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IN VIVO AND IN VITRO ANTI-ANDROGENIC EFFECTS OF DE-71, A COMMERCIAL POLYBROMINATED DIPHENYL ETHER MIXTURE, IN THE RAT
Citation:
Stoker, T E., C R. Lambright, AND L E. Gray Jr. IN VIVO AND IN VITRO ANTI-ANDROGENIC EFFECTS OF DE-71, A COMMERCIAL POLYBROMINATED DIPHENYL ETHER MIXTURE, IN THE RAT. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
In Vivo and In Vitro Anti-androgenic Effects of DE-71, A Commerical Polybrominated Diphenyl Ether (PBDE) Mixture.
Stoker, T.E., Lambright, C.S. and Gray, L.E.
Endocrinology Branch, RTD, NHEERL, ORD, U.S. EPA, Research Triangle Park, NC.
PBDEs are synthesized in large quantities as flame retardants for commercial products, such as electronic equipment and textiles. The detection of PBDEs in tissues in wildlife species and in human milk and plasma samples has raised concerns about possible health effects. Recently, we showed that DE-71 delayed preputial separation (PPS) and suppressed the growth of androgen-dependent tissues in the Wistar rat following peri-pubertal exposure. These effects occurred concurrently with hypothyroidism and hepatomegaly and suggested that DE-71 may be either inducing steroid hormone metabolism or acting as an androgen receptor (AR) antagonist. To elucidate the anti-androgenic effects of this mixture, we evaluated DE-71 in several in vivo and in vitro assays. In a pubertal exposure study, we observed a delay in PPS with 30, 60 and 120 mg/kg/day of DE-71 (3, 4 and 5 days) and a suppression of ventral prostate (VP) and seminal vesicle growth. In another study, in which adult male rats were exposed to DE-71 for three days, luteinizing hormone, testosterone, androstendione and estrone concentrations were increased following exposure to 60 mg/kg/day. DE-71 and DE-100 (2, 4, 6-pentaBDE), one of the congeners in this mixture, both inhibited AR binding in a competition assay using rat VP cytosol (both with IC50s approximately 5 uM). In addition, both DE-71 and DE-100 inhibited DHT-induced transcriptional activation in MDA-kb2 cells. DE-71 was also positive for anti-androgenic activity in a weanling rat Hershberger assay. In conclusion, DE-71 and -100 have anti-androgenic activity, which appears to be mediated via AR antagonism. This alteration of androgen function may be the mechanism by which DE-71 delayed PPS and suppressed the growth of the androgen dependent tissues in the previous study. Additional studies are in progress to determine the specific (competitive verses noncompetitive) nature of the chemicals in the rat AR binding assays and to repeat the Hershberger assay. (Abstract does not necessarily reflect EPA policy.)