Mixtures of environmental pharmaceuticals in marine organisms: Mechanistic evidence of carbamazepine and valsartan effects on Mytilus galloprovincialis

Unravelling the adverse outcomes of pharmaceuticals mixture represents a research priority to characterize the risk for marine ecosystems. The present study investigated, for the first time, the interactions between two of the most largely detected pharmaceuticals in marine species: carbamazepine (CBZ) and valsartan (VAL), elucidating mechanisms that can modulate bioaccumulation, excretion and the onset of toxicity. Mytilus galloprovincialis were exposed to environmental levels of CBZ and VAL dosed alone or in combination: measurement of drug bioaccumulation was integrated with changes in the whole transcriptome and responsiveness of various biochemical and cellular biomarkers. Interactive and competing mechanisms between tested drugs were revealed by the much higher CBZ accumulation in mussels exposed to this compound alone, while an opposite trend was observed for VAL. A complex network of responses was observed as variations of gene expression, functional effects on neurotransmission, cell cycle, immune responses and redox homeostasis. The elaboration of results through a quantitative Weight of Evidence model summarized a greater biological reactivity of CBZ compared to VAL and antagonistic interactions between these compounds, resulting in a reduced effect of the antiepileptic when combined with valsartan. Overall, new perspectives are highlighted for a more comprehensive risk assessment of environmental mixtures of pharmaceuticals.