Development of methods for analyzing phthalate-type plasticizers and bile acids in biological matrices : applications in different pathophysiological contexts ; Développements de méthodes d'analyse des plastifiants de type phtalates et des acides biliaires dans des matrices biologiques : applications dans différents contextes physiopathologiques

This thesis has two main focuses:1/ Plasticizers, including phthalates, have been identified as category 1b carcinogenic, mutagenic and reprotoxic (CMR) and as endocrine disruptors. Di-2-ethylhexyl phthalate (DEHP) is one of the most common plasticizers and is generally associated with polyvinyl chloride (PVC) in medical devices. As DEHP is not covalently bound to PVC, it can easily migrate into lipophilic matrices and then reach the bloodstream. It is metabolized by the liver into mono-2-ethylhexyl phthalate (MEHP), which is just as toxic. In recent years, alternative plasticizers to DEHP have been developed, notably di-2-ethylhexyl terephthalate (DEHT), which is metabolized in vivo to mono-2-ethylhexyl terephthalate (MEHT).The first part of this thesis involved developing methods for measuring plasticizers and their metabolites in various biological matrices, such as plasma. Two LC-MS/MS methods were developed for the determination of DEHP and MEHP as well as DEHT metabolites. As the ionization in mass spectrometry of DEHT is very low, a LC-UV method was developed to quantify this terephthalate. These methods have made it possible to estimate the release of DEHP and DEHT from blood bags and to measure their primary metabolites in blood products.2/ Bile acids (BA) are a large family of steroids made up of numerous species. They are synthesized in the liver and intestine and represent the main route of cholesterol catabolism. 7a-hydroxy-4-cholesten-3-one (C4) is the precursor of BA. BA play an essential role in lipid absorption but also in cell signaling, as they are ligands for the nuclear receptor 'Farnesoid X receptor' (FXR) and/or the G protein-coupled membrane receptor, TGR5. These receptors, and hence their ligands, are involved in glucose homeostasis, lipid homeostasis and energy expenditure. Any modulation of the BA profile can therefore lead to changes in metabolic homeostasis. The second part of this thesis involved developing two LC-MS/MS assay methods for 31 BA species and C4 in different biological ...