Effects of perinatal exposure to flutamide on sex hormone responsiveness in F1 male rats.

Pregnant rats were administered flutamide (0 and 10 mg/kg, p.o.) from gestation Day 14 to post-parturition Day 3 and effects on responsiveness to androgens (testosterone propionate, TP; dihydrotestosterone, DHT) in male offspring were examined with a Hershberger assay. Male pups of each group were assigned to 6 subgroups as follows: Group 1, castration and euthanized at postnatal Day 46 (PND 46); Group 2, castration + vehicle; Group 3, castration + TP; Group 4, castration + DHT; Group 5, vehicle; Group 6, DHT. After castrations were conducted at PND 36, animals were treated with TP (2 mg/kg in corn oil, s.c.) or DHT (1.25 mg/kg in corn oil, s.c.) once a day for 10 days, beginning at PND 46. At PND 56, the following organs/tissues were removed and weighed: ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, levator ani muscle plus bulbocavernosus muscle, Cowper's gland, and glands penis. Analysis of serum testosterone, LH and FSH in Groups 2, 3, 4, 5 and 6, and RT-PCR using prostate tissue from Groups 2, 3 and 4 were carried out. Perinatal exposure to flutamide caused decreased weights of androgen-dependent organs. Responses to androgens were recognized in organs of all castrated groups, with increased organ weights, especially in animals administered TP where values were essentially equal to or greater than those of intact animals in both the control and the 10 mg/kg group. On the other hand, the degree of weight increase of the ventral prostate and seminal vesicles with TP or DHT treatment in castrated animals was smaller in the flutamide administration group than in the controls. In hormone assays, castrated + vehicle animals showed higher serum LH than the other groups. Serum FSH was high in the castrated groups (Group 2>Group 4>Group 3), while in the noncastrated group a constant level was noted, with or without flutamide. No effect of flutamide administration was observed regarding sex hormone. RT-PCR using ventral prostate tissue revealed no significant differences in expression of AR, C3, VEGF, TGF-beta1, beta2, KGF and CK8 mRNA after androgen treatment between the control and flutamide treatment groups. C3 mRNA was increased in androgen-treated animals, whereas AR, TGF-beta and KGF mRNAs were decreased. Perinatal exposure to anti-androgen causes irreversible abnormalities in male pups. Concerning the responsiveness to TP and DHT, the degrees of weight changes in ventral prostate and seminal vesicles in castrated animals were decreased. However, the other organ weights, the sex hormone levels and androgen-reactive gene expression in the ventral prostate were not influenced by perinatal flutamide treatment in the present study.