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Relationship between placental location and intrauterine fetal growth
A68
Abstracts / Placenta 34 (2013) A1–A99
The acquisition of monoallelic, parent-of-origin dependent expression of a subset of mammalian genes was critical for evolution of viviparity and the placenta. Aberrant imprinted gene expression is frequently associated with defective placentation or impaired placental function, often with adverse consequences for fetal growth (intrauterine growth restriction (IUGR)) and in some instances, fetal death. IUGR resulting as a consequence of placental insufficiency generally results in a sparing of brain growth (asymmetric IUGR) to the detriment of other organs, and is further associated with programming of metabolic diseases including type II diabetes, cardiovascular disease, hypertension and central obesity. Elevated placental expression of the maternally expressed PHLDA2 gene has been associated with IUGR in several human studies. We previously reported a severe placental defect and impaired fetal growth were associated with elevated Phlda2 expression in a BAC transgenic model. Here we report transgenic placentae are characterised by a specific loss of the endocrine spongiotrophoblast population, resulting in a significantly reduced expression of pregnancy specific glycoprotein (Psg) and prolactin related (Prl) genes. Consequently fetal growth during late gestation is significantly impaired, with a relative sparing of brain growth, with both phenotypes specifically attributable to elevated Phlda2. Transgenic mice exhibit post-natal catch up growth within two weeks of birth, and thus portray the key facets commonly associated with metabolic programming, namely placental insufficiency, late gestation asymmetric growth restriction and rapid post-natal catch up growth. Here we report the initial metabolic characterisation of these mice demonstrating reduced glucose tolerance and increased adiposity in aged animals. http://dx.doi.org/10.1016/j.placenta.2013.06.203
P2.37. ABNORMAL MATERNAL INFLAMMATION IN THE RAT IS ASSOCIATED WITH PLACENTAL HIF-1a ACCUMULATION AND NITROSATIVE STRESS Arissa Sperou, Tiziana Cotechini, Shannyn K. MacDonald-Goodfellow, Charles H. Graham Queen's University, Kingston, ON, Canada Objectives: Aberrant maternal inflammation is often associated with pregnancy pathologies, such as pre-eclampsia (PE) and fetal growth restriction (FGR). Using a rat model, we have provided evidence that abnormal maternal inflammation is causally linked to deficient spiral arterial remodeling and altered utero-placental perfusion leading to FGR/ PE. This study determined if placental oxidative/nitrosative stress occurs in this model, identified through the expression of the hypoxia-inducible factor (HIF-1a) and nitrotyrosine. Additionally, we determined whether glyceryl trinitrate (GTN) improves utero-placental perfusion and attenuates downstream effects of placental ischemia. Methods of Study: We developed a model of FGR/PE in which pregnant Wistar rats are administered low-dose lipopolysaccharide (LPS) daily on gestational days (GD) 13.5-16.5 (10mg/Kg on GD 13.5, 40mg/Kg on GD 14.5, 15.5, 16.5). Controls consisted of dams injected with saline. Transdermal patches delivering nitroglycerin (glyceryl trinitrate or GTN) at a dose of 25 mg/h were administered to some rats and changed daily on GD 12.5-16.5. Upon sacrifice on GD 17.5, implantation sites were either snap frozen and assayed for nitrotyrosine, or fixed and processed for histological analysis of HIF-1a. Results: Placentas of LPS-treated dams expressed significantly greater HIF1a staining distribution and intensity in comparison to placentas of salinetreated controls. The number of placentas expressing nitrotyrosine was greater in placentas from LPS-treated dams compared to saline-treated controls. Administration of GTN to LPS-treated dams prevented FGR, and decreased HIF-1a staining and nitrotyrosine expression. Conclusion: This study provides evidence that inflammation-induced FGR is associated with increased placental HIF-1a accumulation and nitrosative stress. Our findings indicate that GTN has potential applications for the
treatment and/or prevention of pregnancy complications associated with abnormal maternal inflammation. http://dx.doi.org/10.1016/j.placenta.2013.06.204
P2.38. RELATIONSHIP BETWEEN PLACENTAL LOCATION AND INTRAUTERINE FETAL GROWTH Dong Wook Kwak 1, Yong Won Park 2, Young Han Kim 2 Cheil General Hospital, Seoul, Republic of Korea; 2 Yonsei University Health System, Seoul, Republic of Korea
1
