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PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF PUBERTY IN THE MALE SPRAGUE DAWLEY RAT
BLYSTONE, C., J. R. FURR, C. R. LAMBRIGHT, B. C. RYAN, K. HOWDESHELL, V. S. WILSON, G. A. LEBLANC, AND L. E. GRAY. PROCHLORAZ INHIBITS TESTOSTERONE PRODUCTION AT DOSAGE BELOW THOSE THAT AFFECT ANDROGEN-DEPENDENT ORGAN WEIGHTS OR THE ONSET OF PUBERTY IN THE MALE SPRAGUE DAWLEY RAT. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 97(1):65-74, (2007).
To determine whether pubertal exposure to prochloraz would delay male rat reproductive development
ABSTRACT: 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 17¿-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.
IMPACT STATEMENT: This manuscript describes the first pesticide to disrupt steroidogenesis in male rat pubertal development. An enhanced version of the pubertal protocol, which included serum and ex vivo hormone data, was used to measure the effects of prochloraz on pubertal development. The hormone data in this enhanced version increased the sensitivity of the assay while animal numbers were reduced. Furthermore, these data validated the ability of the pubertal protocol to detect chemicals that inhibit testosterone production.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
REPRODUCTIVE TOXICOLOGY DIVISION