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Identification of a novel androgen receptor agonist (or “androgen mimic”) of environmental concern: spironolactone
LaLone, C., D. Villeneuve, M. Kahl, E. Durhan, L. Makynen, K. Jensen, J. Cavallin, K. Stevens, M. Severson, J. Berninger, AND S. Skolness. Identification of a novel androgen receptor agonist (or “androgen mimic”) of environmental concern: spironolactone. Presented at Society for Environmental Toxicology and Chemistry, November 11 - 15, 2012.
Spironolactone is a pharmaceutical that acts as an androgen receptor (AR) antagonist in humans to treat certain conditions such as hirsutism, various dermatologic afflictions, and female pattern hair loss. The drug is also used to treat hypertension as a diuretic. With this common usage in humans it is conceivable that spironolactone could enter aquatic environments, and indeed has been detected downstream of a pharmaceutical manufacturer. Predictive methods to analyze human AR orthology suggest that vertebrates would be highly sensitive to chemicals that target the AR compared to invertebrate species. As a means to assess the predictive nature of molecular target orthology leading to unintended effects, 21-d reproduction studies were conducted with two fish species, Pimephales promelas (fathead minnow) and Oryzias latipes (Japanese medaka) and the invertebrate Daphnia magna. Spironolactone significantly reduced fecundity of medaka and fathead minnows at test concentrations of 50 and 5 µg/L, respectively, whereas Daphnia reproduction was not affected at 500 µg/L. Masculinization of females of both fish species was observed at 5 µg/L and 0.5 µg/L as evidenced by development of papillary complexes on medaka and tubercle formation on fathead minnows, respectively. Effects in fish occurred at concentrations below those reported in the environment. These results suggest that species with greater orthology to the human AR are susceptible to spironolactone. Further, this drug has the potential to affect reproduction in fish and should be included in environmental monitoring for contaminants of emerging concern.