Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male but not female rat offspring.
Prochloraz (PZ) is an imidazole fungicide that displays multiple endocrine activities. It inhibits steroid synthesis via P450 modulation and acts as an androgen receptor (AR) antagonist, but its effects on male sexual differentiation have not been described. The purpose of the current study was to expand in vitro observations and to determine whether PZ affected sexual differentiation. PZ effects on AR-mediated gene expression were tested using a cell line (MDA-kb2) containing endogenous AR and stably transfected with an MMTV-luc reporter. PZ concentrations greater than 1 microM caused a dose-dependent inhibition of dihydrotestosterone-induced gene expression. PZ also inhibited R1881 binding to the rat AR (IC50 approximately 60 microM). In vivo, pregnant rats received PZ by gavage from Gestational Day 14 to 18 at doses of 31.25, 62.5, 125, and 250 mg/kg of body weight per day. PZ delayed delivery in a dose-dependent manner and resulted in pup mortalities at the two highest doses. In male offspring, anogenital distance and body weight were slightly reduced at 3 days of age. Additionally, female-like areolas were observed at 13 days of age at frequencies of 31%, 43%, 41%, and 71% in the lowest-dose to highest-dose groups, respectively. Weights of androgen-dependent tissues showed dose-dependent reductions. Hypospadias and vaginal pouches were noted in all males treated with 250 mg/kg, whereas those defects were observed in 12.5% and 6.25%, respectively, of males treated with 125 mg/kg. Treatment did not affect age of preputial separation in animals without penile malformations. Despite severe malformations in males, no malformations were noted in females. Together, these results indicate that PZ alters sexual differentiation in an antiandrogenic manner.
Noriega
Nigel C
NC
Endocrinology Branch, MD-72, RTD, NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. noriega.nigel@epa.gov
Ostby
Joseph
J
Lambright
Christy
C
Wilson
Vickie S
VS
Gray
L Earl
LE
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D059002:Androgen Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005659:Fungicides, Industrial / Q000378:metabolism / Q000494:pharmacology*; D005865:Gestational Age; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D036801:Parturition / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects*; D012733:Sex Differentiation / Q000187:drug effects; D012737:Sex Factors; D013737:Testis / Q000002:abnormalities / Q000473:pathology; D015533:Transcriptional Activation
D059002:Androgen Receptor Antagonists; D005659:Fungicides, Industrial; D007093:Imidazoles; D011944:Receptors, Androgen; C045362:prochloraz