IN-UTERO AND LACTATIONAL EXPOSURE OF THE MALE-RAT TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN IMPAIRS PROSTATE DEVELOPMENT - 2 - EFFECTS ON GROWTH AND CYTODIFFERENTIATION

In the male Holtzman rat, in utero and lactational 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) exposure decreases prostate weight without inh ibiting testicular androgen production or decreasing circulating andro gen concentrations. Therefore, the present study sought to characteriz e effects of TCDD exposure on prostate development, from very early ou tgrowth from the urogenital sinus (Gestation Day [GD] 20) until rapid growth and differentiation are essentially complete (Posnatal Day [PND ] 32). Pregnant Holtzman rats were administered a single dose of TCDD (1.0 mu g/kg po) or vehicle on GD 15 and offspring were exposed via pl acental transfer (GD 20 euthanasia) or placental and subsequent lactat ional transfer until euthanasia (if before PND 21) or weaning. Results show that the prostatic epithelial budding process was impaired by in utero TCDD exposure, as evidenced by significant decreases in the num ber of buds emerging from dorsal, lateral, and ventral aspects of the GD 20 urogenital sinus. Ventral prostate cell proliferation index was significantly decreased on PND 1 but was similar to or higher than con trol at later times, whereas apoptosis was an extremely rare event in ventral prostates from both control and TCDD-exposed animals. Delays w ere noted in the differentiation of pericordal smooth muscle cells and luminal epithelial cells. In addition, ventral prostates from approxi mately 40% of TCDD-exposed animals examined on PNDs 21 and 32 exhibite d alterations in the histological arrangement of cell types that could not be explained by a developmental delay. Compared to controls, thes e ventral prostates exhibited a disorganized, hyperplastic epithelium containing fewer luminal epithelial cells and an increased density or continuous layer of basal epithelial cells, as well as thicker periduc tal smooth muscle sheaths. In addition, in ventral prostates from TCDD -exposed animals, the intensity of androgen receptor staining was rela tively low in the central and distal epithelium, and the number of and rogen receptor-positive cells was relatively high in the periductal st roma. These data suggest that in utero and lactational TCDD exposure i nterferes with prostate development by decreasing very early epithelia l growth, delaying cytodifferentiation, and, in the most severely affe cted animals, producing alterations in epithelial and stromal cell his tological arrangement and the spatial distribution of androgen recepto r expression that may be Of permanent consequence. (C) 1998 Academic P ress.