Inhibition of Fin Regeneration in Fathead Minnow (<i>Pimephales promelas</i>) by a Potent Synthetic Glucocorticoid and Development of Adverse Outcome Pathway 334

Despite structural and functional conservation across vertebrate species, the glucocorticoid receptor has been minimally studied in comparison to other biological targets for endocrine-disrupting compounds in aquatic systems. Because prolonged use of pharmaceutical glucocorticoids in humans has been linked to osteoporosis and impaired bone growth, we hypothesized that the ability of teleost fish to regenerate fins following damage may be inhibited by exposure to synthetic glucocorticoids in the environment. In the present study, we examined fin regeneration following a 7 days waterborne exposure of juvenile fathead minnows (<i>Pimephales promelas</i>) to the synthetic glucocorticoids, fluticasone propionate and dexamethasone. Expression of several biologically relevant gene products (<i>sgk1, tdgf1, runx2a, lef1, shha</i>, and <i>tsc22d3</i>) was measured in paired caudal fin and whole-body tissues. Fluticasone propionate and dexamethasone significantly impaired fin regeneration at measured water concentrations of 2.62 μg/L and 4.62 mg/L, respectively. Changes in gene expression indicated disruption of intercellular communication in the Wnt/β-catenin and bone morphogenetic protein (BMP) signaling pathways after exposure to 4.86 μg/L fluticasone propionate. Upregulation of <i>tsc22d3</i>, a transcription factor responsible for suppression of anti-inflammatory response, may be the plausible cause of repressed cellular signaling. These findings advance the development of adverse outcome pathway 334─Glucocorticoid Receptor Activation Leads to Impaired Fin Regeneration─and elucidate both the mechanistic relationship between activation of the glucocorticoid receptor by fluticasone propionate and inhibition of fin regeneration, which could plausibly reduce individual fitness in aquatic systems.