Effects of flutamide on puberty in male rats: an evaluation of the protocol for the assessment of pubertal development and thyroid function.
To establish a test protocol for the rodent 20-d thyroid/pubertal assay, flutamide, a non-steroidal androgen antagonist, was administered to intact male Sprague-Dawley rats from postnatal d 33 for 20 d, and several reproductive endpoints were examined to assess the sensitivity of a number of parameters with respect to the detection of endocrine-related effects. Immature male rats were divided into 4 groups and given flutamide once daily by oral gavage at doses of 0, 1, 5, or 25 mg/kg/d. Prepuce separation was significantly delayed in flutamide-treated rats (5 and 25 mg/kg/d). One day after the last dose, the rats were sacrificed. Flutamide treatment resulted in a significant reduction in the weights of epididymides, ventral prostate, seminal vesicles plus coagulating glands and fluid, levator ani plus bulbocavernosus muscles, Cowper's glands, and glans penis. The weight of adrenal glands decreased at 25 mg/kg/d, while testes and any other organ weights were unaffected. No microscopic changes were observed in the thyroid glands. Serum levels of testosterone were significantly increased in the flutamide-treated groups (5 and 25 mg/ kg/d) and serum levels of estradiol were also increased (25 mg/kg/d). No differences were observed in the serum thyroxine levels. These results indicate that flutamide delays puberty in the male rat, and its mode of action appears to be via altered secretion of steroids, which subsequently affect the development of the reproductive tract. Thus, this assay might be used as an alternative for screening antiandrogenic activities of chemicals.
Shin
Jae-Ho
JH
Endocrine Toxicology Division, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul.
Kim
Hyung Sik
HS
Moon
Hyun Ju
HJ
Kang
Hyun
H
Kim
Tae Sung
TS
Seok
Ji Hyun
JH
Kim
In Young
IY
Park
Kui Lea
KL
Han
Soon Young
SY
Nam
Sang Yoon
SY
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004334:Drug Administration Schedule; D023381:Endpoint Determination; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology*; D005837:Genitalia, Male / Q000187:drug effects* / Q000473:pathology; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000726:Androgen Antagonists; D012739:Gonadal Steroid Hormones; D005485:Flutamide