Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide
To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0...
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| creator | Efremenko, A.Y. Campbell, J.L. Dodd, D.E. Oller, A.R. Clewell, H.J. |
| description | To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure.
Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60mg/m3 (0.03, 0.06, 0.11, and 0.44mgNi/m3) for one and four weeks (6h/day, 5days/week).
Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1week to up-regulation at 4weeks.
These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026mgNi/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64μgNi/g lung, for immune/inflammatory signaling.
These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
•The mode of action for lung carcinogenicity of inhaled Ni3S2 was investigated in rats.•Gene expression changes were determined in micro-dissected lung tissue at 1–4weeks.•A non-genotoxic mode of action (toxicity, inflammation, proliferation) was supported.•Analyses of lung lavage fluid and histopathology provided complementary results.•Transcriptional benchmark doses could inform point of departure for risk assessment. |
| doi_str_mv | 10.1016/j.taap.2014.06.007 |
| format | Article |
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Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60mg/m3 (0.03, 0.06, 0.11, and 0.44mgNi/m3) for one and four weeks (6h/day, 5days/week).
Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1week to up-regulation at 4weeks.
These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026mgNi/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64μgNi/g lung, for immune/inflammatory signaling.
These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
•The mode of action for lung carcinogenicity of inhaled Ni3S2 was investigated in rats.•Gene expression changes were determined in micro-dissected lung tissue at 1–4weeks.•A non-genotoxic mode of action (toxicity, inflammation, proliferation) was supported.•Analyses of lung lavage fluid and histopathology provided complementary results.•Transcriptional benchmark doses could inform point of departure for risk assessment.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2014.06.007</identifier><identifier>PMID: 24952340</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; Animals ; APOPTOSIS ; Apoptosis - drug effects ; Benchmarking ; BIOASSAY ; Biological and medical sciences ; Body Weight - drug effects ; Bronchoalveolar Lavage Fluid - cytology ; Carcinogenicity ; Carcinogens - administration & dosage ; Carcinogens - toxicity ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Chemical and industrial products toxicology. Toxic occupational diseases ; CONCENTRATION RATIO ; Dose-Response Relationship, Drug ; DOSES ; Down-Regulation - drug effects ; ECOLOGICAL CONCENTRATION ; FLUIDS ; Gene expression ; Gene Expression - drug effects ; GENES ; INFLAMMATION ; Inflammation - chemically induced ; Inflammation - pathology ; INHALATION ; Inhalation Exposure ; LAVAGE ; Lung - metabolism ; Lung - pathology ; LUNGS ; Male ; Medical sciences ; Metals and various inorganic compounds ; Microarray Analysis ; Microscopy, Electron, Transmission ; Mutagens ; NICKEL ; Nickel - administration & dosage ; Nickel - metabolism ; Nickel - toxicity ; Nickel subsulfide ; RATS ; Rats, Inbred F344 ; Real-Time Polymerase Chain Reaction ; RISK ASSESSMENT ; Signal Transduction - drug effects ; SIGNALS ; TOXICITY ; Toxicology ; Up-Regulation - drug effects</subject><ispartof>Toxicology and applied pharmacology, 2014-09, Vol.279 (3), p.441-454</ispartof><rights>2014 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-446b584044f033c4f92cda7297775b42073d1a55f81c4eab46646691723b7e653</citedby><cites>FETCH-LOGICAL-c447t-446b584044f033c4f92cda7297775b42073d1a55f81c4eab46646691723b7e653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0041008X14002300$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28992848$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24952340$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22439842$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Efremenko, A.Y.</creatorcontrib><creatorcontrib>Campbell, J.L.</creatorcontrib><creatorcontrib>Dodd, D.E.</creatorcontrib><creatorcontrib>Oller, A.R.</creatorcontrib><creatorcontrib>Clewell, H.J.</creatorcontrib><title>Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure.
Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60mg/m3 (0.03, 0.06, 0.11, and 0.44mgNi/m3) for one and four weeks (6h/day, 5days/week).
Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1week to up-regulation at 4weeks.
These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026mgNi/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64μgNi/g lung, for immune/inflammatory signaling.
