Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta
Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper...
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| description | Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p |
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Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1α and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine exposure during pregnancy on placental health.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0122295</identifier><identifier>PMID: 25811377</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Amino acids ; Amino Acids - metabolism ; Animals ; Apoptosis ; Biomarkers ; Birth weight ; Bonding ; Brain research ; Cell cycle ; Chemical bonds ; Cigarettes ; Deprivation ; Diabetic retinopathy ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Drug dosages ; Embryos ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress ; Enzymes ; Exposure ; Female ; Fetuses ; Gene expression ; Gene Expression Regulation ; Gynecology ; Health risk assessment ; Hypoxia ; Hypoxia - metabolism ; In vivo methods and tests ; Kinases ; Maternal Exposure - adverse effects ; Medical research ; Molecular biology ; Nicotine ; Nicotine - adverse effects ; Obstetrics ; Oxidases ; Oxidoreductases - genetics ; Oxidoreductases - metabolism ; Oxygen ; Phosphorylation ; Physiology ; Placenta ; Placenta - metabolism ; Postpartum period ; Pregnancy ; Protein disulfide-isomerase ; Protein Disulfide-Isomerases - genetics ; Protein Disulfide-Isomerases - metabolism ; Proteins ; Rats ; Regulatory Factor X Transcription Factors ; RNA ; RNA Splicing ; Signal Transduction ; Smoking ; Stress ; Stresses ; Tobacco smoke ; Transcription Factor CHOP - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Unfolded Protein Response</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0122295-e0122295</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Wong et al 2015 Wong et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-f8d9739648aecf33e54f6f2d4b40418baf0871744d250faf94a5275a0fa2b85a3</citedby><cites>FETCH-LOGICAL-c692t-f8d9739648aecf33e54f6f2d4b40418baf0871744d250faf94a5275a0fa2b85a3</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/PMC4374683/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374683/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25811377$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Jin, Dong-Yan</contributor><creatorcontrib>Wong, Michael K</creatorcontrib><creatorcontrib>Nicholson, Catherine J</creatorcontrib><creatorcontrib>Holloway, Alison C</creatorcontrib><creatorcontrib>Hardy, Daniel B</creatorcontrib><title>Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1α and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine exposure during pregnancy on placental health.</description><subject>Acids</subject><subject>Amino acids</subject><subject>Amino Acids - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biomarkers</subject><subject>Birth weight</subject><subject>Bonding</subject><subject>Brain research</subject><subject>Cell cycle</subject><subject>Chemical bonds</subject><subject>Cigarettes</subject><subject>Deprivation</subject><subject>Diabetic retinopathy</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug dosages</subject><subject>Embryos</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress</subject><subject>Enzymes</subject><subject>Exposure</subject><subject>Female</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gynecology</subject><subject>Health risk assessment</subject><subject>Hypoxia</subject><subject>Hypoxia - metabolism</subject><subject>In vivo methods and tests</subject><subject>Kinases</subject><subject>Maternal Exposure - adverse effects</subject><subject>Medical research</subject><subject>Molecular biology</subject><subject>Nicotine</subject><subject>Nicotine - adverse effects</subject><subject>Obstetrics</subject><subject>Oxidases</subject><subject>Oxidoreductases - genetics</subject><subject>Oxidoreductases - metabolism</subject><subject>Oxygen</subject><subject>Phosphorylation</subject><subject>Physiology</subject><subject>Placenta</subject><subject>Placenta - metabolism</subject><subject>Postpartum period</subject><subject>Pregnancy</subject><subject>Protein disulfide-isomerase</subject><subject>Protein Disulfide-Isomerases - genetics</subject><subject>Protein Disulfide-Isomerases - metabolism</subject><subject>Proteins</subject><subject>Rats</subject><subject>Regulatory Factor X Transcription Factors</subject><subject>RNA</subject><subject>RNA Splicing</subject><subject>Signal Transduction</subject><subject>Smoking</subject><subject>Stress</subject><subject>Stresses</subject><subject>Tobacco smoke</subject><subject>Transcription Factor CHOP - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Unfolded Protein