Premium
Ablation of the Carotenoid Cleavage Enzyme β‐Carotene‐15,15′‐Dioxygenase (BCO1) Reduces Serum Testosterone and Prostatic Androgen Receptor Signaling in Mice
Author(s) -
Smith Joshua W.,
Ford Nikki A.,
ThomasAhner Jennifer M.,
Moran Nancy E.,
Bolton Eric C.,
Clinton Steven K.,
Erdman John W.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1247.3
Subject(s) - endocrinology , medicine , androgen , testosterone (patch) , androgen receptor , biology , gene expression , carotenoid , prostate cancer , hormone , gene , cancer , biochemistry
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. Ablation of this gene in mice fed carotenoid‐rich diets has been shown to affect tissue carotenoid accumulation. However, Bco1 ablation also impacts diverse physiologic endpoints 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 ablation on testicular steroidogenesis, serum testosterone levels, and prostatic androgen signaling. Male wild‐type (WT) and Bco1 − / − mice were weaned and raised on carotenoid‐free, semi‐purified AIN‐93G diets before sacrifice at 10–14 weeks of age. In three independent trials, Bco1 ablation significantly and consistently decreased serum testosterone and altered prostatic homeostasis. Organ weights of the prostate (all lobes) and seminal vesicles were significantly lower in Bco1 − / − than WT mice (−18% and −29%, respectively; p<0.001). Bco1 − / − mice had significantly reduced levels of serum testosterone (−79%; p<0.05). Additionally, Bco1 ablation decreased testicular mRNA expression of Hsd17b3 (−32% p<0.01), while increasing Hsd17b2 expression (+34%, p<0.05), suggesting a possible inhibition of testosterone synthesis. Furthermore, prostatic NanoString gene expression analysis revealed that Bco1 loss significantly (p<0.005) disrupted androgen receptor signaling, cell cycle progression, and proliferation. Reduced mRNA expression (by qPCR) of the androgen‐induced gene Msmb (−30%, p<0.05) and reduced protein expression of the proliferation marker Ki67 (by immunofluorescence microscopy; −47%, p<0.001) support these findings. While BCO1 has been suggested to function in physiologic processes more diverse than carotenoid cleavage and production of vitamin A, this is the first demonstration that Bco1 ablation impacts murine prostatic proliferation and androgen receptor signaling. Support or Funding Information Funded by NIH grant PHS‐1‐R01 CA125384