Over the past decade, a number of epidemiological studies have provided significant evidence that certain major adult noncommunicable diseases, such as hypertension, ischaemic heart disease and non-insulin dependent diabetes mellitus, may be associated with impaired fetal growth. This phenomenon has been termed "programming" which is essentially the term used for persisting changes in structure and function caused by undernutrition or other adverse influences acting during critical periods of early development. Programming has been used as the mechanistic basis to explain the long term sequelae of intrauterine growth retardation (IUGR). The mechanisms underlying the epidemiological observations remain to be elucidated and developed. While it is well established that severe maternal undernutrition during pregnancy leads to IUGR, there has been relatively little well defined animal studies of the somatotrophic axis and postnatal development of growth retarded offspring. The major objectives of this thesis were to establish a model in the rat of IUGR by nutritional restriction of the dam throughout gestation and to examine the effects of fetal growth retardation on endocrine, molecular and growth parameters during postnatal development. In addition, the development of an animal model for IUGR enabled well defined studies testing distinct hypotheses suggested by the epidemiological observations of professor David Barker and colleagues. Timed matings were performed in Wistar rats and dams were randomly assigned to one of two dietary treatment groups. A control group was fed ad libitum throughout pregnancy and a restricted group was fed 30% of ad libitum intake. Restricted fed dams were observed to lose a significant amount of body weight throughout gestation, due to undernutrition, but caught up to the ad libitum group during the lactating period. Maternal undernutrition significantly reduced fetal and placental weights without altering litter size. Postnatally, body weights of offspring from undernourished dams continued to be reduced until at least 18 weeks of age, although they were observed to be growing at the same rate as ad libitum offspring by 2 weeks of age. A cohort of animals from undernourished dams were maintained to measure blood pressure by tail cuff plethysmography. Offspring from undernourished dams were found to have significantly elevated systolic blood pressures from 18 weeks of age. This observation provides direct experimental support for the hypothesis, derived from human epidemiological studies, that the origin of adult hypertension may originate during fetal life as a result of exposure to a sub-optimal intrauterine environment. Parallel reductions in plasma IGF-I and hepatic IGF-I mRNA concentrations before 15 days of age were also observed in growth retarded offspring. Hepatic IGF-I transcription start sites within exon 1 and exon 2 were coordinately reduced with IUGR up to 15 days of age without changes in GHR and GHBP mRNA abundance. The lack of catch-up growth observed in the IUGR offspring despite normalization of their plasma IGF-I and IGF-I mRNA levels from 15 days of age may be due to a state of partial resistance to GH. This observation lead to a series of treatment studies in which neonatal and juvenile offspring from ad libitum and undernourished dams were treated with growth factors to investigate somatic growth responses as a measure for hormone sensitivity. In both treatment studies, ad libitum offspring from both age groups and juvenile IUGR offspring responded to GH treatment However, neonatal IUGR offspring did not exhibit any response to GH treatment.. Analysis of IGF-I gene expression in neonatal offspring showed that GH treatment elevated IGF-I Eb mRNA in ad libitum but not IUGR offspring. These results suggest a possible mechanism for transient GH resistance in that a post-receptor defect in GH action may contribute to the development of temporary postnatal GH resistance as a consequence of IUGR and fetal programming of IGF-I gene expression. In summary, the development of a model of IUGR in the rat using maternal undernutrition throughout gestation has enabled detailed investigation of nutritional regulation of the somatotrophic axis during fetal development and postnatal sequelae. The studies in this thesis have shown that the somatotrophic axis is markedly altered postnatally by nutritional restriction of the dam throughout gestation, leading to prolonged postnatal growth retardation and elevated blood pressure The mechanisms which lead to the induction of such fetal programming and whether these changes may contribute to the development of subsequent adult-onset disease remain to be addressed in future studies.
| Identifer | oai:union.ndltd.org:ADTP/277221 |
| Date | January 1998 |
| Creators | Woodall, Sonja Mary |
| Publisher | ResearchSpace@Auckland |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated., http://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm, Copyright: The author |
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