A role of aryl hydrocarbon receptor in the antiandrogenic effects of polycyclic aromatic hydrocarbons in LNCaP human prostate carcinoma cells

Abstract

The role of aryl hydrocarbon receptor (AhR) on the antiandrogenic effects of polycyclic aromatic hydrocarbons (PAHs) was studied in LNCaP cells. The PAHs used in this study were chrysene (Chr), benzo[ k]fluoranthene (BkF), benzo[ a]pyrene (BaP), anthracene (Ant) and pyrene (Pyr). Chr, BkF and BaP acted as AhR agonists in LNCaP cells, while Ant and Pyr did not. The antiandrogenic effects of the PAHs were evaluated on the basis of regulation of prostate-specific antigen (PSA) mRNA and protein levels by 5alpha-dihydrotestosterone (DHT). Chr, BkF and BaP exhibited an antiandrogenic effect, but Ant and Pyr did not. alpha-Naphthoflavone (alpha-NF), an AhR antagonist, reversed the antiandrogen action of Chr, BkF and BaP, suggesting a requirement for activated AhR. The antiandrogenic PAHs did not significantly decrease androgen receptor (AR) levels or cellular DHT concentrations. Gel mobility shift assays revealed that Chr, BkF and BaP inhibited the binding of AR in nuclear extracts to oligonucleotide probes containing the AR-responsive element (ARE), whereas Ant and Pyr had no effect. The antiandrogenic PAHs elevated mRNA levels of c-fos and c-jun. Since activator protein-1 (AP-1), a heterodimer of c-jun and c-fos proteins, is known to inhibit binding of AR to ARE by protein-protein interaction with AR, the findings in the present study suggest a possible involvement of AP-1 in the antiandrogenic effects of PAHs acting as AhR agonists. These results suggest that AhR can stimulate AP-1 expression resulting in inhibition of the binding of AR to ARE in the transcription regulatory region of target genes such as PSA.

Alteration of fertility endpoints in adult male F-344 rats by subchronic exposure to inhaled benzo(a)pyrene

“…This observation is significant because it suggests that the reduced sperm motility observed among treated rats is secondary to reduced epididymal exposure to physiological concentrations of androgens. According to Vinggaard et al (2000), Kizu et al (2003), and Charles et al (2005), PAHs including BaP and/or their metabolites perturb the androgen-dependent processes in target tissues by acting as antiandrogens. Benzo(a)pyrene may interrupt epididymal function by competing for androgen receptors in this organ (Mahony and Hodgen, 1995).…”

Association between a biomarker of exposure to polycyclic aromatic hydrocarbons and semen quality

“…PAHs and their metabolites may be hormonally active [48,49]. PAHs can bind and stimulate the acryl hydrocarbon receptor (AhR) which, in turn, may induce increased metabolism of PAHs to biologically active products that can interact with DNA and promote cancer, or other adverse outcomes [50].…”

A New Luciferase Reporter Gene Assay for the Detection of Androgenic and Antiandrogenic Effects Based on a Human Prostate Specific Antigen Promoter and PC3/AR Human Prostate Cancer Cells

“…Typical AhR agonists, such as 2,3,7,8-TCDD and certain PAHs, are found to elicit antiandrogenic effects through AhR-mediated mechanisms without binding to AR. [16][17][18] We demonstrated that diesel exhaust particle extracts exhibited antiandrogenic effects in PC3/AR cells, and that the major part of the antiandrogenic effects are caused by constituents with AhR agonist activity. 22 Further, the importance of the AhR agonist on male reproductive-system functions has been suggested by in vivo studies.…”

“…[16][17][18] We demonstrated that diesel exhaust particle extracts exhibited antiandrogenic effects in PC3/AR cells, and that the major part of the antiandrogenic effects are caused by constituents with AhR agonist activity. 22 Further, the importance of the AhR agonist on male reproductive-system functions has been suggested by in vivo studies. It has been shown that 2,3,7,8-TCDD impairs male reproductive functions in animal models 4 and that TCDD exerts its adverse effects without affecting the circulatory androgen 56…”

“…On the other hand, it has been reported that chemicals with aryl hydrocarbon receptor (AhR) agonist activity, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and some polycyclic aromatic hydrocarbons (PAHs) having four or more rings, shows antiandrogenic effects through AhR-mediated mechanisms without binding to AR. [16][17][18] There is also no assay system which responds correctly to AhR agonists. Dioxins and polycyclic aromatic hydrocarbons are ubiquitous environmental pollutants.…”