Effects of perinatal exposure to flutamide on sex hormones and androgen-dependent organs in F1 male rats.

Abstract

Flutamide, which has antiandrogenic properties, was administered to pregnant rats, and effects on male offspring were examined. Crj: CD (SD) IGS (SPF) females were administered flutamide (0.15, 0.6, 2.5, 10.0, 100 mg/kg, p.o.) from gestation Day 14 to post parturition Day 3. The number of pups, body weights, clinical features, anogenital distance (AGD), nipple retention, testicular descent, and urogenital malformation in F1 males were examined. Hormone measurement, necropsy and histopathological examination were carried out at post-neonatal Day 4 (PND 4) and PND 60. Sperm analysis was also carried out at PND 60. Decrease in body weight was seen in the 100 mg/kg group and the AGD was decreased at 2.5 mg/kg and above. Retention of nipples, hypospadia, vaginal pouches, penis malformation, unilateral ectopic testis, and decrease of organ weights (prostate, seminal vesicles, levator ani muscle plus bulbocavernosus muscle, testis) were observed at 10 mg/kg and above. Testicular testosterone (T) was increased significantly with 100 mg/kg at PND 4 and tendencies for increase were observed in serum T, LH and FSH at 10 mg/kg and more at the same time point. In contrast, elevated levels of LH and FSH were seen with 100 mg/kg at PND 60. Histopathological examination revealed defects or hypoplastic changes of genital organs (> or = 10 mg/kg), squamous metaplasia (10 mg/kg) or mucification (100 mg/kg) of the urethral diverticulum epithelium and inflammation of genital organs (100 mg/kg). Though only undescended testes lacked spermatogenesis at 10 mg/kg, atrophic change of seminiferous tubules and azoospermia were observed in the 100 mg/kg group, despite testicular descent. Perinatal administration of flutamide affected F1 male rats at 2.5 mg/kg and above. In addition to urogenital malformation, 100 mg/kg flutamide caused high LH and FSH levels at PND 60. This study indicates that the most sensitive parameter is AGD, whereby reduction was observed at 2.5 mg/kg. A clear no-effect level (NOEL: 0.6 mg/kg) was obtained in this perinatal study of an antiandrogenic chemical.

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

“…Miyata et al (2002) reported that oral administration of flutamide at ≥ 2.5 mg/kg/day from GD 14 to PND 3 decreased AGD, and McIntyre et al (2001) observed similar findings at oral doses of 6.25 mg/kg/day. In our study too, decreased AGD was induced from low dose while abnormalities of the internal genitalia (e.g., prostate hypoplasia) occurred at 10 mg/kg and higher.…”

“…ers have reported similar effects of flutamide (Miyata et al, 2002;McIntyre et al, 2001) and other antiandrogen agents (Shono et al, 2004;Barlow et al, 2004;Ema et al, 2003;Bowman et al, 2003) on sexual maturity in males. Miyata et al (2002) reported that oral administration of flutamide at ≥ 2.5 mg/kg/day from GD 14 to PND 3 decreased AGD, and McIntyre et al (2001) observed similar findings at oral doses of 6.25 mg/kg/day.…”

“…Several investigators have also reported that exposure to antiandrogens such as flutamide during pregnancy is associated with feminization of sexual maturation and behavior in male offspring Gladue and Clemens, 1978;Brand and Slob, 1991;Vega Matuszczyk and Larsson, 1995). Miyata et al (2002), using rats treated with flutamide from late pregnancy to postnatal Day 3, reported abnormalities in AGD, testicular descent and external genitalia, and decreased weights of accessory reproductive organs in F1 male offspring. Effects on sex hormone levels (increased LH, FSH and T) were also noted, and sperm studies identified decreased sperm counts and abnormal morphology.…”

“…Flutamide is commonly used for treatment of prostate cancer (Balk, 2002), and is also widely used in research on endocrine disrupters. Suppressive effects of flutamide on sexual maturation and behavior have been reported in rats when administered during the perinatal period Brand and Slob, 1991;Zimmerberg and Farley, 1993;Lund et al, 2000) or to offspring immediately after birth Clemens, 1978, 1980;Clemens et al, 1978;Brand and Slob, 1991;Vega Matuszczyk and Larsson, 1995;Miyata et al, 2002). Other chemicals such as antiandrogen drugs finasteride (Clark et al, 1990(Clark et al, , 1993Wise et al, 1991;Imperato-McGinley et al, 1992) and cyproterone acetate , and the estrogen-like chemical bisphenol A (Sato et al, 2001;Cagen et al, 1999) have been reported to cause various changes in morphology of the external genitalia and sexual maturation of the offspring born to mothers treated with these chemicals during pregnancy.…”

Impairment on sperm quality and fertility of adult rats after antiandrogen exposure during prepuberty

“…We elected to attempt to alter the differentiation of the epididymis with flutamide, a potent non-steroidal antiandrogen [9] that competes for the androgen receptor and is capable of reducing the physiological action of testosterone on target tissues when endogenous tissue levels of androgen are submaximal [10,11]. Between PND 21 and 44 androgen levels in the epididymis are on the rise, but far less than adult levels [8].…”