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dc.contributor.authorWoods, Laura May
dc.date.accessioned2018-10-30T09:57:44Z
dc.date.available2018-10-30T09:57:44Z
dc.date.issued2018-11-24
dc.date.submitted2018-04-09
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284408
dc.description.abstractMaternal age is a significant risk factor for adverse pregnancy outcomes, and is strongly associated with an increased risk of aneuploidy of the conceptus, as well as a significantly higher frequency of serious pregnancy complications known as the “Great Obstetrical Syndromes”, including miscarriage, pre-eclampsia and fetal growth restriction. In the last 40 years average maternal age has increased considerably in many wealthy countries, and in the UK the number of babies born to women aged 35 and over is set to surpass those born to women under 25. The high incidence of aneuploidy in older mothers can be attributed to abnormalities in the oocyte and embryo, however the “Great Obstetrical Syndromes” do not appear to be related to the oocyte and may instead be linked to abnormal development of the placenta. In this thesis, I show that advanced maternal age in the mouse is associated with a drastically increased variability of developmental progression in utero, including developmental delays and growth restriction, severe embryonic abnormalities and higher resorption rates. I find that these embryonic defects are always accompanied by gross morphological and transcriptomic abnormalities in the placenta. Notably, I show that the increased risk of these complications can be rescued by transfer of embryos from aged females to a young surrogate mother, thus implicating the aged maternal uterus as the basis for embryonic and placental defects. Transcriptomic analysis of the decidua compartment in placentas from aged pregnancies revealed abnormal expression of genes involved in the decidualization process, which occurs during early pregnancy and facilitates implantation and development of the conceptus. I show that these defects are already obvious in the peri-implantation window, with endometrial stromal cells from aged females being unable to mount an adequate decidualization response due to a decline in their ability to respond to pregnancy hormones. This blunted decidualization reaction in turn may lead to abnormal development of the placenta. These age-associated decidualization defects are cell-intrinsic and can be recapitulated in vitro. The detected insufficient activation levels and abnormal intracellular distribution of phospho-STAT3, combined with highly variable progesterone receptor expression, may be possible causes of these defects. In addition, I examined the possible effects of ageing on the epigenome as a potential contributor to the decline in endometrial function. My results indicate that ageing of the uterus displays some of the common epigenetic hallmarks of tissue ageing. However, more importantly, decidual cells of aged females exhibit abnormal distributions of the histone modification H3K4me3, and are refractory to the profound DNA methylation remodeling that I find takes place during pregnancy. These age-related changes in the epigenome may underpin, or contribute to, the observed decline in uterine function during pregnancy. Understanding the mechanism underlying these epigenomic and functional changes in the ageing reproductive tract may pave the way for new therapeutic strategies to improve maternal and fetal outcomes of pregnancy in older mothers.
dc.description.sponsorshipPhD studentship funded by the MRC
dc.language.isoen
dc.rightsAll rights reserved
dc.subjectReproduction
dc.subjectplacenta
dc.subjectendometrium
dc.subjectepigenetics
dc.subjectageing
dc.subjectmouse
dc.subjectuterus
dc.subjectdecidualization
dc.subjectdecidua
dc.subjectpregnancy
dc.subjectprogesterone
dc.subjectdna methylation
dc.subjecthistone modifications
dc.titleThe impact of advanced maternal age on endometrial differentiation and placental development
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.publisher.institutionUniversity of Cambridge
dc.publisher.departmentBabraham Institute
dc.date.updated2018-10-09T15:12:09Z
dc.identifier.doi10.17863/CAM.31778
dc.identifier.doi10.17863/CAM.31778
dc.identifier.doi10.17863/CAM.31778
dc.publisher.collegeSidney Sussex
dc.type.qualificationtitleDPhil in Biological sciences
cam.supervisorHemberger, Myriam
cam.thesis.fundingtrue
rioxxterms.freetoread.startdate2019-10-30


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