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Pharmaceuticals, such as the antidepressant venlafaxine (VFX), have been frequently detected in coastal waters and marine biota, and there is a growing body of evidence that these pollutants can be toxic to non-target marine biota, even at low concentrations. Alongside, climate change effects (e.g. warming and acidification) can also affect marine species' physiological fitness and, consequently, compromising their ability to cope with the presence of pollutants. Yet, information regarding interactive effects between pollutants and climate change related stressors is still scarce. Within this context, the present study aims to assess the differential ecotoxicological responses (antioxidant activity, heat shock response, protein degradation, endocrine disruption and neurotoxicity) of juvenile fish (Argyrosomus regius) tissues (muscle, gills, liver and brain) exposed to VFX (via water or feed), as well as to the interactive effects of warming (Delta T degrees C = +5 degrees C) and acidification (Delta pCO(2) similar to +1000 mu atm, equivalent to Delta pH = -0.4 units), using an integrated multi-biomarker response (IBR) approach.

Overall, results showed that VFX toxicity was strongly influenced by the uptake pathway, as well as by warming and acidification. More significant changes (e.g. increases surpassing 100% in lipid peroxidation, LPO, heat shock response protein content, HSP70/HSC70, and total ubiquitin content, Ub,) and higher IBR index values were observed when VFX exposure occurred via water (i.e. average IBR = 19, against 17 in VFX-feed treatment). The co-exposure to climate change-related stressors either enhanced (e.g. glutathione S-transferases activity (GST) in fish muscle was further increased by warming) or attenuated the changes elicited by VFX (e.g. vitellogenin, VTG, liver content increased with VFX feed exposure acting alone, but not when co-exposed with acidification). Yet, increased stress severity was observed when the three stressors acted simultaneously, particularly in fish exposed to VFX via water (i.e. average IBR = 21). Hence, the distinct fish tissues responses elicited by the different scenarios emphasized the relevance of performing multi-stressors ecotoxicological studies, as such approach enables a better estimation of the environmental hazards posed by pollutants in a changing ocean and, consequently, the development of strategies to mitigate them.