Adult male rats previously exposed on gestation days (GD) 12-21 to
di(n-butyl) phthalate (DBP) have reproductive tract malformations, particularly agenesis of the epididymis, decreased sperm production, and Leydig cell
hyperplasia and
adenomas. Although similar effects are produced by the potent
androgen receptor (AR) antagonist
flutamide and are indicative of disruption of male sexual differentiation via an antiandrogenic mechanism, DBP is not an AR antagonist. The purpose of the study was to determine whether DBP causes pathologic changes and alterations in
androgen status in the testis during the prenatal period of male reproductive tract differentiation. Pregnant CD rats were given
corn oil, DBP (500 mg/kg/day), or
flutamide (100 mg/kg/day) p.o. on GD 12-21. At GD 16-21, DBP caused
hyperplasia of Leydig cells, many of which were 3beta-hydroxysteroid
dehydrogenase- and/or AR-positive. Focal areas of
hyperplasia had increased numbers of Leydig cells positive for
proliferating cell nuclear antigen (
PCNA). At GD 21, testis
atrophy was apparent, seminiferous cords in DBP-exposed fetuses were enlarged and contained multinucleated gonocytes that, unlike controls, were
PCNA-positive. DBP, but not
flutamide, markedly decreased testicular
testosterone levels at GD 18 and 21. Fewer epididymal ducts and reduced AR staining in some ducts were evident with DBP treatment, whereas decreased overall AR staining was seen with
flutamide in the presence of mild Leydig cell
hyperplasia. Leydig cell proliferation is likely a compensatory mechanism to increase testicular steroidogenesis triggered by
testosterone insufficiency. The overall decrease in
androgen concentration is not corrected and results in reproductive tract malformations. The multinuclearity and proliferation of gonocytes suggests an underlying Sertoli cell dysfunction.