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Probing the impact of the maternal environment on foetal development: Can high-resolution telomere analysis predict prenatal adversity?

Garcia Martin, Isabel 2019. Probing the impact of the maternal environment on foetal development: Can high-resolution telomere analysis predict prenatal adversity? PhD Thesis, Cardiff University.
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Abstract

Telomeres are nucleoprotein structures located at the end of eukaryotic chromosomes. They maintain genomic stability avoiding fusion and degradation events. Telomeres shorten as cells divide and the length of a telomere is related to its function. Studies in animal models and humans suggest that telomere shortening contributes to the development of cancer, several age-related diseases and premature ageing syndromes. In the context of human pregnancy, it has been hypothesised that in utero exposure to different forms of physiological stress can impact the telomere biology of the foetus accelerating dysfunction, ageing and disease risk. Given the potential importance of critically shortened telomeres, detecting and using them as a biomarker of pregnancy complications linked to placental dysfunction is of significant interest. The primary aim of this thesis was to utilise single telomere length analysis (STELA), a high-resolution single-molecule technique, to examine telomere length distributions at individual chromosome ends in the human placenta. Telomere length profiles were obtained from placental samples from two different human cohort studies, including healthy pregnancies and pregnancies complicated by prenatal depression and gestational diabetes. Placental telomeres were also analysed in relation to maternal lifestyle factors. STELA revealed no effect of sampling site, mode of delivery or foetal sex on telomere length when placenta from healthy pregnancies were examined. However, the first novel finding was that human placenta exhibit substantial telomere length heterogeneity, that may be related to the number of cell divisions taken to generate the term tissue. GDM did not impact the telomere length distributions in placenta from female infants, but placental telomeres from male infants exposed to GDM in medically untreated pregnancies were significantly shorter than placental telomeres from control male infants (P = 0.02). This was not observed in GDM pregnancies treated with metformin and/or insulin (P = 0.003). In contrast to GDM, prenatal depression symptoms were associated with telomere shortening in female placenta but not male placenta (P = 0.026). In conclusion, this work suggests that prenatal adversities can have a sexually dimorphic impact on placental telomere length and distribution detectable using STELA. Telomere length therefore provides a useful biomarker of prenatal adversities.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Date of First Compliant Deposit: 19 December 2019
Last Modified: 20 Dec 2019 15:12
URI: http://orca.cf.ac.uk/id/eprint/127661

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