title: Prochloraz inhibits testosterone production at dosages below those that affect androgen-dependent organ weights or the onset of puberty in the male Sprague Dawley rat.
abstract: Prochloraz (PCZ) is an imidazole fungicide that inhibits gonadal steroidogenesis and antagonizes the androgen receptor (AR). We hypothesized that pubertal exposure to PCZ would reduce testosterone production and delay male rat reproductive development. Sprague Dawley rats were dosed by gavage with 0, 31.3, 62.5, or 125 mg/kg/day of PCZ from postnatal day (PND) 23 to 42 or 51. There was a significant delay in preputial separation (PPS) at 125 mg/kg/day PCZ and several of the androgen-dependent organ weights were decreased significantly, but the significant organ weight effects were not consistent between the 2 necropsies (PND 42 vs. 51). At both ages, serum testosterone levels and ex vivo testosterone release from the testis were significantly decreased whereas serum progesterone and 17alpha-hydroxyprogesterone levels were significantly increased at dose levels below those that affected PPS or reproductive organ weights. The hormone results suggested that PCZ was inhibiting CYP17 activity. In a second pubertal study (0, 3.9, 7.8, 15.6, 31.3, or 62.5 mg/kg/day PCZ), serum testosterone levels and ex vivo testosterone production were significantly reduced at 15.6 mg/kg/day PCZ. In order to examine the AR antagonism 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, or 125 mg/kg/day PCZ for 10-11 days (Hershberger assay). In this assay, androgen-sensitive organ weights were only significantly decreased at 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 eightfold below that which 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.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Blystone
authors.forename: Johnathan
authors.initials: J
authors.lastname: Furr
authors.forename: Christy S
authors.initials: CS
authors.lastname: Lambright
authors.forename: Kembra L
authors.initials: KL
authors.lastname: Howdeshell
authors.forename: Bryce C
authors.initials: BC
authors.lastname: Ryan
authors.forename: Vickie S
authors.initials: VS
authors.lastname: Wilson
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Leblanc
authors.forename: Leon Earl
authors.initials: LE
authors.lastname: Gray
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000726:Androgen Antagonists / Q000633:toxicity*; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005659:Fungicides, Industrial / Q000633:toxicity*; D005837:Genitalia, Male / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism; D007093:Imidazoles / Q000633:toxicity*; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011374:Progesterone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D046468:Sexual Development / Q000187:drug effects*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000378:metabolism*; D043343:Testosterone Propionate / Q000494:pharmacology; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D004791:Enzyme Inhibitors; D005659:Fungicides, Industrial; D007093:Imidazoles; D011944:Receptors, Androgen; D013739:Testosterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; C045362:prochloraz; D013254:Steroid 17-alpha-Hydroxylase; D043343:Testosterone Propionate