Journal
TOXICOLOGICAL SCIENCES
Volume 150, Issue 2, Pages 429-440Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfw009
Keywords
Lower urinary tract symptoms (LUTS); fetal basis of adult disease; TCDD; mouse; prostate; hydronephrosis
Categories
Funding
- National Institute of Environmental Health Sciences [R01ES001332, R25ES020720]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01DK093690, R01DK099328, U54DK104310]
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Benign prostatic hyperplasia, 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(+/-);Pten(fl/+) 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 mu g/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17 beta-estradiol (2.5 mg) and testosterone (25 mg) (T+E-2) 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 2-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life.
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