These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
•The mode of action for lung carcinogenicity of inhaled Ni3S2 was investigated in rats.•Gene expression changes were determined in micro-dissected lung tissue at 1–4weeks.•A non-genotoxic mode of action (toxicity, inflammation, proliferation) was supported.•Analyses of lung lavage fluid and histopathology provided complementary results.•Transcriptional benchmark doses could inform point of departure for risk assessment.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Animals</subject><subject>APOPTOSIS</subject><subject>Apoptosis - drug effects</subject><subject>Benchmarking</subject><subject>BIOASSAY</subject><subject>Biological and medical sciences</subject><subject>Body Weight - drug effects</subject><subject>Bronchoalveolar Lavage Fluid - cytology</subject><subject>Carcinogenicity</subject><subject>Carcinogens - administration & dosage</subject><subject>Carcinogens - toxicity</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>CONCENTRATION RATIO</subject><subject>Dose-Response Relationship, Drug</subject><subject>DOSES</subject><subject>Down-Regulation - drug effects</subject><subject>ECOLOGICAL CONCENTRATION</subject><subject>FLUIDS</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>GENES</subject><subject>INFLAMMATION</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - pathology</subject><subject>INHALATION</subject><subject>Inhalation Exposure</subject><subject>LAVAGE</subject><subject>Lung - metabolism</subject><subject>Lung - pathology</subject><subject>LUNGS</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metals and various inorganic compounds</subject><subject>Microarray Analysis</subject><subject>Microscopy, Electron, Transmission</subject><subject>Mutagens</subject><subject>NICKEL</subject><subject>Nickel - administration & dosage</subject><subject>Nickel - metabolism</subject><subject>Nickel - toxicity</subject><subject>Nickel subsulfide</subject><subject>RATS</subject><subject>Rats, Inbred F344</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>RISK ASSESSMENT</subject><subject>Signal Transduction - drug effects</subject><subject>SIGNALS</subject><subject>TOXICITY</subject><subject>Toxicology</subject><subject>Up-Regulation - drug effects</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2L1TAUhosozp3RP-BCAiK46TUfp2kDbmTQURhwM4K7kKan3lzbpCapMv_elHvVnUIgBJ5zeN88VfWM0T2jTL4-7rMxy55TBnsq95S2D6odo0rWVAjxsNpRCqymtPtyUV2mdKSUKgD2uLrgoBougO6q_s7NWBPjB2KDt-hzNNkFXw-4oB_Km3xFH2ZnScS0BJ8wkTCSfEBSSGJc_GnuSQ7E-YOZcCDe2W84kbT2aZ1GN-CT6tFopoRPz_dV9fn9u7vrD_Xtp5uP129vawvQ5hpA9k0HFGAs8S2MitvBtFy1bdv0wGkrBmaaZuyYBTQ9SFmOYi0XfYuyEVfVi9PekLLTybqM9lBKebRZcw5CdcAL9epELTF8XzFlPbtkcZqMx7AmzaRQqhOd7P6PNhJEwxSogvITamNIKeKol-hmE-81o3qTpY96k6U3WZpKXWSVoefn_Ws_4_Bn5LedArw8AyZZM43ReOvSX65TinewBX1z4rB87w-HcWuPxebg4lZ-CO5fOX4BlW2w2Q</recordid><startdate>20140915</startdate><enddate>20140915</enddate><creator>Efremenko, A.Y.</creator><creator>Campbell, J.L.</creator><creator>Dodd, D.E.</creator><creator>Oller, A.R.</creator><creator>Clewell, H.J.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><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>7X8</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>OTOTI</scope></search><sort><creationdate>20140915</creationdate><title>Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide</title><author>Efremenko, A.Y. ; Campbell, J.L. ; Dodd, D.E. ; Oller, A.R. ; Clewell, H.J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-446b584044f033c4f92cda7297775b42073d1a55f81c4eab46646691723b7e653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Animals</topic><topic>APOPTOSIS</topic><topic>Apoptosis - drug effects</topic><topic>Benchmarking</topic><topic>BIOASSAY</topic><topic>Biological and medical sciences</topic><topic>Body Weight - drug effects</topic><topic>Bronchoalveolar Lavage Fluid - cytology</topic><topic>Carcinogenicity</topic><topic>Carcinogens - administration & dosage</topic><topic>Carcinogens - toxicity</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>CONCENTRATION RATIO</topic><topic>Dose-Response Relationship, Drug</topic><topic>DOSES</topic><topic>Down-Regulation - drug effects</topic><topic>ECOLOGICAL