The role of the phosphoinositol kinase (PI3K) p110α in regulating placental phenotype and fetal...
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intercotyledonary area and umbilical cord, and fetal anasarca in the last trimester of pregnancy. We hypothesized that the transition from the cho- riovitelline placenta to the allantochorionic placenta is a critical period for SCNT conceptus survival. Our cloning program started one year ago and 236 recipient cows have been synchronized for embryo transfer on fixed time. The synchronization rate was 62.7% (148/236). One hundred twenty six cloned embryos by SCNT were transferred to recipients. The pregnancy rate on day 25 was 11.9% (15/126). Only one (1/15) pregnancy loss was observed until day 30. However, four pregnancies losses were observed from days 30 to 40 (42.9%; 4/14) and four from days 50 to 60 (50%; 4/8). This preliminary data confirmed the low efficiency of SCNT cloning in bovine as reported in the literature. The experimental number is still small, but the data shows that the most critical period for the conceptus development is between the embryo transfer to the first pregnancy detection. An important event at this time is the maternal recognition of pregnancy. Also, our hypothesis that the transi- tion from the choriovitelline placenta to the allantochorionic placenta is a critical period for SCNT conceptus survival was confirmed. P1.51. THE ROLE OF THE PHOSPHOINOSITOL KINASE (PI3K) P110a IN REGULATING PLACENTAL PHENOTYPE AND FETAL GROWTH Amanda Sferruzzi-Perri, Jaspreet Khaira, Abigail Fowden, Miguel Constancia Centre for Trophoblast Research, University of Cambridge, Cambridge, UK The mouse placenta adapts its structural and transport phenotype in response to mismatches between fetal demand and placental supply of nutrients induced either nutritionally or genetically. These adaptations are accompanied by altered placental PI3K signalling, particularly down- stream of PI3K-p110〈 1,2 . However, very little is known about the role of PI3K-p110〈 in the placenta. Aim: To determine the effect of PI3K-p110〈 deficiency on placental phenotype and fetal growth. Methods: PI3K-p110〈 was knocked-down by 50% in the fetus and placenta in mice heterozygous for a dominant negative mutation in p110a (p110〈 D933A ) or heterozygous gene deletion (p110〈 Flox/DEL ). The second p110〈 allele was also deleted conditionally in placental trophoblast using the Cyp19Cre transgenic mouse. At embryonic (E) day 16 or 19 (term¼E20.5), placental transport of 14 C-methyl aminoisobutyric acid (MeAIB) and 3 H-methyl D- glucose (MeG) was measured in vivo and placental structure assessed ste- reologically. Experiments were in accordance with UK Animals Act. Results: At both ages, p110〈 D933A/+ fetuses were ~12-15% lighter than wildtype whereas placentas were 7% and 16% lighter on E16 and E19, respectively (Table 1). At both ages, the labyrinthine zone (Lz) was smaller in p110〈 D933A/+ mutants with decreased fetal capillaries and exchange surface area and a thicker exchange barrier, versus wildtype (Table 1). At E16, p110〈 D933A/+ placentas transported less MeAIB and MeG than wild- type, whereas, at E19, they transported more (Figure 1). At E19, p110〈 Flox/DEL placentas also transported more MeAIB and MeG than wildtype, despite a compromised Lz (Table 2, Figure 2). However, deletion of the second p110〈 allele in Cyp19Cre/〈 Del/Del placentas prevented this upregulation and further restricted fetal growth ensued. ĂConclusions: Total feto-placental PI3K-p110a knock-down compromises both fetal growth and placental Lz development at E16. However, between E16 and E19, fetuses maintained near normal growth via adaptive up- regulation of placental nutrient transfer, which was dependent on residual placental p110a expression. 1 Endocrinology(2011)152:3202-3212. 2 FASEB(2013)27(10):3928-37. P1.52. MATERNAL OBESITY IS ASSOCIATED WITH ALTERED PLACENTAL EXPRESSION OF THYROID ASSOCIATED GENES AND INCREASED FETAL FT4 Melissa Suter, Min Hu, Melanie Arndt, Kjersti Aagaard Baylor College of Medicine, Houston, TX, USA Objective: Obesity has been associated with sub-clinical hypothyroidism, and obesity during pregnancy is associated with large for gestational age infants. Throughout gestation the placenta regulates the amount of maternal thyroid hormone (TH) which reaches the fetus. We sought to determine if maternal obesity is associated with changes in genes which regulate TH homeostasis in the placenta, and to determine if newborns of obese mothers have alterations in free T4 (FT4) and free T3 (FT3) levels. Methods: We collected placentas from normal weight (BMI 18.5-24.9, n¼28), overweight (BMI 25.0-29.9, n¼25) and obese (BMI 30.0, n¼72) subjects immediately following delivery. They were flash frozen and stored at -80 C until use. mRNA was extracted from each placenta, converted to cDNA and subjected to qPCR analysis using TaqMan probes. Maternal and cord blood was collected immediately following delivery, snap frozen and stored at -80 C until use. Cord serum FT3 and FT4 was analyzed using ELISA. Subjects were categorized by pre-pregnancy or first trimester weight. Ă Abstracts / Placenta 35 (2014) A1eA112 A26
Transcript of The role of the phosphoinositol kinase (PI3K) p110α in regulating placental phenotype and fetal...
