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IN VIVO AND IN VITRO ANTI-ANDROGENIC EFFECTS OF DE-71
Citation:
STOKER, T. E., R. L. COOPER, C. R. LAMBRIGHT, V. S. WILSON, AND L. E. GRAY. IN VIVO AND IN VITRO ANTI-ANDROGENIC EFFECTS OF DE-71. Presented at Annual Brominated Flame Retardants Meeting, Baltimore, MD, June 13, 2005.
Description:
Recently, we showed that the PBDE mixture, DE-71, delayed preputial separation (PPS) and suppressed the growth of androgen-dependent tissues in the Wistar rat following a peri-pubertal exposure. These effects occurred concurrently with hypothyroidism and suggested that in addition to the effects on thyroid hormone homeostasis, 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 assays which are responsive to alterations in androgen activity. In a pubertal exposure study designed to further evaluate the delay in PPS, we observed a dose-dependent delay in PPS with 60 and 120 mg/kg/day of DE-71 (4 and 5 days) and a corresponding suppression of ventral prostate (VP) and seminal vesicle growth at both doses. Adult males exposed to DE-71 (3, 30 and 60 mg/kg) for three days resulted in a dose-related rise in the concentrations of luteinizing hormone, testosterone, androstendione and estrone. DE-71 also tested positive for anti-androgenic activity in a weanling rat Hershberger assay, with decreases in mean ventral prostate and seminal vesicle weight following doses of 30 to 240 mg/kg. DE-71 and the individual congeners which comprise the mixture (BDE-47, -99, -100, -153, -154) were also evaluated in vitro. AR binding was first evaluated in a competitive binding assay using rat ventral prostate cytosol. In addition, we evaluated gene activation in a transcriptional activation assay using the MDA-kb2 cell line which contains an endogenous human AR and a transfected luciferase reporter. DE-71 and BDE-100 (2, 4, 6-pentaBDE) both inhibited AR binding, with IC50s of approximately 5 �M. In addition, this mixture and two of the congeners (BDE-100 and BDE-47) inhibited DHT-induced transcriptional activation. The pattern of inhibition shown in the double-reciprocal plot for BDE-100 and the linear slope replot confirmed that the in vitro mechanism is pure competitive inhibition, with a inhibition constant (Ki ) of 1 �M. The anti-androgenic effects observed previously following exposure to DE-71 were likely due to this inhibition of AR binding by several of the congeners which make up this mixture. This abstract does not necessarily reflect EPA policy.