Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis
The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role...
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| Veröffentlicht in: | PloS one 2012-06, Vol.7 (6), p.e38713 |
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| description | The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans. |
| doi_str_mv | 10.1371/journal.pone.0038713 |
| format | Article |
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Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0038713</identifier><identifier>PMID: 22719926</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Animals ; Annotations ; Antigen presentation ; Antigen processing ; Antigens ; Apolipoprotein E ; Apolipoproteins ; Apoptosis ; Arsenic ; Arsenic - toxicity ; Arteriosclerosis ; Arthritis ; Atherogenesis ; Atherosclerosis ; Atherosclerosis - etiology ; Binding sites ; Bioinformatics ; Biology ; Blotting, Western ; Cancer ; Cardiovascular diseases ; Cascades ; Chronic diseases ; Chronic illnesses ; Clustering ; Coagulation ; Data analysis ; Diabetes ; Diabetes mellitus ; DNA microarrays ; Drinking water ; Endoplasmic reticulum ; Environmental toxicology ; Exposure ; Female ; Fetuses ; Gene expression ; Gene Expression Regulation - drug effects ; Genes ; Genetics ; Genomes ; Genomics ; Gluconeogenesis ; Glycolysis ; Health risk assessment ; Heat shock ; Heat shock proteins ; Hepatocyte nuclear factor 4 ; Hsp70 protein ; Hybridization ; Immunoglobulin M ; Inflammation ; Laboratories ; Liver ; Liver - drug effects ; Liver - metabolism ; Liver diseases ; Medicine ; Messenger RNA ; Metabolic disorders ; Metabolic syndrome ; Mice ; Mice, Knockout ; MicroRNA ; MicroRNAs - genetics ; miRNA ; Models, Animal ; Oxidative stress ; Pathways ; Pharmacology ; Pregnancy ; Pregnant women ; Prenatal experience ; Prenatal Exposure Delayed Effects ; Protein transport ; Rheumatoid arthritis ; Rheumatoid factor ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; Studies ; Toxicants ; Toxicology ; Tumors ; Type 2 diabetes</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e38713</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 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, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-8e989ac3e9351fbd759dc01205b1ab8b740a272744b47aa4db0d0dbe7ec41cd03</citedby><cites>FETCH-LOGICAL-c758t-8e989ac3e9351fbd759dc01205b1ab8b740a272744b47aa4db0d0dbe7ec41cd03</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/PMC3376138/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376138/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22719926$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>States, J Christopher</creatorcontrib><creatorcontrib>Singh, Amar V</creatorcontrib><creatorcontrib>Knudsen, Thomas B</creatorcontrib><creatorcontrib>Rouchka, Eric C</creatorcontrib><creatorcontrib>Ngalame, Ntube O</creatorcontrib><creatorcontrib>Arteel, Gavin E</creatorcontrib><creatorcontrib>Piao, Yulan</creatorcontrib><creatorcontrib>Ko, Minoru S H</creatorcontrib><title>Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.</description><subject>Acids</subject><subject>Animals</subject><subject>Annotations</subject><subject>Antigen presentation</subject><subject>Antigen processing</subject><subject>Antigens</subject><subject>Apolipoprotein E</subject><subject>Apolipoproteins</subject><subject>Apoptosis</subject><subject>Arsenic</subject><subject>Arsenic - toxicity</subject><subject>Arteriosclerosis</subject><subject>Arthritis</subject><subject>Atherogenesis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - etiology</subject><subject>Binding sites</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Cardiovascular diseases</subject><subject>Cascades</subject><subject>Chronic diseases</subject><subject>Chronic illnesses</subject><subject>Clustering</subject><subject>Coagulation</subject><subject>Data analysis</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>DNA microarrays</subject><subject>Drinking water</subject><subject>Endoplasmic reticulum</subject><subject>Environmental toxicology</subject><subject>Exposure</subject><subject>Female</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genes</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Gluconeogenesis</subject><subject>Glycolysis</subject><subject>Health risk assessment</subject><subject>Heat shock</subject><subject>Heat shock proteins</subject><subject>Hepatocyte nuclear factor 4</subject><subject>Hsp70 protein</subject><subject>Hybridization</subject><subject>Immunoglobulin M</subject><subject>Inflammation</subject><subject>Laboratories</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver diseases</subject><subject>Medicine</subject><subject>Messenger RNA</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>MicroRNA</subject><subject>MicroRNAs - genetics</subject><subject>miRNA</subject><subject>Models, Animal</subject><subject>Oxidative stress</subject><subject>Pathways</subject><subject>Pharmacology</subject><subject>Pregnancy</subject><subject>Pregnant women</subject><subject>Prenatal experience</subject><subject>Prenatal Exposure Delayed Effects</subject><subject>Protein transport</subject><subject>Rheumatoid arthritis</subject><subject>Rheumatoid