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SENSITIVITY OF FETAL RAT TESTICULAR STEROIDOGENESIS TO MATERNAL PROCHLORAZ EXPOSURE AND THE UNDERLYING MECHANISM OF INHIBITION
Citation:
BLYSTONE, C., C. R. LAMBRIGHT, K. HOWDESHELL, J. R. FURR, R. M. STERNBERG, B. C. BUTTERWORTH, E. J. DURHAN, E. A. MAKYNEN, G. T. ANKLEY, V. S. WILSON, G. A. LEBLANC, AND L. E. GRAY. SENSITIVITY OF FETAL RAT TESTICULAR STEROIDOGENESIS TO MATERNAL PROCHLORAZ EXPOSURE AND THE UNDERLYING MECHANISM OF INHIBITION. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 97(2):512-519, (2007).
Impact/Purpose:
This manuscript associates the reported adverse effects in androgen-dependent tissues of adult male rats after in utero prochloraz exposure to reduced fetal testis testosterone production. Prochloraz’s inhibition of testosterone production was partially identified using testis microsomes, generating a Ki value for CYP17 hydroxylase activity. Furthermore, the amniotic concentrations of prochloraz were quantified and associated with reduced testosterone production. Taken together, this manuscript characterizes one of prochloraz’s anti-androgenic mechanisms (enzyme inhibition), relates this mechanism to observed adverse effects in adult males, and compares this enzyme inhibition to prochloraz’s reported AR antagonism.
Description:
Since prochloraz (PCZ) is an imidazole fungicide that inhibits gonadal steroidogenesis and antagonizes the androgen receptor (AR), we hypothesized that pubertal exposure to PCZ would delay male rat reproductive development. Sprague Dawley rats were dosed by gavage with 0, 31.3, 62.5, 125 mg/kg/day of PCZ from postnatal day (PND) 23 to 42 or 51. There was a significant delay in preputial separation (PPS) by 125mg/kg/day PCZ and several of the androgen-dependent organ weights were decreased significantly, but the effects varied depending on the age at necropsy (42 vs 51). At both ages serum levels and ex vivo testosterone release from the testis were significantly decreased whereas serum progesterone and 17α-hydroxyprogesterone levels were significantly increased at dose levels below those that affected PPS or reproductive organ weights. The hormone results are indicative of an inhibition of CYP17 activity. In a second pubertal study, serum and ex vivo testosterone production were significantly reduced by 15.6 mg/kg/day PCZ. In order to examine the anti-androgenic effects of PCZ, independent of its effects on testosterone synthesis, castrated-immature male rats were dosed with androgen and 0, 15.6, 31.3, 62.5, 125 mg/kg/day for 10-11 days (Hershberger assay). In this assay, androgen-sensitive organ weights were only significantly decreased by 125 mg/kg/day PCZ. These data from the pubertal assays demonstrate that PCZ decreases testosterone levels and delays rat pubertal development, as hypothesized. However, the fact that hormone levels were affected at dosage eight fold below that delayed the onset of puberty suggests that rather large reductions in serum testosterone may be required to delay puberty and consistently reduce androgen-dependent tissue weights.
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SENSITIVITY OF FETAL RAT TESTICULAR STEROIDOGENESIS TO MATERNAL PROCHLORAZ EXPOSURE AND THE UNDERLYING MECHANISM OF INHIBITION