Neonatal treatment of rats with diethylstilboestrol (DES) induces stromal-epithelial abnormalities of the vas deferens and cauda epididymis in adulthood following delayed basal cell development

Abstract

This study investigated whether transient, neonatal (days 2-12) treatment of rats with the potent oestrogen, diethylstilboestrol (DES), altered the structure of the cauda epididymis/vas deferens in adulthood, and if the changes observed related to altered development of basal cells in early puberty. Neonatal treatment with 10 microg DES resulted in the following during adulthood: (a) coiling of the normally straight initial vas deferens, (b) gross epithelial abnormalities, (c) 4-fold widening of the periductal non-muscle layer, (d) infiltration of immune cells across the epithelium into the lumen, and (e) reduction/absence of sperm from the vas deferens lumen. Amongst affected animals>75% exhibited reduced epithelial immunoexpression of androgen receptor and aberrant oestrogen receptor-alpha immunoexpression and 63% exhibited multi-layering of basal cells coincident with increased epithelial cell proliferation. None of the aforementioned changes occurred in rats treated neonatally with 0.1 microg DES. As basal cells play a key role in the development of epithelia such as that in the epididymis and vas deferens, we went on to investigate if neonatal DES treatment affected basal cell development. In controls, basal cells were first evident at day 10 (vas deferens) or day 18 (cauda). Rats treated with 10 microg, but not those treated with 0.1 microg, DES, showed approximately 90% reduction (P<0.001) in basal cell numbers at day 15 and day 18. This decrease coincided with gross suppression of testosterone levels; co-treatment of rats with 10 microg DES+testosterone maintained basal cell numbers at control levels at day 18. However, suppression of testosterone production (GnRH antagonist treatment) or action (flutamide treatment) did not alter basal cell numbers. It is concluded that neonatal exposure to high oestrogen levels coincident with reduced testosterone action results in abnormal changes in the adult cauda/vas deferens that are preceded by delayed differentiation of basal cells. These findings imply a role for androgens and oestrogens in basal cell development and suggest that this may be pivotal in determining normal epithelial (and stromal) development of the cauda/vas deferens.