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Human epidemiological and experimental animal studies show that a poor intra-uterine environment induced by restricted maternal diet during pregnancy leads to persistent alterations in the metabolism and physiology of the offspring and an altered susceptibility to chronic disease in adult life such as cardiovascular disease and metabolic syndrome. This phenomenon has been termed fetal programming. In rats, maternal protein restriction (MPR) during pregnancy alters the expression of specific genes involved in lipid and carbohydrate homeostasis such as glucocorticoid receptor (GR) and peroxisomal proliferator-activated receptor–alpha (PPARα). Evidence is accumulating which indicates that persistent changes in the expression of GR and PPARα are mediated by changes in the epigenetic regulation of these genes within the offspring. Epigenetics refers to processes that stably alter gene activity without altering DNA sequence. DNA methylation and histone modification are the most significant epigenetic modifications. However the mechanism by which alterations in maternal diet can induce the altered epigenetic regulation of genes such as GR or PPARα is currently unknown. The aim therefore of this project was to investigate the role of the DNA methyltransferase1 (Dnmt1). Dnmt1 is essential for the maintenance of DNA methylation patterns in the induction of the altered epigenetic regulation of genes in response to maternal diet. We initially investigated the effect of MPR on Dnmt1 mRNA expression in heart, brain and spleen from control and protein restriction (PR) offspring on PN34. We found that MPR altered the expression of Dnmt1 and the de novo DNA methyltransferases Dnmt3a, and 3b in a tissue specific manner. The effect of MPR on the expression and methylation of GR and PPARα was also tissue specific. However, in most tissues examined there was not a simple inverse relationship between GR or PPARα expression and methylation or with levels of Dnmt1 expression. To assess how widespread the changes in gene expression induced by MPR are, microarray analysis was conducted in E8 embryos from control and PR fed dams and results were validated by RT-PCR. Results showed that only relatively small subsets of genes were affected by MPR or global dietary restriction (UN). Gene ontology analysis also revealed that similar pathways were altered under condition of both maternal PR and UN and interestingly one of the pathways altered by both maternal PR and UN was chromatin modification. In both PR and UN embryos on E8 a decrease in Dnmt1, Dnmt3a and 3b expression was observed as well as a decrease in the histone methyltransferases EZH2, Suv39H1 and the HDAC Sirt1 in the embryos from PR dams compared to controls. Alterations in the expression of the DNA and histone methyltransferases in response to MPR were accompanied by changes in DNA methylation and histone modification at the GR promoter as early as E14.

Foetal MRI represents a non-invasive imaging technique that allows detailed visualisation of foetus in utero and the maternal structure. This thesis outlines the quantitative imaging techniques used to investigate the effect of maternal diabetes and maternal smoking on foetal development at 1.5 Tesla. The effect of maternal diabetes on placental blood flow and foetal growth was studied. The placental images were acquired using Echo Planar Imaging and blood flow was measured using Intra Voxel Incoherent Motion. The results indicate that peak blood flow in the basal plate and chorionic plate increases across gestation in both normal and diabetic pregnancies. Conversely, diffusion in the whole placenta decreases across gestation, with a more pronounced decrease in diabetic placentae. Following this, a method was developed to use a Tl weighted fat suppressed MRI scan to quantify foetal fat images in-utero. In addition, HAlf Fourier Single-shot Turbo spin Echo (HASTE) and balanced Fast Field Echo (bFFE) were used to acquire images encompassing the whole foetus in three orthogonal planes. These scans were used to measure foetal volume, foetal length and shoulder width. The data shows that foetal fat volume and intra-abdominal fat were increased in foetuses of diabetic mothers at third trimester. The HASTE and bFFE sequences were also used to study the effect of maternal smoking on foetal development. Here, foetal organ volumes, foetal and placental volume, shoulder width and foetal length were measured using a semiautomatic approach based on the concept of edge detection and a stereological method, the Cavalieri technique. The data shows that maternal smoking has significant negative effect on foetal organ growth and foetal growth, predominantly foetal kidney and foetal volume. The work described here certainly has a great potential in non-invasive assessment of abnormal placental function and can be used to study foetal development.

