Disruption of androgen-regulated male reproductive development by Di(n-butyl) phthalate during late gestation in rats is different from flutamide

Gestational and lactational exposure to di(n-butyl) phthalate (DBP) at grea ter than or equal to 250 mg/kg/day disrupts male rat reproductive developme nt and function. Although this indicates an antiandrogenic mechanism, DBP a nd its biologically active metabolite do not interact with the androgen rec eptor (AR) in vitro. In the present study, we compared the effects of DBP a nd the antiandrogen flutamide using a shorter exposure during the prenatal period of male sexual differentiation in rats. Pregnant CD rats received DB P at 0, 100, 250, or 500 mg/kg/day po (n = 10) or flutamide at 100 mg/kg/da y po (n = 5) from Gestation Days 12 to 21. In F-1 males, DBP (500 mg/kg/day ) and flutamide caused hypospadias; cryptorchidism; agenesis of the prostat e, epididymis, and vas deferens; degeneration of the seminiferous epitheliu m; and interstitial cell hyperplasia of the testis. Flutamide and DBP (250 and 500 mg/kg/day) also produced retained thoracic nipples and decreased an ogenital distance. Interstitial cell adenoma occurred at 500 mg DBP/kg/day in two males. The only effect seen at 100 mg DBP/kg/day was delayed preputi al separation. In contrast to flutamide, DBP caused a low incidence of pros tate agenesis and hypospadias with no vaginal pouch. The low incidence of D BP-induced intraabdominal testes contrasted with the high incidence of ingu inal testes seen with flutamide. Thus prenatal male sexual differentiation is a sensitive period for the reproductive toxicity of DBP. A no observed a dverse effect level was not established and the lowest observed (adverse) e ffect level was 100 mg/kg/day. Flutamide and DBP disrupted the androgen sig naling necessary for male sexual differentiation but with a different patte rn of antiandrogenic effects. DBP is an example of an environmental antiand rogen that disrupts androgen-regulated male sexual differentiation without interacting directly With the AR, as does flutamide. (C) 1999 Academic Pres s.