Objective: The purpose of this study was to determine whether placental location is associated with intrauterine fetal growth or pregnancy complications including hypertensive disorders. Methods: We conducted a retrospective study of 11,885 singleton births in women who underwent ultrasonography at the time of third trimester and delivered between January 2010 and December 2011. Placental location was divided into central, lateral and fundal implantation. We assessed newborn weight, incidence of SGA (small for gestational age) and LGA (large for gestational age), low birth weight, macrosomia, preterm birth, malpresentation, hypertensive disorders of pregnancy and gestational diabetes mellitus. Results: The proportion of central, lateral and fundal placentas was 81.3%, 4.5% and 2.3%, respectively. The rest of placentas (11.9%) were not clearly assorted in three categories. Mean birth weights of central, lateral and fundal placentas were 3269g, 3228g and 3174g, incidences of SGA were 8.7%, 12.2% and 13.5%, and incidences of hypertensive disorder of pregnancy were 1.3%, 2.4% and 1.1%, respectively. Compared to central placenta, incidences of SGA were significantly increased in both lateral and fundal placentas (p¼0.015, 0.022) but newborn weight was decreased significantly in fundal placentas but not in lateral (p<0.001, p¼0.058). Conclusion: Fundal placentas were not associated with hypertensive disorder of pregnancy, but significantly more likely than central implantation to decrease newborn weight. http://dx.doi.org/10.1016/j.placenta.2013.06.205
P2.39. DECIDUAL NATURAL KILLER CELLS REGULATE FUT4 EXPRESSION IN EVT THROUGH DNA ENHANCER METHYLATION Yuxiang Hu 1, John Blair 1, Ryan Yuen 2, Wendy Robinson 1, Peter von Dadelszen 1 Child and Family Research Institute, Vancouver, Canada; 2 The Hospital for Sick Children, Toronto, Canada
1
We have previously shown that extravillous cytotrophoblast (EVT) outgrowth and migration on a collagen gel explant model were restricted by exposure to decidual natural killer cells (dNK) or dNK-derived conditioned medium (dNK-CM). This study investigates the molecular causes behind this phenomenon. Genome wide DNA methylation of exposed and unexposed EVT was assessed using the Illumina Infinium HumanMethylation450 BeadChip. We identified that Fucosyltransferase IV (FUT4) DNA methylation in an enhancer region was increased by exposing EVT to dNK but not to dNK-CM. FUT4 is a member of the fucosyltransferase family of glycosyltransferases, and is responsible for CD15 synthesis in some cell types. FUT4 has been implicated in cell adhesion and mobility, and enhanced FUT4 expression correlates with increased tumor malignancy in many carcinomas, however little is known about FUT4 expression in EVT. We validated the FUT4 methylation results by bisulphite pyrosequencing. To confirm the effects of DNA methylation on gene and protein expression, we measured FUT4 mRNA by qRT-PCR and protein by flow cytometry
Abstracts / Placenta 34 (2013) A1–A99
The acquisition of monoallelic, parent-of-origin dependent expression of a subset of mammalian genes was critical for evolution of viviparity and the placenta. Aberrant imprinted gene expression is frequently associated with defective placentation or impaired placental function, often with adverse consequences for fetal growth (intrauterine growth restriction (IUGR)) and in some instances, fetal death. IUGR resulting as a consequence of placental insufficiency generally results in a sparing of brain growth (asymmetric IUGR) to the detriment of other organs, and is further associated with programming of metabolic diseases including type II diabetes, cardiovascular disease, hypertension and central obesity. Elevated placental expression of the maternally expressed PHLDA2 gene has been associated with IUGR in several human studies. We previously reported a severe placental defect and impaired fetal growth were associated with elevated Phlda2 expression in a BAC transgenic model. Here we report transgenic placentae are characterised by a specific loss of the endocrine spongiotrophoblast population, resulting in a significantly reduced expression of pregnancy specific glycoprotein (Psg) and prolactin related (Prl) genes. Consequently fetal growth during late gestation is significantly impaired, with a relative sparing of brain growth, with both phenotypes specifically attributable to elevated Phlda2. Transgenic mice exhibit post-natal catch up growth within two weeks of birth, and thus portray the key facets commonly associated with metabolic programming, namely placental insufficiency, late gestation asymmetric growth restriction and rapid post-natal catch up growth. Here we report the initial metabolic characterisation of these mice demonstrating reduced glucose tolerance and increased adiposity in aged animals. http://dx.doi.org/10.1016/j.placenta.2013.06.203
