Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation
The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlyin...
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| Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 2005-03, Vol.19 (3), p.669-682 |
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| container_title | Molecular endocrinology (Baltimore, Md.) |
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| creator | Huang, Wei-Wei Yin, Yan Bi, Qun Chiang, Tung-Chin Garner, Neysa Vuoristo, Jussi McLachlan, John A Ma, Liang |
| description | The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2−/− uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation. |
| doi_str_mv | 10.1210/me.2004-0155 |
| format | Article |
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Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2−/− uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/me.2004-0155</identifier><identifier>PMID: 15591538</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Alkaline Phosphatase - metabolism ; Animals ; Apoptosis ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Cell Transformation, Neoplastic ; Diethylstilbestrol - adverse effects ; DNA Primers - chemistry ; DNA, Complementary - metabolism ; DNA-Binding Proteins - genetics ; Epithelium - metabolism ; Estrogens, Non-Steroidal - adverse effects ; Female ; Homeodomain Proteins ; In Situ Hybridization ; Infertility ; Keratins - metabolism ; Metaplasia ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Biological ; Mutation ; Oligonucleotide Array Sequence Analysis ; Pregnancy ; Pregnancy, Animal ; Prenatal Exposure Delayed Effects ; Proto-Oncogene Proteins - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleases - metabolism ; Time Factors ; Transcription, Genetic ; Up-Regulation ; Uterus - drug effects ; Uterus - embryology ; Uterus - metabolism ; Wnt Proteins ; Wnt-5a Protein</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2005-03, Vol.19 (3), p.669-682</ispartof><rights>Copyright © 2005 by The Endocrine Society 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-f0ca9a199e350b1dfe5278032af9a0a555ae2ccc4678f056b17c931acececf583</citedby><cites>FETCH-LOGICAL-c500t-f0ca9a199e350b1dfe5278032af9a0a555ae2ccc4678f056b17c931acececf583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15591538$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Wei-Wei</creatorcontrib><creatorcontrib>Yin, Yan</creatorcontrib><creatorcontrib>Bi, Qun</creatorcontrib><creatorcontrib>Chiang, Tung-Chin</creatorcontrib><creatorcontrib>Garner, Neysa</creatorcontrib><creatorcontrib>Vuoristo, Jussi</creatorcontrib><creatorcontrib>McLachlan, John A</creatorcontrib><creatorcontrib>Ma, Liang</creatorcontrib><title>Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2−/− uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.</description><subject>Alkaline Phosphatase - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cell Differentiation</subject><subject>Cell Lineage</subject><subject>Cell Proliferation</subject><subject>Cell Transformation, Neoplastic</subject><subject>Diethylstilbestrol - adverse effects</subject><subject>DNA Primers - chemistry</subject><subject>DNA, Complementary - metabolism</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Epithelium - metabolism</subject><subject>Estrogens, Non-Steroidal - adverse effects</subject><subject>Female</subject><subject>Homeodomain Proteins</subject><subject>In Situ Hybridization</subject><subject>Infertility</subject><subject>Keratins - metabolism</subject><subject>Metaplasia</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Models, Biological</subject><subject>Mutation</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Pregnancy</subject><subject>Pregnancy, Animal</subject><subject>Prenatal Exposure Delayed Effects</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Ribonucleases - metabolism</subject><subject>Time Factors</subject><subject>Transcription, Genetic</subject><subject>Up-Regulation</subject><subject>Uterus - drug effects</subject><subject>Uterus - embryology</subject><subject>Uterus - metabolism</subject><subject>Wnt Proteins</subject><subject>Wnt-5a