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PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE LEVELS BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF MALE RAT PUBERTY
Citation:
BLYSTONE, C., JONATHAN R. FURR, C. R. LAMBRIGHT, K. HOWDESHELL, B. C. RYAN, V. S. WILSON, G. A. LEBLANC, AND L. E. GRAY. PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE LEVELS BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF MALE RAT PUBERTY. Presented at Society for the Study of Reproduction, Omaha, NE, July 29 - August 01, 2006.
Description:
Prochloraz (PCZ) is an imidazole fungicide that has several endocrine modes of action. In vitro, PCZ inhibits steroidogenesis and acts as an androgen receptor (AR) antagonist. We hypothesized that pubertal exposure to prochloraz would delay preputial separation and growth of androgen-dependent organs. Sprague Dawley rats were dosed with PCZ (0, 31.25, 62.5, 125 mg/kg) from postnatal day (PND) 23 to 42 or 51. The timing of preputial separation (PPS), mid- and post-puberty organ weights (n=8-10), serum hormone levels, and ex vivo testicular steroid production were measured. The start and completion of PPS were significantly delayed, 1.1 and 1.8 days respectively, in the 125mg/kg treatment group. Epididymides and levator ani plus bulbocavernosus muscle (LABC) weights were decreased significantly in the 62.5 and 125mg/kg treatment groups at mid-puberty (PND42) while the ventral prostate and seminal vesicle weights were decreased in the 125mg/kg group at post-puberty (PND51). At all doses and time points serum testosterone and androstenedione levels were significantly decreased as was ex vivo androgen release from the testis. Serum progesterone and 17¿-hydroxyprogesterone levels were significantly increased at almost all treatment levels suggesting inhibition of CYP17. We also are examining the ability of PCZ to act as an AR antagonist in vivo by determining if PCZ antagonizes the effects of testosterone (sc) in the castrated-immature male rat. The data from the pubertal assay demonstrate that PCZ decreases testosterone levels and delays rat pubertal development. However, the effects on testosterone levels were observed at dose levels well below those that delayed puberty, which suggests that rather large reductions in serum testosterone may be required to delay puberty. It remains to be determined how potent, if at all, PCZ is in blocking androgen action in vivo. Research supported by NCSU EPA Co-op# CT 826512010. This abstract has been reviewed by the US EPA and does not necessarily reflect US EPA views or policy.