factor</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>Studies</subject><subject>Toxicants</subject><subject>Toxicology</subject><subject>Tumors</subject><subject>Type 2 diabetes</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9tq3DAQhk1padK0b1BaQaHQi91Klm3ZN4UQelgIpPR0K8bSrFdBa20kOSSv0KeunHXCGlooBtnMfPN7NIcse8noknHB3l-6wfdglzvX45JSXgvGH2XHrOH5osopf3zwfZQ9C-GS0pLXVfU0O8pzwZomr46z31899hDBEvABe6MI3uxcGDwSsBF9IB32OBo9hmBcT0xP4iZ59WAjseYaPYmOANl5Z_q1he0WovO3JESISJTrozftEE3f3XFKoUWfXJpA0vEuKDueJjzPnqzBBnwxvU-yn58-_jj7sji_-Lw6Oz1fKFHWcVFjUzegODa8ZOtWi7LRirKcli2Dtm5FQSEXuSiKthAAhW6pprpFgapgSlN-kr3e6-6sC3IqY5CM5xWr64LViVjtCe3gUu682YK_lQ6MvDM430nw0aTEZQkVaGBlWea6qISuSwDGWU0rhTSnRdL6MP1taLeoFaZ6gJ2Jzj292cjOXUvORcX4mMybScC7qwFD_EfKE9VByio1wiUxtTVBydNCCFpzzsarL_9CpUfj1qRW4dok-yzg3SxgbCfexA6GEOTq-7f_Zy9-zdm3B-wG06xtgrNpTFwf5mCxB1WakeBx_VA5RuW4B_fVkOMeyGkPUtirw6o_BN0PPv8Dw-0GeQ</recordid><startdate>20120615</startdate><enddate>20120615</enddate><creator>States, J Christopher</creator><creator>Singh, Amar V</creator><creator>Knudsen, Thomas B</creator><creator>Rouchka, Eric C</creator><creator>Ngalame, Ntube O</creator><creator>Arteel, Gavin E</creator><creator>Piao, Yulan</creator><creator>Ko, Minoru S H</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120615</creationdate><title>Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis</title><author>States, J Christopher ; Singh, Amar V ; Knudsen, Thomas B ; Rouchka, Eric C ; Ngalame, Ntube O ; Arteel, Gavin E ; Piao, Yulan ; Ko, Minoru S H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-8e989ac3e9351fbd759dc01205b1ab8b740a272744b47aa4db0d0dbe7ec41cd03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Acids</topic><topic>Animals</topic><topic>Annotations</topic><topic>Antigen presentation</topic><topic>Antigen processing</topic><topic>Antigens</topic><topic>Apolipoprotein E</topic><topic>Apolipoproteins</topic><topic>Apoptosis</topic><topic>Arsenic</topic><topic>Arsenic - 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drug effects</topic><topic>Liver - metabolism</topic><topic>Liver diseases</topic><topic>Medicine</topic><topic>Messenger RNA</topic><topic>Metabolic disorders</topic><topic>Metabolic syndrome</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>MicroRNA</topic><topic>MicroRNAs - genetics</topic><topic>miRNA</topic><topic>Models, Animal</topic><topic>Oxidative stress</topic><topic>Pathways</topic><topic>Pharmacology</topic><topic>Pregnancy</topic><topic>Pregnant women</topic><topic>Prenatal experience</topic><topic>Prenatal Exposure Delayed Effects</topic><topic>Protein transport</topic><topic>Rheumatoid arthritis</topic><topic>Rheumatoid factor</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - genetics</topic><topic>Studies</topic><topic>Toxicants</topic><topic>Toxicology</topic><topic>Tumors</topic><topic>Type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>States, J Christopher</creatorcontrib><creatorcontrib>Singh, Amar V</creatorcontrib><creatorcontrib>Knudsen, Thomas B</creatorcontrib><creatorcontrib>Rouchka, Eric C</creatorcontrib><creatorcontrib>Ngalame, Ntube O</creatorcontrib><creatorcontrib>Arteel, Gavin E</creatorcontrib><creatorcontrib>Piao, Yulan</creatorcontrib><creatorcontrib>Ko, Minoru S H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>States, J Christopher</au><au>Singh, Amar V</au><au>Knudsen, Thomas B</au><au>Rouchka, Eric C</au><au>Ngalame, Ntube O</au><au>Arteel, Gavin E</au><au>Piao, Yulan</au><au>Ko, Minoru S H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-15</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e38713</spage><pages>e38713-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22719926</pmid><doi>10.1371/journal.pone.0038713</doi><tpages>e38713</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e38713 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326188418 |
| 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 | Acids Animals Annotations Antigen presentation Antigen processing Antigens Apolipoprotein E Apolipoproteins Apoptosis Arsenic Arsenic - toxicity Arteriosclerosis Arthritis Atherogenesis Atherosclerosis Atherosclerosis - etiology Binding sites Bioinformatics Biology Blotting, Western Cancer Cardiovascular diseases Cascades Chronic diseases Chronic illnesses Clustering Coagulation Data analysis Diabetes Diabetes mellitus DNA microarrays Drinking water Endoplasmic reticulum Environmental toxicology Exposure Female Fetuses Gene expression Gene Expression Regulation - drug effects Genes Genetics Genomes Genomics Gluconeogenesis Glycolysis Health risk assessment Heat shock Heat shock proteins Hepatocyte nuclear factor 4 Hsp70 protein Hybridization Immunoglobulin M Inflammation Laboratories Liver Liver - drug effects Liver - metabolism Liver diseases Medicine Messenger RNA Metabolic disorders Metabolic syndrome Mice Mice, Knockout MicroRNA MicroRNAs - genetics miRNA Models, Animal Oxidative stress Pathways Pharmacology Pregnancy Pregnant women Prenatal experience Prenatal Exposure Delayed Effects Protein transport Rheumatoid arthritis Rheumatoid factor Ribonucleic acid RNA RNA, Messenger - genetics Studies Toxicants Toxicology Tumors Type 2 diabetes |
| title | Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis |
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