metabolism ; Mice ; Microarray Analysis ; Molecular Biology ; Multivariate analysis ; Nuclear receptors ; Pathology/Histopathology ; Peroxisome proliferator-activated receptors ; Phosphatase ; Pollutants ; R&D ; Rats ; Receptors ; Receptors, Cytoplasmic and Nuclear - metabolism ; Receptors, Cytoplasmic and Nuclear - physiology ; Research & development ; Retinoid X receptors ; Rodents ; Steroid hormone receptors ; Toxicity ; Toxicology ; Transcription factors</subject><ispartof>PloS one, 2011-02, Vol.6 (2), p.e14584</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-136550762f239e02d1e789e38e4e9fcf5764ca5d3c919c7d308c3f5bf8e7d3323</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038857/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038857/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21339822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wölfl, Stefan</contributor><creatorcontrib>Shah, Imran</creatorcontrib><creatorcontrib>Houck, Keith</creatorcontrib><creatorcontrib>Judson, Richard S</creatorcontrib><creatorcontrib>Kavlock, Robert J</creatorcontrib><creatorcontrib>Martin, Matthew T</creatorcontrib><creatorcontrib>Reif, David M</creatorcontrib><creatorcontrib>Wambaugh, John</creatorcontrib><creatorcontrib>Dix, David J</creatorcontrib><title>Using nuclear receptor activity to stratify hepatocarcinogens</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.
The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).
The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.</description><subject>Algorithms</subject><subject>Animals</subject><subject>Aromatic compounds</subject><subject>Biocompatibility</subject><subject>Biological activity</subject><subject>Cancer</subject><subject>Carcinogens</subject><subject>Carcinogens - classification</subject><subject>Carcinogens - toxicity</subject><subject>Carcinoma, Hepatocellular - chemically induced</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cell Biology/Chemical Biology of the Cell</subject><subject>Cells, Cultured</subject><subject>Chemicals</subject><subject>Cluster analysis</subject><subject>Clustering</subject><subject>Contaminants</subject><subject>Development and progression</subject><subject>Disease Progression</subject><subject>DNA binding proteins</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Environmental effects</subject><subject>Environmental protection</subject><subject>Gastroenterology and Hepatology/Hepatology</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Gene Expression Profiling</subject><subject>Gene Regulatory Networks - drug effects</subject><subject>Genotoxicity</subject><subject>High-Throughput Screening Assays - methods</subject><subject>Histopathology</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lesions</subject><subject>Ligands</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - chemically induced</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - metabolism</subject><subject>liver X receptors</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Microarray Analysis</subject><subject>Molecular Biology</subject><subject>Multivariate analysis</subject><subject>Nuclear receptors</subject><subject>Pathology/Histopathology</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Phosphatase</subject><subject>Pollutants</subject><subject>R&D</subject><subject>Rats</subject><subject>Receptors</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Receptors, Cytoplasmic and Nuclear - physiology</subject><subject>Research & development</subject><subject>Retinoid X receptors</subject><subject>Rodents</subject><subject>Steroid hormone receptors</subject><subject>Toxicity</subject><subject>Toxicology</subject><subject>Transcription factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7of-A9GCsODFjPlo0uRCYVn8GFhYUNfbkKannQydppuki_PvzTjdZQoKkoskJ8_75uTkZNkrjJaYlvj9xo2-191ycD0sEcIFE8WT7BRLShacIPr0aH2SnYWwQYhRwfnz7IRgSqUg5DT7cBts3-b9aDrQPvdgYIjO59pEe2_jLo8uD9HraJtdvoZBR2e0N7Z3LfThRfas0V2Al9N8nt1-_vTj6uvi-ubL6uryemFKVsYFppwxVHLSECoBkRpDKSRQAQXIxjSs5IXRrKZGYmnKmiJhaMOqRkDaUELPszcH36FzQU0vDwoTSTgvCEWJWB2I2umNGrzdar9TTlv1J-B8q7SPNr1SQc0MZxKJuiQFqriucIFRXVEuCBW1TF4fp9vGagu1gT4VoJuZzk96u1atu1cpDyFYmQzeTgbe3Y0Q4j9SnqhWp6xs37hkZrY2GHVZlFwixsQ-meVfqDRq2FqT_r6xKT4TvJsJEhPhV2z1GIJaff_2_-zNzzl7ccSuQXdxHVw3Ruv6MAeLA2i8C8FD81g5jNS-dR-qofatq6bWTbLXx1V_FD30Kv0NW6DolQ</recordid><startdate>20110214</startdate><enddate>20110214</enddate><creator>Shah, Imran</creator><creator>Houck, Keith</creator><creator>Judson, Richard S</creator><creator>Kavlock, Robert J</creator><creator>Martin, Matthew T</creator><creator>Reif, David M</creator><creator>Wambaugh, John</creator><creator>Dix, David J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110214</creationdate><title>Using nuclear receptor activity to stratify hepatocarcinogens</title><author>Shah, Imran ; Houck, Keith ; Judson, Richard S ; Kavlock, Robert J ; Martin, Matthew T ; Reif, David M ; Wambaugh, John ; Dix, David J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c757t-136550762f239e02d1e789e38e4e9fcf5764ca5d3c919c7d308c3f5bf8e7d3323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Algorithms</topic><topic>Animals</topic><topic>Aromatic compounds</topic><topic>Biocompatibility</topic><topic>Biological activity</topic><topic>Cancer</topic><topic>Carcinogens</topic><topic>Carcinogens - 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Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.
The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).
The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21339822</pmid><doi>10.1371/journal.pone.0014584</doi><tpages>e14584</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-02, Vol.6 (2), p.e14584 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1292664230 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Algorithms Animals Aromatic compounds Biocompatibility Biological activity Cancer Carcinogens Carcinogens - classification Carcinogens - toxicity Carcinoma, Hepatocellular - chemically induced Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - metabolism Cell Biology/Chemical Biology of the Cell Cells, Cultured Chemicals Cluster analysis Clustering Contaminants Development and progression Disease Progression DNA binding proteins Drug Evaluation, Preclinical - methods Environmental effects Environmental protection Gastroenterology and Hepatology/Hepatology Gene expression Gene Expression - drug effects Gene Expression Profiling Gene Regulatory Networks - drug effects Genotoxicity High-Throughput Screening Assays - methods Histopathology Humans Kinases Lesions Ligands Liver Liver - drug effects Liver - metabolism Liver - pathology Liver cancer Liver Neoplasms - chemically induced Liver Neoplasms - genetics Liver Neoplasms - metabolism liver X receptors Metabolism Mice Microarray Analysis Molecular Biology Multivariate analysis Nuclear receptors Pathology/Histopathology Peroxisome proliferator-activated receptors Phosphatase Pollutants R&D Rats Receptors Receptors, Cytoplasmic and Nuclear - metabolism Receptors, Cytoplasmic and Nuclear - physiology Research & development Retinoid X receptors Rodents Steroid hormone receptors Toxicity Toxicology Transcription factors |
| title | Using nuclear receptor activity to stratify hepatocarcinogens |
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