Effects of in utero exposure to linuron on androgen-dependent reproductivedevelopment in the male Crl : CD(SD)BR rat

Linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) is a herbicide that blocks androgen action in the male rat. Studies were undertaken to charact erize the ability of linuron to activate transcription through the human an drogen receptor (AR) in vitro and to determine whether in utero linuron exp osure induces dose-responsive alterations in androgen-dependent reproductiv e development in the male rat. In vitro, linuron competitively antagonized transcriptional activity of the AR induced by dihydrotestosterone (DHT) in a dose-responsive manner with an equilibrium dissociation constant (K-B) of 75.8 x 10(-8) M. Pregnant rats were administered linuron by gavage at 0, 1 2.5, 25, or 50 mg/kg/day (n = 11/group) from gestation day 12 to 21. Anogen ital distance of resulting offspring was unaffected, whereas male areola/ni pple retention was increased in a dose-responsive manner. Hypoplastic teste s in adult offspring were seen in 2/56 rats (2/10 litters), 8/69 rats (4/11 litters), and 5/44 rats (3/8 litters), while hypoplastic epididymides occu rred in 1/56 rats (1/10 litters), 8/69 rats (4/11 litters), and 2/44 rats ( 1/8 litters) in the 12.5, 25, and 50 mg/kg/day dose groups, respectively. P artial agenesis of the epididymides was observed in 3/44 rats (2/8 litters) only in the 50 mg/kg/day group. These data indicate that in utero exposure to linuron preferentially impairs testosterone-mediated, rather than DHT-m ediated, reproductive development. This effect is distinctly different from the effects induced by flutamide, an AR antagonist that shares structural similarities with linuron. Furthermore, these data suggest that dose-respon se studies utilizing late gestational exposure to endocrine-active compound s may be more robust than the traditional or EPA-modified multigeneration p rotocols in identifying adverse effects. (C) 2000 Academic Press.