Effect of neonatal exposure to estrogenic compounds on development of the excurrent ducts of the rat testis through puberty to adulthood

Neonatal exposure to diethylstilbestrol (DES) can alter the structure of th e testicular excurrent ducts in rats. We characterized these changes accord ing to dose and time posttreatment and established whether potent estrogens (ethinyl estradiol), environmental estrogens (genistein, octylphenol, bisp henol A, parabens), and tamoxifen induce such changes. Rats were administer ed these compounds neonatally and assessed at several time points during (d ay 10, or day 18 for some treatments) and after (days 18, 25, 35, and 75) t he treatment period to detect any changes in testis weight, distension of t he rete testis and efferent ducts, epithelial cell height in the efferent d ucts, and immunoexpression of the water channel aquaporin-1 (AQP-1). Treatm ent with DES (10, 1, or 0.1 mu g/injection; equivalent to 0.37, 0.037, or 0 .0037 mg/kg/day, respectively) induced dose-dependent changes in testis wei ght and all parameters. These effects were most pronounced at days 18 and 2 5 and appeared to lessen with rime, although some persisted into adulthood. Neonatal treatment with ethinyl estradiol (10 mu g/injection; equivalent t o 0.37 mg/kg/day) caused changes broadly similar to those induced by 10 pg DES. Administration of tamoxifen (2 mg/kg/day) caused changes at 18 days th at were similar to those induced by 1 pg DES. Treatment with genistein (4 m g/kg/day), octylphenol (2 mg/injection; equivalent to 150 mg/kg/day), or bi sphenol A (0.5 mg/injection; equivalent to 37 mg/kg/day) caused minor but s ignificant (p<0.05) decreases in epithelial cell height of the efferent duc ts at days 18 and/or 25 In animals that were followed through to 35 days an d/or adulthood, these changes were no longer obvious; other parameters were either unaffected or were affected only marginally and transiently. Admini stration of parabens (2 mg/kg/day) had no detectable effect on any paramete r at day 18. To establish whether these effects of estrogens were direct or indirect (i.e., resulting from reduced follicle-stimulating hormone/lutein izing hormone secretion), the above end points were assessed in animals in which gonadotropin secretion was suppressed neonatally by administration of a gonadotropin-releasing hormone antagonist. This treatment permanently re duced testis weight, but did not affect any of the other end points, apart from a minor transient reduction in efferent duct epithelial cell height at 18 days. This study suggests that structural and functional (expression of AQP-1) development of the excurrent ducts is susceptible to impairment by neonatal estrogen exposure, probably as a consequence of direct effects. Th e magnitude and duration of adverse changes induced by treatment with a ran ge of estrogenic compounds was broadly comparable to their estrogenic poten cies reported from in vitro assays.