Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention
Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P...
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| Veröffentlicht in: | PloS one 2019-05, Vol.14 (5), p.e0214873-e0214873 |
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| creator | Tang, Changqing Luo, Chunyan Hua, Yimin Zhou, Kaiyu Duan, Hongyu Ma, Fan Zhang, Yi Li, Yifei Qiu, Dajian Wang, Chuan |
| description | Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice.
The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5-14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR.
Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group.
Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice. |
| doi_str_mv | 10.1371/journal.pone.0214873 |
| format | Article |
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The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5-14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR.
Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group.
Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0214873</identifier><identifier>PMID: 31086358</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Anomalies ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; Biology and Life Sciences ; Birth defects ; Cardiology ; Congenital defects ; Congenital diseases ; Congenital heart defects ; Contaminants ; Corn ; Corn oil ; Desertification ; Diethylhexyl Phthalate - toxicity ; Education ; Female ; Fetal Heart - drug effects ; Fetal Heart - metabolism ; Fetal Heart - pathology ; Fetuses ; GATA4 Transcription Factor - genetics ; GATA4 Transcription Factor - metabolism ; Gene expression ; Gene Expression Regulation, Developmental - drug effects ; Genetic disorders ; Glycoproteins ; Health aspects ; Heart ; Heart Defects, Congenital - chemically induced ; Heart Defects, Congenital - metabolism ; Heart Defects, Congenital - pathology ; Homeobox Protein Nkx-2.5 - genetics ; Homeobox Protein Nkx-2.5 - metabolism ; Hospitals ; House mouse ; Inhibition ; Laboratories ; Maternal Exposure ; Medicine and Health Sciences ; Membrane proteins ; Messenger RNA ; Mice ; Mice, Inbred C57BL ; Myocardium ; Nkx2.5 protein ; P-Glycoprotein ; Pediatrics ; Pharmaceuticals ; Phenotypes ; Phthalates ; Physical Sciences ; Physiological aspects ; Placenta ; Placenta - metabolism ; Polymerase chain reaction ; Polymorphism ; PPAR gamma - genetics ; PPAR gamma - metabolism ; Pregnancy ; Pregnant women ; Prenatal influences ; Prevention ; Research and Analysis Methods ; Risk factors ; Risk reduction ; RNA ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; Toxicants ; Ventricle ; Verapamil ; Verapamil - pharmacology ; Womens health</subject><ispartof>PloS one, 2019-05, Vol.14 (5), p.e0214873-e0214873</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Tang 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>2019 Tang et al 2019 Tang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-e2b253f2ed81d2d4d59c4e3841822aa28ddc72767db5f4a65b3e37dd861ef63d3</citedby><cites>FETCH-LOGICAL-c593t-e2b253f2ed81d2d4d59c4e3841822aa28ddc72767db5f4a65b3e37dd861ef63d3</cites><orcidid>0000-0001-5165-8273 ; 0000-0002-3096-4287</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516658/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516658/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31086358$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Rosenfeld, Cheryl S.</contributor><creatorcontrib>Tang, Changqing</creatorcontrib><creatorcontrib>Luo, Chunyan</creatorcontrib><creatorcontrib>Hua, Yimin</creatorcontrib><creatorcontrib>Zhou, Kaiyu</creatorcontrib><creatorcontrib>Duan, Hongyu</creatorcontrib><creatorcontrib>Ma, Fan</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Li, Yifei</creatorcontrib><creatorcontrib>Qiu, Dajian</creatorcontrib><creatorcontrib>Wang, Chuan</creatorcontrib><title>Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice.
The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5-14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR.
Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group.
Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.</description><subject>Animals</subject><subject>Anomalies</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</subject><subject>Biology and Life Sciences</subject><subject>Birth defects</subject><subject>Cardiology</subject><subject>Congenital defects</subject><subject>Congenital diseases</subject><subject>Congenital heart defects</subject><subject>Contaminants</subject><subject>Corn</subject><subject>Corn oil</subject><subject>Desertification</subject><subject>Diethylhexyl Phthalate - toxicity</subject><subject>Education</subject><subject>Female</subject><subject>Fetal Heart - drug effects</subject><subject>Fetal Heart - metabolism</subject><subject>Fetal Heart - pathology</subject><subject>Fetuses</subject><subject>GATA4 Transcription Factor - genetics</subject><subject>GATA4 Transcription Factor - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Developmental - drug effects</subject><subject>Genetic disorders</subject><subject>Glycoproteins</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heart Defects, Congenital - chemically induced</subject><subject>Heart Defects, Congenital - metabolism</subject><subject>Heart Defects, Congenital - pathology</subject><subject>Homeobox Protein Nkx-2.5 - genetics</subject><subject>Homeobox Protein Nkx-2.5 - metabolism</subject><subject>Hospitals</subject><subject>House mouse</subject><subject>Inhibition</subject><subject>Laboratories</subject><subject>Maternal Exposure</subject><subject>Medicine and Health Sciences</subject><subject>Membrane proteins</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Myocardium</subject><subject>Nkx2.5 protein</subject><subject>P-Glycoprotein</subject><subject>Pediatrics</subject><subject>Pharmaceuticals</subject><subject>Phenotypes</subject><subject>Phthalates</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Placenta</subject><subject>Placenta - metabolism</subject><subject>Polymerase chain reaction</subject><subject>Polymorphism</subject><subject>PPAR gamma - genetics</subject><subject>PPAR gamma - metabolism</subject><subject>Pregnancy</subject><subject>Pregnant women</subject><subject>Prenatal influences</subject><subject>Prevention</subject><subject>Research and Analysis Methods</subject><subject>Risk factors</subject><subject>Risk reduction</subject><subject>RNA</subject><subject>T-Box Domain Proteins - genetics</subject><subject>T-Box Domain Proteins - metabolism</subject><subject>Toxicants</subject><subject>Ventricle</subject><subject>Verapamil</subject><subject>Verapamil - pharmacology</subject><subject>Womens health</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</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>eNptkstu1DAUhiMEoqXwBggssSmLDLEdO04XSKNyq1SJLmBtOfZJ4pHHDrGnYh6Q98Kh06pFVRaOjv_znYv_oniNqxWmDf6wCbvZK7eagodVRXAtGvqkOMYtJSUnFX167_-oeBHjpqoYFZw_L44orgSnTBwXf66c0uCTcuiqHNxeh2kOCaxH1o-2s8kGj8CPymuIKO6ihinluLNpj1JAn2x5SkpI496N8Hvv3pfTmEblVIJMMDsNBmk1G6s02irXh3mrFmbMt2hrNZyhNZpCjLZze5Rrb220fkBJzQMklPVIBz-At0uLI6g5IQM96BSzGq5z65n2snjWKxfh1eE8KX5--fzj_Ft5-f3rxfn6stSspakE0hFGewJGYENMbVira6CixoIQpYgwRjek4Y3pWF8rzjoKtDFGcAw9p4aeFG9vuJMLUR5eIEpCCMOkqWqaFRc3ChPURk6z3ap5L4Oy8l8gzIPMI1jtQNZC8IazSkNT122HBWaMtVDngl0mksz6eKi267ZglmealXsAfXjj7SiHcC05w5wzkQGnB8Acfu0gJpm3q8E55SHslr4pqTBnbZOl7_6TPj7dQTWoPID1fch19QKVayZY3iNteVatHlHlz0B-8WzX3ub4g4T6JkHP2Qkz9Hcz4kouZr9tRi5mlwez57Q39_dzl3TrbvoXCZkBAg</recordid><startdate>20190514</startdate><enddate>20190514</enddate><creator>Tang, Changqing</creator><creator>Luo, Chunyan</creator><creator>Hua, Yimin</creator><creator>Zhou, Kaiyu</creator><creator>Duan, Hongyu</creator><creator>Ma, Fan</creator><creator>Zhang, Yi</creator><creator>Li, Yifei</creator><creator>Qiu, Dajian</creator><creator>Wang, Chuan</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>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>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-5165-8273</orcidid><orcidid>https://orcid.org/0000-0002-3096-4287</orcidid></search><sort><creationdate>20190514</creationdate><title>Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention</title><author>Tang, Changqing ; Luo, Chunyan ; Hua, Yimin ; Zhou, Kaiyu ; Duan, Hongyu ; Ma, Fan ; Zhang, Yi ; Li, Yifei ; Qiu, Dajian ; Wang, Chuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c593t-e2b253f2ed81d2d4d59c4e3841822aa28ddc72767db5f4a65b3e37dd861ef63d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Anomalies</topic><topic>ATP Binding Cassette Transporter, Subfamily B, Member 1 - 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metabolism</topic><topic>Heart Defects, Congenital - pathology</topic><topic>Homeobox Protein Nkx-2.5 - genetics</topic><topic>Homeobox Protein Nkx-2.5 - metabolism</topic><topic>Hospitals</topic><topic>House mouse</topic><topic>Inhibition</topic><topic>Laboratories</topic><topic>Maternal Exposure</topic><topic>Medicine and Health Sciences</topic><topic>Membrane proteins</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Myocardium</topic><topic>Nkx2.5 protein</topic><topic>P-Glycoprotein</topic><topic>Pediatrics</topic><topic>Pharmaceuticals</topic><topic>Phenotypes</topic><topic>Phthalates</topic><topic>Physical Sciences</topic><topic>Physiological aspects</topic><topic>Placenta</topic><topic>Placenta - metabolism</topic><topic>Polymerase chain reaction</topic><topic>Polymorphism</topic><topic>PPAR gamma - genetics</topic><topic>PPAR gamma - metabolism</topic><topic>Pregnancy</topic><topic>Pregnant