Disruption of androgen regulation in the prostate by the environmental contaminant hexachlorobenzene.
Hexachlorobenzene (HCB) is a persistent environmental contaminant that has the potential to interfere with steroid hormone regulation. The prostate requires precise control by androgens to regulate its growth and function. To determine if HCB impacts androgen action in the prostate, we used a number of methods. Our in vitro cell-culture-based assay used a firefly luciferase reporter gene driven by an androgen-responsive promoter. In the presence of dihydrotestosterone, low concentrations (0.5-5 nM) of HCB increased the androgen-responsive production of firefly luciferase and high concentrations of HCB (> 10 microM) suppressed this transcriptional activity. Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role.
Ralph
Jody L
JL
The Prostate Centre at Vancouver General Hospital, Vancouver, British Columbia, Canada.
Orgebin-Crist
Marie-Claire
MC
Lareyre
Jean-Jacques
JJ
Nelson
Colleen C
CC
D000728:Androgens / Q000096:biosynthesis / Q000494:pharmacology*; D000818:Animals; D001681:Biological Assay / Q000379:methods; D018929:Cell Culture Techniques; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000494:pharmacology; D004195:Disease Models, Animal; D005659:Fungicides, Industrial / Q000009:adverse effects*; D006581:Hexachlorobenzene / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000209:etiology; D051381:Rats
D000728:Androgens; D005659:Fungicides, Industrial; D006581:Hexachlorobenzene; D015500:Chloramphenicol O-Acetyltransferase