Effects of Perinatal Exposure to Flutamide on Sex Hormone Responsiveness in F1 Male Rats

Abstract

-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 (Group2>Group 4>Group3), 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.

Differential Effects of Flutamide and Di-(2-ethylhexyl) phthalate on Male Reproductive Organs in a Rat Model

“…In this study, in utero exposure to DEHP and Flu caused an increase in the number of nipples and /or areolae in a dose-dependent manner. Our results are in agreement with the previous reports [22,25].…”

“…In this study, in utero exposure to DEHP and Flu caused an increase in the number of nipples and /or areolae in a dose-dependent manner. Our results are in agreement with the previous reports [22,25]. We demonstrated in this study that DEHP and Flu interfered with the development of reproductive organs in a dose-dependent manner, in agreement with previous reports [12,26].…”

Sex differences in β-amyloid accumulation in 3xTg-AD mice: Role of neonatal sex steroid hormone exposure

“…Elevated testosterone and estrogen levels in neonates affect structural organization of several brain regions, particularly hypothalamic and hippocampal structures (Gore, 2008; McCarthy et al, 2008; Morris et al, 2004). Experimental manipulations that affect the normal developmental hormone levels results in neural changes that persist in the adult brain (Anderson et al, 2005; Bakker and Baum, 2008; Becu-Villalobos et al, 1997; Breedlove, 1997; Dominguez-Salazar et al, 2002; Houtsmuller et al, 1994; Isgor and Sengelaub, 1998; McCormick et al, 1998; McCormick and Mahoney, 1999; Miyata et al, 2003; Seale et al, 2005; Yang et al, 2004). Our data show that disruption of androgen signaling in neonatal male 3xTg-AD mice by administration of the androgen receptor antagonist flutamide resulted in elevated Aβ levels in CA1 hippocampus and subiculum.…”

“…Next, we assessed how the adult pattern of Aβ pathology is affected by disruption of the normal organizational effects of sex steroid hormones during critical developmental periods. Specifically, we defeminized neonatal female 3xTg-AD mice using transient testosterone treatment (Meek et al, 2006; Isgor and Sengelaub, 2003; Akhmadeev and Kalimullina, 2005) and demasculinized neonatal male 3xTg-AD mice by temporarily blocking testosterone action using the androgen receptor antagonist flutamide (Miyata et al, 2003; Houtsmuller et al, 1994; Meek et al, 2006; Kudwa et al, 2005). Alterations in adult pathology following these neonatal manipulations provide novel insight into the organizational role of sex steroid hormones on AD-related pathology.…”

Prenatal Exposure to Flutamide Induces Increased Keratinocyte Growth Factor mRNA, Irreversible Alteration of the Ductal Architecture, but No Change in Receptor Binding Capacity in the Rat Prostate Later in Life

“…However, it has remained controversial whether all the effects, including those on morphology and function, are actually irreversible. There have appeared reports describing effects of perinatal exposure to anti-androgens on subsequent responsiveness to androgens or anti-androgens [13][14][15] . Furthermore, other studies have revealed change of immunohistochemicallydemonstrable androgen receptor (AR) or nuclear AR concentrations in testis or prostate in adulthood after exposure to estrogenic or anti-androgenic compounds perinatally or prenatally 2,7 .…”