Σκοπός: Επειδή η μεγαλύτερη συχνότητα της αναπτυξιακής δυσπλασίας του ισχίου στα θήλεα νεογνά μπορεί να οφείλεται σε ενδοκρινικούς παράγοντες και επίσης έχει βρεθεί ότι το κάπνισμα στη διάρκεια της εγκυμοσύνης προκαλεί ενδοκρινικές διαταραχές, αποφασίσαμε να μελετήσουμε την ανατομία του ισχίου σε νεογνά των οποίων οι μητέρες κάπνιζαν ή δεν κάπνιζαν στην διάρκεια της εγκυμοσύνης. Μεθοδολογία-σχεδιασμός μελέτης: Εξετάσθηκαν κλινικά και υπερηχογραφικά 2066 ισχία, εκ των οποίων 521 αρένων και 512 θηλέων νεογνών. Εξ’ αυτών 48 ήταν άρρενα και 53 θήλεα νεογνά, των οποίων οι μητέρες κάπνιζαν κατά την διάρκεια της εγκυμοσύνης. 93 Αποτελέσματα : Η μέση τιμή ±ΣΑ της γωνίας α στα άρρενα νεογνά των μητέρων οι οποίες δεν κάπνιζαν ήταν 62,3ο ± 5,1ο και των μητέρων οι οποίες κάπνιζαν κατά την εγκυμοσύνη ήταν 62,1ο ± 4,9ο (η διαφορά δεν είναι στατιστικά σημαντική). Στα θήλεα νεογνά των μη καπνιστριών και καπνιστριών μητέρων η α γωνία ήταν 60,7ο ± 5,3ο και 61,9ο ± 4,9ο αντίστοιχα (η διαφορά είναι σημαντική, p= 0,02). Η διαφορά μεταξύ αρρένων και θηλέων νεογνών, τα οποία γεννήθηκαν από μη καπνίστριες μητέρες είναι σημαντική (p<0,000001), ενώ δεν υπήρχε στατιστικώς σημαντική διαφορά μεταξύ αρρένων και θηλέων νεογνών που γεννήθηκαν από καπνίστριες μητέρες. Μεταξύ των θηλέων νεογνών, των οποίων οι μητέρες δεν ήταν καπνίστριες, ο αριθμός των νεογνών με ισχίο τύπου ΙΙα ή χειρότερου ήταν σημαντικά μεγαλύτερος από ότι μεταξύ εκείνων των θηλέων νεογνών, των οποίων οι μητέρες κάπνιζαν. Τα ευρήματα της κλινικής εξέτασης ήταν προς την ίδια κατεύθυνση με εκείνη των υπερηχογραφικών ευρημάτων, γεγονός το οποίο δείχνει ότι το μητρικό κάπνισμα κατά την εγκυμοσύνη προστατεύει το ισχίο στα θήλεα νεογνά. Συμπεράσματα: Το κάπνισμα της μητέρας κατά την διάρκεια της εγκυμοσύνης μειώνει την συχνότητα της υπερηχογραφικής και πιθανότατα της κλινικά διαπιστούμενης αναπτυξιακής δυσπλασίας του ισχίου στα θήλεα, αλλά όχι στα άρρενα νεογνά. Η προστασία του ισχίου η οποία προκαλείται από τον καπνό του τσιγάρου, μπορεί να έχει ενδοκρινική βάση. / Objective: Because the greater frequency of developmental dyplasia of the hip (DDH) in the female could have an endrocrine etiology and maternal smoking in pregnancy causes fetal endocrine disequilibrium, we investigated the anatomy of the hip in neonates of smoking (SM) and nonsmoking mothers (NSM). Study design: Clinical – sonographic examination was performed on 2066 hips of 521 male and 512 female neonates. In 48 male and 53 female neonates the mothers smoked during pregnancy. Results : The mean + SD a angle in the male neonates of the NSM was 62.3ο ± 5.1ο and of the SM 62.1ο ±4.9ο (NS). In the female neonates 95 of the NSM and the SM it was 60.7ο ±5.3ο and 61.9ο ±4.8ο, respectively (p=0.02). The difference between the male and the female neonates of the NSM is significant (p<0.000001), but there is no significant difference between the female neonates of the SM and the male neonates. Among the female neonates whose mothers were nonsmokers the number of those with hip Type IIa or worse was significantly greater that among those whose mothers were smokers. The clinical findings were in the same direction as those of the sonographic findings suggesting hip protection by maternal smoking in the female. Conclusions: Maternal smoking during pregnancy reduces the frequency of sonographic and possibly clinically detected DDH in female but not in male neonates. The tobacco – induced hip protection may have an endocrine basis.

Bibliography: leaves 284-298 / 4 microfiches (339 fr.) : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Summary: Shows that foetal acidosis is related to prolongation of the QT interval, a change which cannot be accounted for in foetal heart rate. Describes the configuration and time constants of the foetal electrocardiogram both during labour and at the time of delivery in normal and acidotic subjects. Confirms that foetal acidosis during labour is associated with acidosis at the time of delivery and with clinical depression of the newborn infant / Thesis (M.D.)--Dept. of Obstetrics and Gynaecology, University of Adelaide, 1970