{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/113330"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/113330","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Mechanisms underlying establishment and maintenance of pregnancy","abstract":"Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during maternal adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy. Endocrine-disrupting chemicals like di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are ubiquitous in nature and human exposure to these chemicals is inevitable. The impact of exposure to these phthalates in the establishment and maintenance of pregnancy remains largely unknown. The current study focuses on understanding the effect of exposure to an environmentally relevant dose (20 µg/kg/day) of DEHP or DiNP on pregnancy. The study shows that phthalate exposure during early pregnancy results in loss of fetuses at latter stages of gestation, causing a reduction in the litter size. Interestingly, between the two phthalates, the extent of fetal loss was significantly greater in the DiNP group. While both DEHP and DiNP affect stromal cell differentiation and decidual angiogenesis, significant disorganization of the placental layers was only observed in the DiNP-treated mice. Interestingly, the fetuses from the DiNP group that do manage to survive in the sub-optimum uterine environment, though weigh less at birth, eventually gain weight and develop normally. Further studies are needed to gain a comprehensive understanding of how phthalates affect different cell types during placentation.","abstract_html":"Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during maternal adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy. Endocrine-disrupting chemicals like di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are ubiquitous in nature and human exposure to these chemicals is inevitable. The impact of exposure to these phthalates in the establishment and maintenance of pregnancy remains largely unknown. The current study focuses on understanding the effect of exposure to an environmentally relevant dose (20 µg/kg/day) of DEHP or DiNP on pregnancy. The study shows that phthalate exposure during early pregnancy results in loss of fetuses at latter stages of gestation, causing a reduction in the litter size. Interestingly, between the two phthalates, the extent of fetal loss was significantly greater in the DiNP group. While both DEHP and DiNP affect stromal cell differentiation and decidual angiogenesis, significant disorganization of the placental layers was only observed in the DiNP-treated mice. Interestingly, the fetuses from the DiNP group that do manage to survive in the sub-optimum uterine environment, though weigh less at birth, eventually gain weight and develop normally. Further studies are needed to gain a comprehensive understanding of how phthalates affect different cell types during placentation.","abstract_has_math":false,"creators":["Bhurke, Arpita Shridhar"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"VMS - Comparative Biosciences","degree_department":null,"school":null,"contributors":["Bagchi, Indrani C","Bagchi, Milan","Yang, Jing","Nowak, Romana"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-01-12T22:56:12Z","date_published":"2022-01-12T22:56:12Z","updated_at":"2026-07-22T22:24:53Z","subjects":["pregnancy","embryo implantation","HIF2α","RAB27B","DEHP","DiNP"],"languages":["en"],"rights":["copyright 2021 Arpita Bhurke"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/113330","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Bagchi, Indrani C","Bagchi, Milan","Yang, Jing","Nowak, Romana"]},{"key":"dc:creator","label":"Author","values":["Bhurke, Arpita Shridhar"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-01-12T22:56:12Z","2024-01-12T22:56:20Z","2021-07-16","2021-08"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["VMS - Comparative Biosciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["pregnancy","embryo implantation","HIF2α","RAB27B","DEHP","DiNP"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["copyright 2021 Arpita Bhurke"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/113330"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Implantation is initiated when an embryo attaches to the uterine luminal epithelium and subsequently penetrates into the underlying stroma to firmly embed in the endometrium. These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during maternal adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy. Endocrine-disrupting chemicals like di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are ubiquitous in nature and human exposure to these chemicals is inevitable. The impact of exposure to these phthalates in the establishment and maintenance of pregnancy remains largely unknown. The current study focuses on understanding the effect of exposure to an environmentally relevant dose (20 µg/kg/day) of DEHP or DiNP on pregnancy. The study shows that phthalate exposure during early pregnancy results in loss of fetuses at latter stages of gestation, causing a reduction in the litter size. Interestingly, between the two phthalates, the extent of fetal loss was significantly greater in the DiNP group. While both DEHP and DiNP affect stromal cell differentiation and decidual angiogenesis, significant disorganization of the placental layers was only observed in the DiNP-treated mice. Interestingly, the fetuses from the DiNP group that do manage to survive in the sub-optimum uterine environment, though weigh less at birth, eventually gain weight and develop normally. Further studies are needed to gain a comprehensive understanding of how phthalates affect different cell types during placentation.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2023-08-01","The student, Arpita Bhurke, accepted the attached license on 2021-07-16 at 09:50.","The student, Arpita Bhurke, submitted this Dissertation for approval on 2021-07-16 at 09:52.","This Dissertation was approved for publication on 2021-07-16 at 14:15.","DSpace SAF Submission Ingestion Package generated from Vireo submission #16979 on 2022-01-12 at 13:05:12","Made available in DSpace on 2022-01-12T22:56:12Z (GMT). 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These events are followed by the formation of an extensive vascular network in the stroma that supports embryonic growth and ensures successful implantation. Interestingly, in many mammalian species, these processes of early pregnancy occur in a hypoxic environment. However, the mechanisms underlying maternal adaptation to hypoxia during early pregnancy remain unclear. In this study, using a knockout mouse model, we show that the transcription factor hypoxia-inducible factor 2 alpha (Hif2α), which is induced in subluminal stromal cells at the time of implantation, plays a crucial role during early pregnancy. Indeed, when preimplantation endometrial stromal cells are exposed to hypoxic conditions in vitro, we observed a striking enhancement in HIF2α expression. Further studies revealed that HIF2α regulates the expression of several metabolic and protein trafficking factors, including RAB27B, at the onset of implantation. RAB27B is a member of the Rab family of GTPases that allows controlled release of secretory granules. These granules are involved in trafficking MMP9 from the stroma to the epithelium to promote luminal epithelial remodeling during embryo invasion. As pregnancy progresses, the HIF2α-RAB27B pathway additionally mediates crosstalk between stromal and endothelial cells via VEGF granules, developing the vascular network critical for establishing pregnancy. Collectively, our study provides insights into the intercellular communication mechanisms that operate during maternal adaptation to hypoxia, which is essential for embryo implantation and establishment of pregnancy. Endocrine-disrupting chemicals like di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) are ubiquitous in nature and human exposure to these chemicals is inevitable. The impact of exposure to these phthalates in the establishment and maintenance of pregnancy remains largely unknown. The current study focuses on understanding the effect of exposure to an environmentally relevant dose (20 µg/kg/day) of DEHP or DiNP on pregnancy. The study shows that phthalate exposure during early pregnancy results in loss of fetuses at latter stages of gestation, causing a reduction in the litter size. Interestingly, between the two phthalates, the extent of fetal loss was significantly greater in the DiNP group. While both DEHP and DiNP affect stromal cell differentiation and decidual angiogenesis, significant disorganization of the placental layers was only observed in the DiNP-treated mice. Interestingly, the fetuses from the DiNP group that do manage to survive in the sub-optimum uterine environment, though weigh less at birth, eventually gain weight and develop normally. Further studies are needed to gain a comprehensive understanding of how phthalates affect different cell types during placentation.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2023-08-01","The student, Arpita Bhurke, accepted the attached license on 2021-07-16 at 09:50.","The student, Arpita Bhurke, submitted this Dissertation for approval on 2021-07-16 at 09:52.","This Dissertation was approved for publication on 2021-07-16 at 14:15.","DSpace SAF Submission Ingestion Package generated from Vireo submission #16979 on 2022-01-12 at 13:05:12","Made available in DSpace on 2022-01-12T22:56:12Z (GMT). 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