Endocrine Abstracts (2006) 11 P679

Mechanisms of Wolffian duct differentiation; development of a model for studying androgen-driven stromal-epithelial interactions

M Welsh, RM Sharpe & PTK Saunders

Medical Research Council Human Repreoductive Sciences Unit, Edinburgh, United Kingdom.

After they are released from the testis, spermatozoa pass into the epididymis where they mature. The epididymis is a single, highly coiled duct that develops from a portion of the embryonic Wolffian duct (WD) under the control of testosterone. We have used a model system in which the androgen receptor (AR) antagonist flutamide is administered to pregnant rats to investigate the cellular mechanisms responsible for androgen-dependent WD differentiation.

Time-mated pregnant rats were treated daily from day 15 of pregnancy (e15) with flutamide (50 or 100 mgkg−1) or vehicle alone (controls). WDs were recovered from fetuses on e19-e21. The appearance and luminal length of the ducts was recorded at isolation. WDs were immunostained for AR, for specific cell compartment markers (e.g. smooth muscle actin, cytokeratin, laminin), for proliferation (histoneH3) and apoptosis (cleaved caspase 3). At e20 and e21 (but not at e19) there was a highly significant reduction in both the length, and degree of coiling, of WDs from flutamide-treated mothers compared to controls. This was associated with a significant decrease in proliferation of stromal and epithelial cells but no change in apoptosis. AR was expressed in control and treated WDs; immunostaining was more intense in stromal cell nuclei than in epithelial cells, consistent with the primary site of action of androgens in WD differentiation being the stromal cell. Changes have been identified in a number of structural proteins that may reflect stromal-epithelial interactions to lay down the basal lamina; laminin showed a treatment-related decrease while vimentin epithelial expression increased in WD from flutamide-treated mothers compared to controls.

In conclusion, we have confirmed that androgen action via AR is essential for normal coiling of the WD, that the primary site of androgen action appears to be the stromal cell and that maintenance of the basal lamina appears vital in WD differentiation.

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