Abstracts / Placenta 35 (2014) A1eA112A26
intercotyledonary area and umbilical cord, and fetal anasarca in the lasttrimester of pregnancy. We hypothesized that the transition from the cho-riovitelline placenta to the allantochorionic placenta is a critical period forSCNT conceptus survival. Our cloning program started one year ago and 236recipient cows have been synchronized for embryo transfer on fixed time.The synchronization rate was 62.7% (148/236). One hundred twenty sixcloned embryos by SCNT were transferred to recipients. The pregnancy rateon day 25 was 11.9% (15/126). Only one (1/15) pregnancy loss was observeduntil day30.However, four pregnancies losseswere observed fromdays 30 to40 (42.9%; 4/14) and four fromdays 50 to 60 (50%; 4/8). This preliminary dataconfirmed the low efficiency of SCNT cloning in bovine as reported in theliterature. The experimental number is still small, but the data shows that themost critical period for the conceptus development is between the embryotransfer to the first pregnancy detection. An important event at this time isthe maternal recognition of pregnancy. Also, our hypothesis that the transi-tion from the choriovitelline placenta to the allantochorionic placenta is acritical period for SCNT conceptus survival was confirmed.
P1.51.THE ROLE OF THE PHOSPHOINOSITOL KINASE (PI3K) P110a INREGULATING PLACENTAL PHENOTYPE AND FETAL GROWTH
Amanda Sferruzzi-Perri, Jaspreet Khaira, Abigail Fowden, MiguelConstancia Centre for Trophoblast Research, University of Cambridge,Cambridge, UK
The mouse placenta adapts its structural and transport phenotype inresponse to mismatches between fetal demand and placental supply ofnutrients induced either nutritionally or genetically. These adaptations areaccompanied by altered placental PI3K signalling, particularly down-stream of PI3K-p110⟨1,2. However, very little is known about the role ofPI3K-p110⟨ in the placenta.
Aim: To determine the effect of PI3K-p110⟨ deficiency on placentalphenotype and fetal growth.Methods: PI3K-p110⟨was knocked-downby 50% in the fetus and placenta inmice heterozygous for a dominant negative mutation in p110a (p110⟨D933A)or heterozygous gene deletion (p110⟨Flox/DEL). The second p110⟨ allele wasalso deleted conditionally in placental trophoblast using the Cyp19Cretransgenic mouse. At embryonic (E) day 16 or 19 (term¼E20.5), placentaltransport of 14C-methyl aminoisobutyric acid (MeAIB) and 3H-methyl D-glucose (MeG) was measured in vivo and placental structure assessed ste-reologically. Experiments were in accordance with UK Animals Act.
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Results: At both ages, p110⟨D933A/+ fetuses were ~12-15% lighter thanwildtype whereas placentas were 7% and 16% lighter on E16 and E19,respectively (Table 1). At both ages, the labyrinthine zone (Lz) was smallerin p110⟨D933A/+mutants with decreased fetal capillaries and exchangesurface area and a thicker exchange barrier, versus wildtype (Table 1). AtE16, p110⟨D933A/+ placentas transported less MeAIB and MeG than wild-type, whereas, at E19, they transported more (Figure 1).At E19, p110⟨Flox/DEL placentas also transported more MeAIB and MeG thanwildtype, despite a compromised Lz (Table 2, Figure 2). However, deletionof the second p110⟨ allele in Cyp19Cre/⟨Del/Del placentas prevented thisupregulation and further restricted fetal growth ensued.
ĂConclusions: Total feto-placental PI3K-p110a knock-down compromisesboth fetal growth and placental Lz development at E16. However, betweenE16 and E19, fetuses maintained near normal growth via adaptive up-regulation of placental nutrient transfer, which was dependent on residualplacental p110a expression.1 Endocrinology(2011)152:3202-3212.2 FASEB(2013)27(10):3928-37.
P1.52.MATERNAL OBESITY IS ASSOCIATED WITH ALTERED PLACENTALEXPRESSION OF THYROID ASSOCIATED GENES AND INCREASED FETALFT4
Melissa Suter, Min Hu, Melanie Arndt, Kjersti Aagaard Baylor College ofMedicine, Houston, TX, USA
Objective: Obesity has been associated with sub-clinical hypothyroidism,and obesity during pregnancy is associated with large for gestational ageinfants. Throughout gestation the placenta regulates the amount ofmaternal thyroid hormone (TH) which reaches the fetus. We sought todetermine if maternal obesity is associated with changes in genes whichregulate TH homeostasis in the placenta, and to determine if newborns ofobese mothers have alterations in free T4 (FT4) and free T3 (FT3) levels.Methods: We collected placentas from normal weight (BMI 18.5-24.9,n¼28), overweight (BMI 25.0-29.9, n¼25) and obese (BMI � 30.0, n¼72)subjects immediately following delivery. Theywere flash frozen and storedat -80�C until use. mRNA was extracted from each placenta, converted tocDNA and subjected to qPCR analysis using TaqMan probes. Maternal andcord blood was collected immediately following delivery, snap frozen andstored at -80�C until use. Cord serum FT3 and FT4 was analyzed usingELISA. Subjects were categorized by pre-pregnancy or first trimesterweight.
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