P2.37. ABNORMAL MATERNAL INFLAMMATION IN THE RAT IS ASSOCIATED WITH PLACENTAL HIF-1a ACCUMULATION AND NITROSATIVE STRESS Arissa Sperou, Tiziana Cotechini, Shannyn K. MacDonald-Goodfellow, Charles H. Graham Queen's University, Kingston, ON, Canada Objectives: Aberrant maternal inflammation is often associated with pregnancy pathologies, such as pre-eclampsia (PE) and fetal growth restriction (FGR). Using a rat model, we have provided evidence that abnormal maternal inflammation is causally linked to deficient spiral arterial remodeling and altered utero-placental perfusion leading to FGR/ PE. This study determined if placental oxidative/nitrosative stress occurs in this model, identified through the expression of the hypoxia-inducible factor (HIF-1a) and nitrotyrosine. Additionally, we determined whether glyceryl trinitrate (GTN) improves utero-placental perfusion and attenuates downstream effects of placental ischemia. Methods of Study: We developed a model of FGR/PE in which pregnant Wistar rats are administered low-dose lipopolysaccharide (LPS) daily on gestational days (GD) 13.5-16.5 (10mg/Kg on GD 13.5, 40mg/Kg on GD 14.5, 15.5, 16.5). Controls consisted of dams injected with saline. Transdermal patches delivering nitroglycerin (glyceryl trinitrate or GTN) at a dose of 25 mg/h were administered to some rats and changed daily on GD 12.5-16.5. Upon sacrifice on GD 17.5, implantation sites were either snap frozen and assayed for nitrotyrosine, or fixed and processed for histological analysis of HIF-1a. Results: Placentas of LPS-treated dams expressed significantly greater HIF1a staining distribution and intensity in comparison to placentas of salinetreated controls. The number of placentas expressing nitrotyrosine was greater in placentas from LPS-treated dams compared to saline-treated controls. Administration of GTN to LPS-treated dams prevented FGR, and decreased HIF-1a staining and nitrotyrosine expression. Conclusion: This study provides evidence that inflammation-induced FGR is associated with increased placental HIF-1a accumulation and nitrosative stress. Our findings indicate that GTN has potential applications for the
treatment and/or prevention of pregnancy complications associated with abnormal maternal inflammation. http://dx.doi.org/10.1016/j.placenta.2013.06.204
P2.38. RELATIONSHIP BETWEEN PLACENTAL LOCATION AND INTRAUTERINE FETAL GROWTH Dong Wook Kwak 1, Yong Won Park 2, Young Han Kim 2 Cheil General Hospital, Seoul, Republic of Korea; 2 Yonsei University Health System, Seoul, Republic of Korea
1
Objective: The purpose of this study was to determine whether placental location is associated with intrauterine fetal growth or pregnancy complications including hypertensive disorders. Methods: We conducted a retrospective study of 11,885 singleton births in women who underwent ultrasonography at the time of third trimester and delivered between January 2010 and December 2011. Placental location was divided into central, lateral and fundal implantation. We assessed newborn weight, incidence of SGA (small for gestational age) and LGA (large for gestational age), low birth weight, macrosomia, preterm birth, malpresentation, hypertensive disorders of pregnancy and gestational diabetes mellitus. Results: The proportion of central, lateral and fundal placentas was 81.3%, 4.5% and 2.3%, respectively. The rest of placentas (11.9%) were not clearly assorted in three categories. Mean birth weights of central, lateral and fundal placentas were 3269g, 3228g and 3174g, incidences of SGA were 8.7%, 12.2% and 13.5%, and incidences of hypertensive disorder of pregnancy were 1.3%, 2.4% and 1.1%, respectively. Compared to central placenta, incidences of SGA were significantly increased in both lateral and fundal placentas (p¼0.015, 0.022) but newborn weight was decreased significantly in fundal placentas but not in lateral (p<0.001, p¼0.058). Conclusion: Fundal placentas were not associated with hypertensive disorder of pregnancy, but significantly more likely than central implantation to decrease newborn weight. http://dx.doi.org/10.1016/j.placenta.2013.06.205
P2.39. DECIDUAL NATURAL KILLER CELLS REGULATE FUT4 EXPRESSION IN EVT THROUGH DNA ENHANCER METHYLATION Yuxiang Hu 1, John Blair 1, Ryan Yuen 2, Wendy Robinson 1, Peter von Dadelszen 1 Child and Family Research Institute, Vancouver, Canada; 2 The Hospital for Sick Children, Toronto, Canada
1
We have previously shown that extravillous cytotrophoblast (EVT) outgrowth and migration on a collagen gel explant model were restricted by exposure to decidual natural killer cells (dNK) or dNK-derived conditioned medium (dNK-CM). This study investigates the molecular causes behind this phenomenon. Genome wide DNA methylation of exposed and unexposed EVT was assessed using the Illumina Infinium HumanMethylation450 BeadChip. We identified that Fucosyltransferase IV (FUT4) DNA methylation in an enhancer region was increased by exposing EVT to dNK but not to dNK-CM. FUT4 is a member of the fucosyltransferase family of glycosyltransferases, and is responsible for CD15 synthesis in some cell types. FUT4 has been implicated in cell adhesion and mobility, and enhanced FUT4 expression correlates with increased tumor malignancy in many carcinomas, however little is known about FUT4 expression in EVT. We validated the FUT4 methylation results by bisulphite pyrosequencing. To confirm the effects of DNA methylation on gene and protein expression, we measured FUT4 mRNA by qRT-PCR and protein by flow cytometry