Proefschr. Rijksuniversiteit Groningen. / Met lit.opg. - Met samenvatting in het Nederlands en Duits.

Proefschrift Rijksuniversiteit Limburg, Maastricht. / Met lit. opg. - Met een samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met samenvatting in het Nederlands. - Met lit. opg.

Th.--Sci. nat.--Paris 6, 1978.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Maastricht. / Met lit. opg. - Met een samenvatting in het Engels.

Proefschrift Universiteit Maastricht. / Teksten in het Engels en Nederlands. - Auteursnaam op omslag: Henk van Dam. Met bibliogr., lit. opg. - Met samenvatting in het Engels.

This work aimed to better understand the early molecular events occasioned in human thyrocytes following exposure to genotoxic agents than can lead to thyroid mutagenesis and cancer. Similar in vitro data in human physiological models remain scarce.The reported incidence of papillary thyroid carcinoma (PTC), has been increasing worldwide but the pathogenesis of sporadic PTC remains unravelled. H2O2 has long been postulated by the host laboratory and by other groups as a potential thyroid mutagen since it is capable to cause DNA damage and it affects γ radiation-induced DNA damage in thyrocytes. Thyrotropin (TSH) has recently been advocated as a potential risk factor for PTC: it has been associated with advanced stage disease and with progression of microcarcinoma during active surveillance. TSH signalling was found to be essential for BRAF-induced thyroid carcinogenesis in mouse models. Radiation (γ and β) is the only clearly established environmental risk factor for PTC; the cancer relative risk is rising linearly beyond a threshold of 100mGy thyroid absorbed dose. We studied in human thyrocytes in primary cultures the early molecular events following 131I exposure (β radiation) in comparison to γ radiation and H2O2 exposure, and their modulation by TSH. We assessed cell survival, DNA damage, DNA repair, gene expression, cell proliferation and apoptosis. Although we globally observed that the thyrocyte responses following exposure to β, γ radiation or H2O2 showed similarities, TSH, unlike other proliferative agents tested, specifically increased DNA damage both in non-exposed and in 131I-exposed thyrocytes. TSH did not influence γ radiation- or H2O2-induced damage. The effect of TSH on DNA damage in non-exposed thyrocytes decreased after incubation with an antioxidant agent and in 131I-exposed thyrocytes was partially alleviated after inhibition of iodide uptake. Therefore, in our experimental conditions, TSH seemed to predispose thyroid cells to greater DNA damage after exposure to 131I via Gαq-mediated increase in ROS/H2O2 levels, independent of its action on iodide uptake or proliferation status. DNA repair timing was similar between β, γ radiation and H2O2. Both β and γ radiation resulted in an extended thyroid cell cycle arrest but no apoptosis. In contrast, H2O2 did not appear to affect cell cycle at the same extent.This works includes the first, to our best knowledge, RNA sequencing to obtain the gene expression profile of human thyrocytes following 131I exposure. Overall transcriptional responses of thyrocytes exposed to 131I, γ radiation and H2O2 overlapped. At this stage, we were not able to attribute a distinct molecular signature to each agent, pointing that they probably employ similar cellular toxicity mechanisms. Regulated genes were involved in inflammatory response, cytokine signaling, DNA repair, apoptosis and cell cycle. Again, TSH yielded a more prominent transcriptomic response, both in number and in expression level of regulated transcripts, exclusively following 131I exposure. Better understanding of the early stages of thyroid carcinogenesis could lead to a more precise, personalized management of thyroid cancer patients and even in novel therapeutic strategies. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

Proefschrift Universiteit Maastricht. / Auteursnaam op omslag: Frank R.M. Stassen. Met bibliogr. van de auteur, lit. opg. - Met samenvatting in het Nederlands.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.