Protein</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kD1PwzAQQC0EgvKxMaNMsBA4JzGxR1Q-JSQYYDauexZGThxsB-i_x1UrsYBuuOGenk6PkEMKZ7SicN7hWQXQlEAZ2yATKpqmFIK2m2QCnPOScxA7ZDfGdwDaME63yU5GBWU1n5DXK_xE54cO-6RccWUxvS1cTNbNMKbgXXH9Pfg4BiwuXcIQi1vsMVldPKn09qUWsfCmeMkX22MxXSQ_t8ZgyDqrkvX9PtkyykU8WO898nJz_Ty9Kx8eb--nlw-lZgCpNKCVUFQIrBnM6Nwgq1oOdaWMUKAYYworrXVz0XID7GJGWy1qqjTmMYzXe-R45R2C_xjz77KzUaNzqkc_Rklb3gBnIoOnK1AHH2NAI4dgOxUWkoJcFpUdymVRuSya8aO1d5x1OP-F1wkzcLIC_Dj8pyrXqnpFYj_3ehlsCBijfPdj6HObvx_4ARwHkQI</recordid><startdate>200503</startdate><enddate>200503</enddate><creator>Huang, Wei-Wei</creator><creator>Yin, Yan</creator><creator>Bi, Qun</creator><creator>Chiang, Tung-Chin</creator><creator>Garner, Neysa</creator><creator>Vuoristo, Jussi</creator><creator>McLachlan, John A</creator><creator>Ma, Liang</creator><general>Endocrine Society</general><general>Oxford University Press</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>7TM</scope></search><sort><creationdate>200503</creationdate><title>Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation</title><author>Huang, Wei-Wei ; Yin, Yan ; Bi, Qun ; Chiang, Tung-Chin ; Garner, Neysa ; Vuoristo, Jussi ; McLachlan, John A ; Ma, Liang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-f0ca9a199e350b1dfe5278032af9a0a555ae2ccc4678f056b17c931acececf583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Alkaline Phosphatase - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Cell Differentiation</topic><topic>Cell Lineage</topic><topic>Cell Proliferation</topic><topic>Cell Transformation, Neoplastic</topic><topic>Diethylstilbestrol - adverse effects</topic><topic>DNA Primers - chemistry</topic><topic>DNA, Complementary - metabolism</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Epithelium - metabolism</topic><topic>Estrogens, Non-Steroidal - adverse effects</topic><topic>Female</topic><topic>Homeodomain Proteins</topic><topic>In Situ Hybridization</topic><topic>Infertility</topic><topic>Keratins - metabolism</topic><topic>Metaplasia</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Models, Biological</topic><topic>Mutation</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Pregnancy</topic><topic>Pregnancy, Animal</topic><topic>Prenatal Exposure Delayed Effects</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Ribonucleases - metabolism</topic><topic>Time Factors</topic><topic>Transcription, Genetic</topic><topic>Up-Regulation</topic><topic>Uterus - drug effects</topic><topic>Uterus - embryology</topic><topic>Uterus - metabolism</topic><topic>Wnt Proteins</topic><topic>Wnt-5a Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Wei-Wei</creatorcontrib><creatorcontrib>Yin, Yan</creatorcontrib><creatorcontrib>Bi, Qun</creatorcontrib><creatorcontrib>Chiang, Tung-Chin</creatorcontrib><creatorcontrib>Garner, Neysa</creatorcontrib><creatorcontrib>Vuoristo, Jussi</creatorcontrib><creatorcontrib>McLachlan, John A</creatorcontrib><creatorcontrib>Ma, Liang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Wei-Wei</au><au>Yin, Yan</au><au>Bi, Qun</au><au>Chiang, Tung-Chin</au><au>Garner, Neysa</au><au>Vuoristo, Jussi</au><au>McLachlan, John A</au><au>Ma, Liang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2005-03</date><risdate>2005</risdate><volume>19</volume><issue>3</issue><spage>669</spage><epage>682</epage><pages>669-682</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2−/− uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>15591538</pmid><doi>10.1210/me.2004-0155</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Alkaline Phosphatase - metabolism Animals Apoptosis Cell Differentiation Cell Lineage Cell Proliferation Cell Transformation, Neoplastic Diethylstilbestrol - adverse effects DNA Primers - chemistry DNA, Complementary - metabolism DNA-Binding Proteins - genetics Epithelium - metabolism Estrogens, Non-Steroidal - adverse effects Female Homeodomain Proteins In Situ Hybridization Infertility Keratins - metabolism Metaplasia Mice Mice, Knockout Mice, Transgenic Models, Biological Mutation Oligonucleotide Array Sequence Analysis Pregnancy Pregnancy, Animal Prenatal Exposure Delayed Effects Proto-Oncogene Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction Ribonucleases - metabolism Time Factors Transcription, Genetic Up-Regulation Uterus - drug effects Uterus - embryology Uterus - metabolism Wnt Proteins Wnt-5a Protein |
| title | Developmental Diethylstilbestrol Exposure Alters Genetic Pathways of Uterine Cytodifferentiation |
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