Mechanisms of cellular and molecular responses in Mytilus galloprovincialis exposed to human pharmaceuticals ibuprofen, paroxetine and their mixture

The toxicological effects of pharmaceutical mixtures on marine ecosystems remain poorly understood, representing a significant research gap. This study investigated the interactions between ibuprofen (IBU) and paroxetine (PAR), two of the most consumed pharmaceuticals in Europe, by characterizing the molecular and cellular mechanisms behind their modes of action (MOAs) in non-target species. Mussels, Mytilus galloprovincialis were exposed to representative environmental concentrations (1 μg/L) of IBU and PAR, dosed alone and as a mixture, for 30 days, followed by a 14-days recovery period. A multidisciplinary approach was applied, combining measurements of drugs bioaccumulation, transcriptomic responses, a wide range of biochemical, cellular biomarkers, and microbiota analysis. The overall results suggested MOA of the two drugs in mussels similar to those reported for target species. PAR-driven effects were clearly observed, particularly in terms of perturbation of redox homeostasis and impairment of lipid metabolism. Remarkable competing effects were also highlighted including a lower uptake of IBU when in mixture with PAR, along with changes on biotransformation, metabolism, and excretion processes at transcriptional level. At the end of the depuration period, mussels showed an almost complete elimination of previously accumulated drugs which, however, did not reflect their capability to restore physiological homeostasis, both in terms of detrimental molecular, cellular effects and changes in bacterial communities. Overall, these findings suggest the need to consider complex environmental interactions when assessing the long-term impacts of pharmaceuticals in marine ecosystems.