Abstract
This PhD thesis describes an investigation of the metabolomic approach performances to characterize the pharmaceuticals environmental exposure and effects in non target organisms. The studied pharmaceutical was diclofenac (DCF), a non-steroidal anti-inflammatory drug recently included in the first watch list of the European Water Framework Directive (2015/495/EC), and the model organism was the Mediterranean mussel Mytilus galloprovincialis. The methodological approach combines target and non-targeted analysis of endogenous and exogenous metabolites in mussel, the endo- and the xeno-metabolome. DCF effects in mussel were investigated considering its known mode of action in human: the prostaglandins (PG) synthesis modulation. In aquatic organisms, PGs are involved in various biological functions, such as reproduction or osmoregulation. This targeted analysis allowed us to determine a PGE2 synthesis disruption with DCF exposure. Otherwise, little information is available about DCF biotransformation in invertebrates. To study DCF biotransformation in mussel, the application of a non-targeted approach seemed promising. This study allows the reveal 13 DCF metabolites formation of which 3 were phase I metabolites and 10 were phase II metabolites. Among them, 5 were described for the first time. Subsequently, the mussel’s endo-metabolome study showed the modulation of two pathways: the tyrosine and the tryptophan metabolism. Inside these pathways, the catecholamines and serotonin appeared as particularly impacted. In mussels, these compounds are involved in important biological functions: the osmoregulation and the reproduction. Such DCF effects are in accordance with those reported in other study conducted on aquatic organisms. The work conducted highlighted the relevance and pertinence of the metabolomic approach as a tool for environmental studies without a priori hypothesis, such as studying the biotransformation and unexpected effects of pharmaceuticals in non-target organisms.