CONCENTRATION</topic><topic>FLUIDS</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>GENES</topic><topic>INFLAMMATION</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - pathology</topic><topic>INHALATION</topic><topic>Inhalation Exposure</topic><topic>LAVAGE</topic><topic>Lung - metabolism</topic><topic>Lung - pathology</topic><topic>LUNGS</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metals and various inorganic compounds</topic><topic>Microarray Analysis</topic><topic>Microscopy, Electron, Transmission</topic><topic>Mutagens</topic><topic>NICKEL</topic><topic>Nickel - administration & dosage</topic><topic>Nickel - metabolism</topic><topic>Nickel - toxicity</topic><topic>Nickel subsulfide</topic><topic>RATS</topic><topic>Rats, Inbred F344</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>RISK ASSESSMENT</topic><topic>Signal Transduction - drug effects</topic><topic>SIGNALS</topic><topic>TOXICITY</topic><topic>Toxicology</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Efremenko, A.Y.</creatorcontrib><creatorcontrib>Campbell, J.L.</creatorcontrib><creatorcontrib>Dodd, D.E.</creatorcontrib><creatorcontrib>Oller, A.R.</creatorcontrib><creatorcontrib>Clewell, H.J.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>OSTI.GOV</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Efremenko, A.Y.</au><au>Campbell, J.L.</au><au>Dodd, D.E.</au><au>Oller, A.R.</au><au>Clewell, H.J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2014-09-15</date><risdate>2014</risdate><volume>279</volume><issue>3</issue><spage>441</spage><epage>454</epage><pages>441-454</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><abstract>To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure.
Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60mg/m3 (0.03, 0.06, 0.11, and 0.44mgNi/m3) for one and four weeks (6h/day, 5days/week).
Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1week to up-regulation at 4weeks.
These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026mgNi/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64μgNi/g lung, for immune/inflammatory signaling.
These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity.
•The mode of action for lung carcinogenicity of inhaled Ni3S2 was investigated in rats.•Gene expression changes were determined in micro-dissected lung tissue at 1–4weeks.•A non-genotoxic mode of action (toxicity, inflammation, proliferation) was supported.•Analyses of lung lavage fluid and histopathology provided complementary results.•Transcriptional benchmark doses could inform point of departure for risk assessment.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>24952340</pmid><doi>10.1016/j.taap.2014.06.007</doi><tpages>14</tpages></addata></record> |
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| ispartof | Toxicology and applied pharmacology, 2014-09, Vol.279 (3), p.441-454 |
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| subjects | 60 APPLIED LIFE SCIENCES Animals APOPTOSIS Apoptosis - drug effects Benchmarking BIOASSAY Biological and medical sciences Body Weight - drug effects Bronchoalveolar Lavage Fluid - cytology Carcinogenicity Carcinogens - administration & dosage Carcinogens - toxicity Cell Proliferation - drug effects Cell Survival - drug effects Chemical and industrial products toxicology. Toxic occupational diseases CONCENTRATION RATIO Dose-Response Relationship, Drug DOSES Down-Regulation - drug effects ECOLOGICAL CONCENTRATION FLUIDS Gene expression Gene Expression - drug effects GENES INFLAMMATION Inflammation - chemically induced Inflammation - pathology INHALATION Inhalation Exposure LAVAGE Lung - metabolism Lung - pathology LUNGS Male Medical sciences Metals and various inorganic compounds Microarray Analysis Microscopy, Electron, Transmission Mutagens NICKEL Nickel - administration & dosage Nickel - metabolism Nickel - toxicity Nickel subsulfide RATS Rats, Inbred F344 Real-Time Polymerase Chain Reaction RISK ASSESSMENT Signal Transduction - drug effects SIGNALS TOXICITY Toxicology Up-Regulation - drug effects |
| title | Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide |
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