Chemistry and the Environment, Contributed Talk (15min)

Metabolomic Profiling and Toxicokinetics Modeling to Assess the Effects of the Pharmaceutical Diclofenac in the Aquatic Invertebrate Hyalella azteca

Q. Fu1, A. Scheidegger1, E. Laczko2, J. Hollender1,3
1Eawag, Swiss Federal Institute of Aquatic Science and Technology, 2Functional Genomics Center Zurich, 3ETH Zurich

The exposure of ecologically critical invertebrate species to biologically active pharmaceuticals poses a serious risk to the aquatic ecosystem. Yet, the fate and toxic effects of pharmaceuticals on these non-target aquatic invertebrates and the underlying mechanisms are poorly studied. Herein, we investigated the toxicokinetic (TK) processes (i.e., uptake, biotransformation, and elimination) of the pharmaceutical diclofenac and its biotransformation in the freshwater invertebrate Hyalella azteca. We further employed mass spectrometry-based metabolomics to assess the toxic effects of diclofenac on the metabolic functions of H. azteca exposed to environmentally relevant concentrations (10 and 100 µg/L). The TK results showed a quick uptake of diclofenac by H. azteca (maximum internal concentration of 1.9 µmol/kg) and rapid formation of the conjugate diclofenac taurine (maximum internal concentration of 80.6 µmol/kg), indicating over 40 times higher accumulation of diclofenac taurine than that of diclofenac in H. azteca. Depuration kinetics demonstrated that the elimination of diclofenac taurine was 64 times slower than diclofenac in H. azteca. Metabolomics results suggested that diclofenac inhibited prostaglandin synthesis similar to in humans and other species (e.g., zebrafish, rainbow trout, and marine musse). Furthermore, the carnitine shuttle pathway was affected at environmentally relevant concentrations. These findings shed light on the significance of the TK process of diclofenac, especially the formation of diclofenac taurine, as well as the sub-lethal effects of diclofenac on the bulk metabolome of H. azteca. Combining the TK processes and metabolomics provides complementary insights and, thus a better mechanistic understanding of the effects of diclofenac in aquatic invertebrates.