Comparison of antiandrogenic activities of vinclozolin and D,L-camphorquinone in androgen receptor gene transcription assay in vitro and mouse in utero exposure assay in vivo.
A chemical substance used as a photoinitiator for light-cure resin compositions, D,L-camphorquinone (CQN) was found to be weakly antiandrogenic in vitro. It competitively antagonized dihydrotestosterone (DHT)-induced transcriptional activity on the yeast-based androgen receptor gene transcription assay (YAA). Antiandrogenic activity of CQN was shown at higher concentration than 10(-4) M while the well-known antiandrogen, vinclozolin (VCZ) showed the activity at concentrations of 10(-6) M and above in YAA. The antiandrogenic activity of CQN was reconfirmed in the human cell line-based androgen receptor gene transcription assay (HCAA). To determine whether CQN affect male reproductive development, CQN or VCZ was administered to pregnant mice daily from gestational days 10 to 18 by gavage. In utero exposure to VCZ at 100 mg/kg/day caused a significant decrease in anogenital distance (AGD) of F1 neonates and reduced spermatogenesis in F1 males at 42 days of age. In contrast, maternal doses (100 and 300 mg/kg/day) of CQN had no affect on these endpoints in F1 offspring. Further, VCZ or CQN had no adverse affect on F1 male fertility. From these observations, CQN is potentially antagonistic to androgen receptor (AR) in vitro, but is estimated to be less antiandrogenic in vivo when it is administered to pregnant mice by gavage. Furthermore, these findings are the first to demonstrate that VCZ exerts significant antiandrogenic effects on reproductive tract development during gestation in mice.
Shimamura
Michiya
M
Analytical Research Center, Kuraray Co., Ltd., 2045-1 Sakazu, Kurashiki 710-8691, Japan. michiya_shimamura@kuraray.co.jp
Kodaira
Kazuhisa
K
Kenichi
Hino
H
Ishimoto
Yoichi
Y
Tamura
Hiroto
H
Iguchi
Taisen
T
D000726:Androgen Antagonists / Q000633:toxicity*; D059002:Androgen Receptor Antagonists; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D005260:Female; D005298:Fertility / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010080:Oxazoles / Q000633:toxicity*; D011247:Pregnancy; D011944:Receptors, Androgen / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013729:Terpenes / Q000633:toxicity; D013737:Testis / Q000187:drug effects / Q000473:pathology
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D010080:Oxazoles; D011944:Receptors, Androgen; D013729:Terpenes; C048339:camphoroquinone; C025643:vinclozolin