Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide
The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily inta...
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| Veröffentlicht in: | Scientific reports 2017-01, Vol.7 (1), p.39328, Article 39328 |
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| description | The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q |
| doi_str_mv | 10.1038/srep39328 |
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Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep39328</identifier><identifier>PMID: 28067231</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/337/475 ; 692/4020/4021/1607/2750 ; Animals ; Ascorbic acid ; Body weight ; Chronic exposure ; Disease Models, Animal ; Fatty liver ; Gene expression ; Glutathione ; Glycine - analogs & derivatives ; Glycine - toxicity ; Glyphosate ; Hepatotoxicity ; Herbicides ; Herbicides - toxicity ; Humanities and Social Sciences ; Liver ; Liver - pathology ; Liver diseases ; Metabolites ; Metabolomics ; multidisciplinary ; Non-alcoholic Fatty Liver Disease - chemically induced ; Non-alcoholic Fatty Liver Disease - pathology ; Oxidative stress ; Proline ; Proteomes ; Proteomics ; Rats ; Rodents ; Science ; Steatosis ; Urine</subject><ispartof>Scientific reports, 2017-01, Vol.7 (1), p.39328, Article 39328</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Jan 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-768f4c8bdb57f5d84748107d457f2cdb066ebe50208373dd4d953893a3c173c13</citedby><cites>FETCH-LOGICAL-c438t-768f4c8bdb57f5d84748107d457f2cdb066ebe50208373dd4d953893a3c173c13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220358/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220358/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28067231$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mesnage, Robin</creatorcontrib><creatorcontrib>Renney, George</creatorcontrib><creatorcontrib>Séralini, Gilles-Eric</creatorcontrib><creatorcontrib>Ward, Malcolm</creatorcontrib><creatorcontrib>Antoniou, Michael N.</creatorcontrib><title>Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The impairment of liver function by low environmentally relevant doses of glyphosate-based herbicides (GBH) is still a debatable and unresolved matter. Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.</description><subject>631/337/475</subject><subject>692/4020/4021/1607/2750</subject><subject>Animals</subject><subject>Ascorbic acid</subject><subject>Body weight</subject><subject>Chronic exposure</subject><subject>Disease Models, Animal</subject><subject>Fatty liver</subject><subject>Gene expression</subject><subject>Glutathione</subject><subject>Glycine - analogs & derivatives</subject><subject>Glycine - toxicity</subject><subject>Glyphosate</subject><subject>Hepatotoxicity</subject><subject>Herbicides</subject><subject>Herbicides - toxicity</subject><subject>Humanities and Social Sciences</subject><subject>Liver</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>Metabolites</subject><subject>Metabolomics</subject><subject>multidisciplinary</subject><subject>Non-alcoholic Fatty Liver Disease - chemically induced</subject><subject>Non-alcoholic Fatty Liver Disease - pathology</subject><subject>Oxidative stress</subject><subject>Proline</subject><subject>Proteomes</subject><subject>Proteomics</subject><subject>Rats</subject><subject>Rodents</subject><subject>Science</subject><subject>Steatosis</subject><subject>Urine</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkV1rFDEUhoNYbGl74R-QgFcKY_M1O5kbQUr9gIogeh0yyZndlGzOmMys9q4_3cjWZcXAITmcJ-954SXkOWdvOJP6qmSYZC-FfkLOBFNtI6QQT4_ep-SylDtWTyt6xftn5FRotuqE5Gfk4fMS54Db4ArNsAMbacLU2OhwgzE4Otp5vqcx7CBTHwrYAjQkmu1c6Igx4s-Q1tRtMqZKw68Jy5KBzkhtolU726Yy1GP9hyP9ikvyy0Q3kIfggocLcjLaWODy8T4n39_ffLv-2Nx--fDp-t1t45TUc9Ot9KicHvzQdmPrteqU5qzzqrbC-YGtVjBAywTTspPeK9-3UvfSSse7WvKcvN3rTsuwBe8gVWvRTDlsbb43aIP5d5LCxqxxZ1ohmGx1FXj5KJDxxwJlNne45FQ9G677XmnBuajUqz3lMpYazXjYwJn5k5c55FXZF8eWDuTfdCrweg-UOkpryEcr_1P7DQW2oec</recordid><startdate>20170109</startdate><enddate>20170109</enddate><creator>Mesnage, Robin</creator><creator>Renney, George</creator><creator>Séralini, Gilles-Eric</creator><creator>Ward, Malcolm</creator><creator>Antoniou, Michael N.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope></search><sort><creationdate>20170109</creationdate><title>Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide</title><author>Mesnage, Robin ; 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Previously we have shown that rats administered for 2 years with 0.1 ppb (50 ng/L glyphosate equivalent dilution; 4 ng/kg body weight/day daily intake) of a Roundup GBH formulation showed signs of enhanced liver injury as indicated by anatomorphological, blood/urine biochemical changes and transcriptome profiling. Here we present a multiomic study combining metabolome and proteome liver analyses to obtain further insight into the Roundup-induced pathology. Proteins significantly disturbed (214 out of 1906 detected, q < 0.05) were involved in organonitrogen metabolism and fatty acid β-oxidation. Proteome disturbances reflected peroxisomal proliferation, steatosis and necrosis. The metabolome analysis (55 metabolites altered out of 673 detected, p < 0.05) confirmed lipotoxic conditions and oxidative stress by showing an activation of glutathione and ascorbate free radical scavenger systems. Additionally, we found metabolite alterations associated with hallmarks of hepatotoxicity such as γ-glutamyl dipeptides, acylcarnitines, and proline derivatives. Overall, metabolome and proteome disturbances showed a substantial overlap with biomarkers of non-alcoholic fatty liver disease and its progression to steatohepatosis and thus confirm liver functional dysfunction resulting from chronic ultra-low dose GBH exposure.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28067231</pmid><doi>10.1038/srep39328</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 631/337/475 692/4020/4021/1607/2750 Animals Ascorbic acid Body weight Chronic exposure Disease Models, Animal Fatty liver Gene expression Glutathione Glycine - analogs & derivatives Glycine - toxicity Glyphosate Hepatotoxicity Herbicides Herbicides - toxicity Humanities and Social Sciences Liver Liver - pathology Liver diseases Metabolites Metabolomics multidisciplinary Non-alcoholic Fatty Liver Disease - chemically induced Non-alcoholic Fatty Liver Disease - pathology Oxidative stress Proline Proteomes Proteomics Rats Rodents Science Steatosis Urine |
| title | Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide |
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