Response</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk0uLFDEQxxtR3HX1G4gGBNHDjJ1Hvy7CsvgYWFnwdQ01ncpMhnSnTdKy3v3gpp3eZUb2IDkknfz-_-qqpLLsKc2XlFf0zc6Nvge7HFyPy5wyxpriXnZKG84WJcv5_YP1SfYohF2eF7wuy4fZCStqmkyq0-z3J4g4-ZDetC6aHgleDy6MHolFUIFER0w3gPGoiDJhtNooJGvXK6Kd7yAa1xNIXzBuOuxjwrBXbrAQOtMSj9G0ox07EqLHEIjpSdwi8RBJYtqkgMfZAw024JN5Psu-vX_39eLj4vLqw-ri_HLRlg2LC12rpuJNKWrAVnOOhdClZkqsRS5ovQad1xWthFCsyDXoRkDBqgLSmq3rAvhZ9nzvO1gX5FzAIGlZVnnOi7JKxGpPKAc7OXjTgf8lHRj5d8P5jQSfErIoVVtpyhDLVHvRNtAIpEqtQdWNFlhO0d7O0cZ1h2rK1IM9Mj0-6c1WbtxPKXglypong1ezgXc_RgxRdia0aC306Mb9f3PBGzahL_5B785upjaQEjC9diluO5nKc8FonUYxUcs7qDQUpgtNr02btH8keH0kSEzE67iBMQS5-vL5_9mr78fsywN2i2DjNjg7Ti8uHINiD7beheBR3xaZ5nJqlptqyKlZ5NwsSfbs8IJuRTfdwf8AdJgSGw</recordid><startdate>20150326</startdate><enddate>20150326</enddate><creator>Wong, Michael K</creator><creator>Nicholson, Catherine J</creator><creator>Holloway, Alison C</creator><creator>Hardy, Daniel B</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>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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150326</creationdate><title>Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta</title><author>Wong, Michael K ; Nicholson, Catherine J ; Holloway, Alison C ; Hardy, Daniel B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-f8d9739648aecf33e54f6f2d4b40418baf0871744d250faf94a5275a0fa2b85a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acids</topic><topic>Amino acids</topic><topic>Amino Acids - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biomarkers</topic><topic>Birth weight</topic><topic>Bonding</topic><topic>Brain research</topic><topic>Cell cycle</topic><topic>Chemical bonds</topic><topic>Cigarettes</topic><topic>Deprivation</topic><topic>Diabetic retinopathy</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug dosages</topic><topic>Embryos</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress</topic><topic>Enzymes</topic><topic>Exposure</topic><topic>Female</topic><topic>Fetuses</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Gynecology</topic><topic>Health risk assessment</topic><topic>Hypoxia</topic><topic>Hypoxia - metabolism</topic><topic>In vivo methods and tests</topic><topic>Kinases</topic><topic>Maternal Exposure - adverse effects</topic><topic>Medical research</topic><topic>Molecular biology</topic><topic>Nicotine</topic><topic>Nicotine - 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Academic</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>Wong, Michael K</au><au>Nicholson, Catherine J</au><au>Holloway, Alison C</au><au>Hardy, Daniel B</au><au>Jin, Dong-Yan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-26</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0122295</spage><epage>e0122295</epage><pages>e0122295-e0122295</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1α and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine exposure during pregnancy on placental health.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25811377</pmid><doi>10.1371/journal.pone.0122295</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1667003567 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acids Amino acids Amino Acids - metabolism Animals Apoptosis Biomarkers Birth weight Bonding Brain research Cell cycle Chemical bonds Cigarettes Deprivation Diabetic retinopathy DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug dosages Embryos Endoplasmic reticulum Endoplasmic Reticulum Stress Enzymes Exposure Female Fetuses Gene expression Gene Expression Regulation Gynecology Health risk assessment Hypoxia Hypoxia - metabolism In vivo methods and tests Kinases Maternal Exposure - adverse effects Medical research Molecular biology Nicotine Nicotine - adverse effects Obstetrics Oxidases Oxidoreductases - genetics Oxidoreductases - metabolism Oxygen Phosphorylation Physiology Placenta Placenta - metabolism Postpartum period Pregnancy Protein disulfide-isomerase Protein Disulfide-Isomerases - genetics Protein Disulfide-Isomerases - metabolism Proteins Rats Regulatory Factor X Transcription Factors RNA RNA Splicing Signal Transduction Smoking Stress Stresses Tobacco smoke Transcription Factor CHOP - metabolism Transcription Factors - genetics Transcription Factors - metabolism Unfolded Protein Response |
| title | Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T08%3A17%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Maternal%20nicotine%20exposure%20leads%20to%20impaired%20disulfide%20bond%20formation%20and%20augmented%20endoplasmic%20reticulum%20stress%20in%20the%20rat%20placenta&rft.jtitle=PloS%20one&rft.au=Wong,%20Michael%20K&rft.date=2015-03-26&rft.volume=10&rft.issue=3&rft.spage=e0122295&rft.epage=e0122295&rft.pages=e0122295-e0122295&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0122295&rft_dat=%3Cgale_plos_%3EA421818157%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1667003567&rft_id=info:pmid/25811377&rft_galeid=A421818157&rft_doaj_id=oai_doaj_org_article_dc7f12ee60124c9a94e1ddbad89f4e6a&rfr_iscdi=true |