Genetic background but not prostatic epithelial beta-catenin influences susceptibility of male mice to testosterone and estradiol-induced urinary dysfunction.

Autor:	Wegner KA; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA.; Molecular and Environmental Toxicology Center, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Ruetten H; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Girardi NM; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., O'Driscoll CA; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Sandhu JK; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Turco AE; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA.; Molecular and Environmental Toxicology Center, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Abler LL; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Wang P; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Wang Z; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Bjorling DE; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA., Malinowski R; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Pharmacy, University of Wisconsin-Madison Madison, WI, USA., Peterson RE; School of Pharmacy, University of Wisconsin-Madison Madison, WI, USA., Strand DW; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; Department of Urology, University of Texas Southwestern Medical Center Dallas, Texas, USA., Marker PC; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Pharmacy, University of Wisconsin-Madison Madison, WI, USA., Vezina CM; University of Wisconsin-Madison/UMASS Boston/UT-Southwestern George M. O'Brien Center for Benign Urologic Research Madison, Wisconsin 53706, USA.; School of Veterinary Medicine, University of Wisconsin-Madison Madison, Wisconsin 53706, USA.; Molecular and Environmental Toxicology Center, University of Wisconsin-Madison Madison, Wisconsin 53706, USA.
Jazyk:	angličtina
Zdroj:	American journal of clinical and experimental urology [Am J Clin Exp Urol] 2021 Feb 15; Vol. 9 (1), pp. 121-131. Date of Electronic Publication: 2021 Feb 15 (Print Publication: 2021).
Abstrakt:	Urinary voiding dysfunction in aging men can cause bothersome symptoms and irreparable tissue damage. Underlying mechanisms are not fully known. We previously demonstrated that subcutaneous, slow-release testosterone and estradiol implants (T+E2) drive a pattern of urinary voiding dysfunction in male mice that resembles that of aging men. The initial goal of this study was to test the hypothesis that prostatic epithelial beta-catenin ( Ctnnb1 ) is required for T+E2-mediated voiding dysfunction. Targeted Ctnnb1 deletion did not significantly change voiding function in control or T+E2 treated mice but led to the surprising discovery that the C57BL/6J × FVB/NJ × 129S1 mixed genetic background onto which Ctnnb1 loss of function alleles were maintained is profoundly susceptible to voiding dysfunction. The mixed background mice develop a more rapid T+E2-mediated increase in spontaneous urine spotting, are more impaired in ability to initiate bladder contraction, and develop larger and heavier bladders than T+E2 treated C57BL/6J pure bred mice. To better understand mechanisms, we separately evaluated contributions of T and E2 and found that E2 mediates voiding dysfunction. Our findings that genetic factors serve as modifiers of responsiveness to T and E2 demonstrate the need to control for genetic background in studies of male voiding dysfunction. We also show that genetic factors could control severity of voiding dysfunction. We demonstrate the importance of E2 as a key mediator of voiding impairment, and show that the concentration of E2 in subcutaneous implants determines the severity of voiding dysfunction in mice, demonstrating that the mouse model is tunable, a factor which is important for future pharmacological intervention studies. Competing Interests: None. (AJCEU Copyright © 2021.)
Databáze:	MEDLINE
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