Birth defects seen after teratogen exposure depend on the nature of the insult and the stage of development of the embryo. Many teratogens induce DNA damage in the organogenesis-stage conceptus; the consequences of this insult depend on the extent of the damage and on the ability of the embryo to repair DNA. The hypothesis for this thesis is that DNA repair capacity plays a role in the response of the conceptus to DNA-damaging teratogens. The first objective of this thesis was to elucidate the expression profile of DNA repair pathway genes during mid-organogenesis (gestational days 10--12) in the rat, a period during which the conceptus is most susceptible to the malformations induced by genotoxic teratogens. Four main repair pathways were examined: the nucleotide excision repair, base excision repair, mismatch repair, and recombination repair pathways. The genotoxic stress-activated cell cycle checkpoint pathway was also examined. Genes from these pathways showed developmental time-specific alterations in transcript and protein levels, as well as activity. Differences in expression between yolk sac and embryo proper were observed at the transcript, protein, and activity levels. / The second goal of this thesis was to determine whether DNA repair machinery expression and activity are modified in the conceptus following exposure to teratogens. Changes in gene transcript, protein, and activity levels were observed following embryo culture with three known teratogens (cyclophosphamide, oxidative stress, methotrexate). While one base excision repair gene increased in expression, the remaining repair genes examined either did not change transcript levels or decreased in expression following teratogen exposure, indicating a near complete inability to induce a DNA repair response following genotoxic stress. These results demonstrate that differential expression and regulation of DNA repair genes and gene products exist in the mid-organogenesis stage rat conceptus, and that the conceptus has a limited capacity to alter DNA repair responses at the transcript, protein, or activity level following genotoxic teratogen exposure.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38432 |
| Date | January 2001 |
| Creators | Vinson, Robert Kenneth. |
| Contributors | Hales, Barbara F. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001861976, proquestno: NQ78793, Theses scanned by UMI/ProQuest. |
Page generated in 0.0019 seconds