title: Mice lacking β-carotene-15,15'-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation.
abstract: β-Carotene-15,15'-dioxygenase (BCO1) cleaves dietary carotenoids at the central 15,15' double bond, most notably acting on β-carotene to yield retinal. However, Bco1 disruption also impacts diverse physiological end points independent of dietary carotenoid feeding, including expression of genes controlling androgen metabolism. Using the Bco1-/-mouse model, we sought to probe the effects of Bco1 disruption on testicular steroidogenesis, prostatic androgen signaling, and prostatic proliferation. Male wild-type (WT) and Bco1-/-mice were raised on carotenoid-free AIN-93G diets before euthanasia between 10 and 14 wk of age. Weights of the prostate and seminal vesicles were significantly lower in Bco1-/-than in WT mice (-18% and -29%, respectively). Serum testosterone levels in Bco1-/-mice were significantly reduced by 73%. Bco1 disruption significantly reduced Leydig cell number and decreased testicular mRNA expression of Hsd17b3, suggesting inhibition of testicular testosterone synthesis. Immunofluorescent staining of the androgen receptor (AR) in the dorsolateral prostate lobes of Bco1-/-mice revealed a decrease in AR nuclear localization. Analysis of prostatic morphology suggested decreases in gland size and secretion. These findings were supported by reduced expression of the proliferation marker Ki-67 in Bco1-/-prostates. Expression analysis of 200 prostate cancer- and androgen-related genes suggested that Bco1 loss significantly disrupted prostatic androgen receptor signaling, cell cycle progression, and proliferation. This is the first demonstration that Bco1 disruption lowers murine circulating testosterone levels and thereby reduces prostatic androgen receptor signaling and prostatic cellular proliferation, further supporting the role of this protein in processes more diverse than carotenoid cleavage.
authors.affiliation: Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Ford
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thomas-Ahner
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Moran
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Bolton
authors.affiliation: Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois.|Department of Veterinary Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wallig
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio; and.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.affiliation: Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois; jwerdman@illinois.edu.|Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: John W
authors.initials: JW
authors.lastname: Erdman
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000502:physiology; D011467:Prostate / Q000166:cytology* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013739:Testosterone / Q000097:blood*; D050559:beta-Carotene 15,15'-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; D013739:Testosterone; D050559:beta-Carotene 15,15'-Monooxygenase
keywords: Bco1; androgen; carotenoid oxygenase; prostate