Using Zebrafish\nG Protein-Coupled Receptors to Obtain\na Better Appreciation of the Impact of Pharmaceuticals in Wastewater\nto Fish

Pharmaceutical discharge to the environment is of concern\ndue to\nits potential adverse effects on aquatic species. It is estimated\nthat around 40% of pharmaceuticals target G protein-coupled receptors\n(GPCRs). The <i>in vitro</i> transforming growth factor-<i>α</i> (TGF<i>α</i>) shedding assay was\napplied to measure the antagonistic activities of pharmaceuticals\nagainst human GPCRs. However, their ability to stimulate fish GPCRs\nremains unclear. Here, antagonistic activities of 30 pharmaceuticals\nagainst zebrafish dopamine (zD2a and zD2c), adrenergic family member\n(z<i>β</i>1), and histamine (zH1 and zH3) receptors\nwere measured by the TGF<i>α</i> shedding assay. The\nstudy found an interspecies difference in binding affinities between\nhuman and zebrafish: pharmaceuticals more strongly inhibited the zD2c\nand zH1 receptors than human D2 (hD2) and hH1 receptors, while zD2a\nand z<i>β</i>1 receptors were less inhibited than\nhD2 and h<i>β</i>1 receptors. The potential molecular\nexplanations for the observed interspecies differences in binding\naffinity for hydroxyzine and bisoprolol were investigated using molecular\ndocking. Pharmaceutical potency against zebrafish GPCRs and predicted\neffluent concentrations were used to predict equivalent quantities\n(EQs), and these EQs were used to prioritize pharmaceuticals of concern\nin wastewater in England and Japan. This study highlights the use\nof the TGF<i>α</i> shedding assay adopting zebrafish\nGPCRs to better understand the ecological effects of pharmaceuticals\non fish.