women</topic><topic>Prenatal influences</topic><topic>Prevention</topic><topic>Research and Analysis Methods</topic><topic>Risk factors</topic><topic>Risk reduction</topic><topic>RNA</topic><topic>T-Box Domain Proteins - genetics</topic><topic>T-Box Domain Proteins - metabolism</topic><topic>Toxicants</topic><topic>Ventricle</topic><topic>Verapamil</topic><topic>Verapamil - pharmacology</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Changqing</creatorcontrib><creatorcontrib>Luo, Chunyan</creatorcontrib><creatorcontrib>Hua, Yimin</creatorcontrib><creatorcontrib>Zhou, Kaiyu</creatorcontrib><creatorcontrib>Duan, Hongyu</creatorcontrib><creatorcontrib>Ma, Fan</creatorcontrib><creatorcontrib>Zhang, Yi</creatorcontrib><creatorcontrib>Li, Yifei</creatorcontrib><creatorcontrib>Qiu, Dajian</creatorcontrib><creatorcontrib>Wang, Chuan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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>Tang, Changqing</au><au>Luo, Chunyan</au><au>Hua, Yimin</au><au>Zhou, Kaiyu</au><au>Duan, Hongyu</au><au>Ma, Fan</au><au>Zhang, Yi</au><au>Li, Yifei</au><au>Qiu, Dajian</au><au>Wang, Chuan</au><au>Rosenfeld, Cheryl S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-05-14</date><risdate>2019</risdate><volume>14</volume><issue>5</issue><spage>e0214873</spage><epage>e0214873</epage><pages>e0214873-e0214873</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Reducing toxicants transplacental rates could contribute to the prevention of congenital heart defects (CHDs). Placental P-glycoprotein (P-gp) plays a vital role in fetal toxicants exposure and subsequently affects the risk of toxicants-induced birth defects. However, data on the role of placental P-gp in decreasing toxicants-induced cardiac anomalies is extremely limited. This study aimed to explore the protective role of placental P-gp in reducing the risk of Di-(2-ethylhexyl)-phthalate (DEHP) induced cardiac anomalies in mice.
The C57BL mice were randomly divided into four groups: the vehicle group (corn oil, n = 10), 500mg/Kg DEHP group (n = 15), 3mg/Kg verapamil group (n = 10) and 500mg/Kg DEHP & 3mg/Kg verapamil group (n = 20). Pregnant dams in different group received respective intervention by gavage once daily from E6.5-14.5. Maternal weights were monitored every day and samples were collected at E15.5. HE staining was used to examine fetal cardiac malformations. Real-time quantitative PCR (RT-qPCR) and Western-Blot were applied to detect Nkx2.5/Gata4/Tbx5/Mef2c/Chf1 mRNA and protein expression, respectively. The mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) was also determined using RT-qPCR.
Co-administration of verapamil and DEHP significantly elevated fetal cardiac malformation rates, in comparison with the DEHP group, the verapamil group and the vehicle group. Different phenotypes of cardiac anomalies, including septal defects and ventricular myocardium noncompaction, were noted both in the DEHP group and the DEHP & verapamil group. The ventricular myocardium noncompaction appeared to be more severe in the DEHP & verapamil group. Fetal cardiac PPARγ mRNA expression was notably increased and Gata4/Mef2c/Chf1 expression was markedly decreased in the DEHP & verapamil group.
Placental P-gp inhibition enhances susceptibility to DEHP induced cardiac malformations in mice.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31086358</pmid><doi>10.1371/journal.pone.0214873</doi><orcidid>https://orcid.org/0000-0001-5165-8273</orcidid><orcidid>https://orcid.org/0000-0002-3096-4287</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-05, Vol.14 (5), p.e0214873-e0214873 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2225127043 |
| 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 | Animals Anomalies ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism Biology and Life Sciences Birth defects Cardiology Congenital defects Congenital diseases Congenital heart defects Contaminants Corn Corn oil Desertification Diethylhexyl Phthalate - toxicity Education Female Fetal Heart - drug effects Fetal Heart - metabolism Fetal Heart - pathology Fetuses GATA4 Transcription Factor - genetics GATA4 Transcription Factor - metabolism Gene expression Gene Expression Regulation, Developmental - drug effects Genetic disorders Glycoproteins Health aspects Heart Heart Defects, Congenital - chemically induced Heart Defects, Congenital - metabolism Heart Defects, Congenital - pathology Homeobox Protein Nkx-2.5 - genetics Homeobox Protein Nkx-2.5 - metabolism Hospitals House mouse Inhibition Laboratories Maternal Exposure Medicine and Health Sciences Membrane proteins Messenger RNA Mice Mice, Inbred C57BL Myocardium Nkx2.5 protein P-Glycoprotein Pediatrics Pharmaceuticals Phenotypes Phthalates Physical Sciences Physiological aspects Placenta Placenta - metabolism Polymerase chain reaction Polymorphism PPAR gamma - genetics PPAR gamma - metabolism Pregnancy Pregnant women Prenatal influences Prevention Research and Analysis Methods Risk factors Risk reduction RNA T-Box Domain Proteins - genetics T-Box Domain Proteins - metabolism Toxicants Ventricle Verapamil Verapamil - pharmacology Womens health |
| title | Placental P-glycoprotein inhibition enhances susceptibility to Di-(2-ethylhexyl)-phthalate induced cardiac malformations in mice: A possibly promising target for congenital heart defects prevention |
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