You are here:
Cross species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone
Citation:
LaLone, C., Dan Villeneuve, J. Cavallin, M. Kahl, E. Durhan, L. Makynen, K. Jensen, K. Stevens, M. Severson, C. Blanksma, K. Flynn, J. Woodard, J. Berninger, T. Norberg-King, R. Johnson, AND G. Ankley. Cross species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 32(11):2528-2541, (2013).
Impact/Purpose:
Spironolactone (SPL) is a pharmaceutical that is used in humans as an androgen receptor (AR) antagonist to treat conditions like hirsutism, various dermatologic afflictions, and female pattern hair loss, in addition to its common usage as a diuretic to treat hypertension. Although not routinely monitored, SPL has been detected downstream of a pharmaceutical manufacturer, signifying a potential for contact with aquatic species. Further, exposure of Western mosquitofish to SPL has been reported to cause female masculinization, indicative of AR activation. Predictive methods to identify homologous proteins to the human and Western mosquitofish AR suggest that vertebrates would be relatively sensitive to chemicals, like SPL, that target the AR compared to invertebrate species which lack a relevant homolog. Additionally, an adverse outcome pathway was previously developed for activation of the AR in fish, delineating key perturbations leading to reproductive toxicity. Together, this information was used to identify SPL as a potential chemical of concern to aquatic vertebrates. To assess the predicted toxicity, 21-d reproduction studies were conducted with two fish species, fathead minnow and Japanese medaka and the invertebrate Daphnia magna. Spironolactone significantly reduced fecundity of medaka and fathead minnows at concentrations of 5 and 50 µg/L, respectively, whereas daphnia reproduction was not affected at ≤500 µg/L. Masculinization of females of both fish species was observed at 0.5 µg/L and 5 µg/L as evidenced by formation of tubercles on fathead minnows and papillary processes on Japanese medaka. Effects in fish occurred at concentrations below those reported in the environment. These results demonstrate how a priori knowledge of an adverse outcome pathway and the conservation of a key molecular target across vertebrates can be utilized to identify potential chemicals of concern, susceptible species and key biomarkers for testing and/or environmental monitoring of contaminants of emerging concern.
Description:
Spironolactone (SPL) is a pharmaceutical that is used in humans as an androgen receptor (AR) antagonist to treat conditions like hirsutism, various dermatologic afflictions, and female pattern hair loss, in addition to its common usage as a diuretic to treat hypertension. Although not routinely monitored, SPL has been detected downstream of a pharmaceutical manufacturer, signifying a potential for contact with aquatic species. Further, exposure of Western mosquitofish to SPL has been reported to cause female masculinization, indicative of AR activation. Predictive methods to identify homologous proteins to the human and Western mosquitofish AR suggest that vertebrates would be relatively sensitive to chemicals, like SPL, that target the AR compared to invertebrate species which lack a relevant homolog. Additionally, an adverse outcome pathway was previously developed for activation of the AR in fish, delineating key perturbations leading to reproductive toxicity. Together, this information was used to identify SPL as a potential chemical of concern to aquatic vertebrates. To assess the predicted toxicity, 21-d reproduction studies were conducted with two fish species, fathead minnow and Japanese medaka and the invertebrate Daphnia magna. Spironolactone significantly reduced fecundity of medaka and fathead minnows at concentrations of 5 and 50 µg/L, respectively, whereas daphnia reproduction was not affected at =500 µg/L. Masculinization of females of both fish species was observed at 0.5 µg/L and 5 µg/L as evidenced by formation of tubercles on fathead minnows and papillary processes on Japanese medaka. Effects in fish occurred at concentrations below those reported in the environment. These results demonstrate how a priori knowledge of an adverse outcome pathway and the conservation of a key molecular target across vertebrates can be utilized to identify potential chemicals of concern, susceptible species and key biomarkers for testing and/or environmental monitoring of contaminants of emerging concern.
URLs/Downloads:
Cross species sensitivity to a novel androgen receptor agonist of potential environmental concern, spironolactone