Pathogenesis of Male Reproductive Tract Lesions from Gestation Through Adulthood Following in Utero Exposure to Di(n-butyl) Phthalate

Abstract

Di( n-butyl) phthalate (DBP) acts as an antiandrogen by decreasing fetal testicular testosterone synthesis when male rats are exposed in utero. DBPexposed male rats develop malformations of the reproductive tract secondary to the reduced fetal androgen levels. However, these malformations and the associated histologic lesions have only been described in adult rats. The objective of this study was to describe the male reproductive tract lesions in fetal, early postnatal, and young adult male rats following DBP exposure in utero. Pregnant Sprague-Dawley rats were exposed to 500 mg/kg/day DBP by gavage on gestation days (GD) 12 to 21. Male reproductive tracts were examined on GD 16 to 21 and on postnatal days (PND) 3, 7, 16, 21, 45, and 70. In the fetal testes, large aggregates of Leydig cells, multinucleated gonocytes, and increased numbers of gonocytes were first detected on GD 17 and increased in incidence to 100% by GD 20 and 21. These lesions resolved during the early postnatal period, while decreased numbers of spermatocytes were noted on PND 16 and 21. On PND 45, there was mild degeneration of the seminiferous epithelium, which progressed to severe seminiferous epithelial degeneration on PND 70. On PND 70, the degeneration was concurrent with ipsilateral malformed epididymides, which caused obstruction of testicular fluid flow and secondary pressure atrophy in the seminiferous tubules. In the fetus, the epididymal lesion was observed as decreased coiling of the epididymal duct. The decreased coiling progressed into the early postnatal period and adulthood, at which time malformed epididymides were apparent. As the animals were only dosed in utero, these findings indicate that DBP can initiate fetal testicular and epididymal changes that may not manifest as clear malformations until adulthood. The pathogenesis of lesion development from the fetus to the adult is important for comparison of antiandrogens with differing modes of action.