Abstract
The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L−1, respectively) followed by promethazine (1.6 and 0.18 mg L−1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L−1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.
Highlights
Pharmaceutical residues are ubiquitous in the environment due to extensive human and veterinary use
The presence of drug target orthologs in D. magna was positively associated with the responses to the pharmaceuticals tested
In the animals exposed to miconazole and promethazine, which have identified drug targets in daphnids, significant effects on reproduction, mortality, RNA content and gene expression were observed
Summary
Pharmaceutical residues are ubiquitous in the environment due to extensive human and veterinary use. To achieve optimal therapeutic function, pharmaceuticals are chemically designed to fit specific molecular targets [2,3], which are often evolutionary conserved and have orthologs in a variety of organisms [4] This raises concerns regarding potential impacts of pharmaceutical pollution on nontarget organisms that have high similarity of molecular targets, such as receptors and enzymes, with humans (so called, the readacross hypothesis [5]). Adverse effects on these organisms may occur already at environmentally relevant concentrations that are well below LC50 (i.e., concentration at which 50% mortality occurs) determined in acute tests. It should be possible to use information on various downstream toxicological effects derived from measuring multiple endpoints across different levels of biological organization for drug screening
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