Benign prostatic hyperplasia (BPH), prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction.
To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1+/-;Ptenfl/+ mice, which are genetically predisposed to prostate neoplasia, were exposed in utero and during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 μg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 dpc, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17β-estradiol (2. 5 mg) and testosterone (25 mg) (T+E2) via slow release subcutaneous implants. In utero and lactational (IUL) TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse LUT anatomy or function. By comparison, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution. We propose a two-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life.
Toxicological sciences : an official journal of the Society of Toxicology. 2016 Feb 09 [Epub ahead of print]
William A Ricke, Calvin W Lee, Tyler R Clapper, Andrew J Schneider, Robert W Moore, Kimberly P Keil, Lisa L Abler, Jalissa L Wynder, Arnaldo López Alvarado, Isaac Beaubrun, Jenny Vo, Tyler M Bauman, Emily A Ricke, Richard E Peterson, Chad M Vezina
*Molecular and Environmental Toxicology Center, Department of Urology, University of Wisconsin Carbone Cancer Center, George M. O'Brien Benign Urology Center of Research Excellence, School of Pharmacy. , School of Pharmacy. , School of Pharmacy. , School of Pharmacy. , School of Veterinary Medicine, University of Wisconsin,-Madison, Madison, Wisconsin 53706. , School of Veterinary Medicine, University of Wisconsin,-Madison, Madison, Wisconsin 53706. , *Molecular and Environmental Toxicology Center. , *Molecular and Environmental Toxicology Center. , *Molecular and Environmental Toxicology Center. , *Molecular and Environmental Toxicology Center. , Department of Urology. , Department of Urology. , *Molecular and Environmental Toxicology Center, Department of Urology, School of Pharmacy. , *Molecular and Environmental Toxicology Center, Department of Urology, University of Wisconsin Carbone Cancer Center, George M. O'Brien Benign Urology Center of Research Excellence, School of Pharmacy, School of Veterinary Medicine, University of Wisconsin,-Madison, Madison, Wisconsin 53706