title: p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) repress prostate specific antigen levels in human prostate cancer cell lines.
abstract: Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disrupting chemicals, DDT and DDE are still ubiquitous in the environment. However, little attention has been directed to p,p'-DDT and the anti-androgen, p,p'-DDE on androgen receptor (AR) target gene transcription in human cells. Inhibitors of androgenic activity may have a deleterious clinical outcome in prostate cancer screens and progression, therefore we determined whether environmentally relevant concentrations of p,p'-DDT and p,p'-DDE negatively impact AR-regulated expression of prostate-specific antigen (PSA), and other AR target genes in human LNCaP and VCaP prostate cancer cells. Quantitative real-time PCR and immuno-blotting techniques were used to measure intracellular PSA, PSMA and AR mRNA and protein levels. We have shown for the first time that p,p'-DDT and p,p'-DDE repressed R1881-inducible PSA mRNA and protein levels in a dose-dependent manner. Additionally, we used the fully automated COBAS PSA detection system to determine that extracellular PSA levels were also significantly repressed. These chemicals achieve this by blocking the recruitment of AR to the PSA promoter region at 10 μM, as demonstrated by the chromatin immunoprecipitation (ChIP) in LNCaP cells. Both p,p'-DDT and p,p'-DDE repressed R1881-inducible AR protein accumulation at 10 μM. Thus, we conclude that men who have been exposed to either DDT or DDE may produce a false-negative PSA test when screening for prostate cancer, resulting in an inaccurate clinical diagnosis. More importantly, prolonged exposure to these anti-androgens may mimic androgen ablation therapy in individuals with prostate cancer, thus exacerbating the condition by inadvertently forcing adaptation to this stress early in the disease.
authors: Department of Biological Sciences, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada.
authors: Lilian I L
authors: LI
authors: Wong
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada.
authors: Mark P
authors: MP
authors: Labrecque
authors: The Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, B.C. V6H 3Z6, Canada.
authors: Naokazu
authors: N
authors: Ibuki
authors: The Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, B.C. V6H 3Z6, Canada.
authors: Michael E
authors: ME
authors: Cox
authors: Environment Canada, Pacific Wildlife Research Centre, Delta, B.C. V4K 3N2, Canada.
authors: John E
authors: JE
authors: Elliott
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, B.C. V5A 1S6, Canada. Electronic address: tvb@sfu.ca.
authors: Timothy V
authors: TV
authors: Beischlag
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000954:Antigens, Surface / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D003634:DDT / Q000633:toxicity*; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017430:Prostate-Specific Antigen / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000954:Antigens, Surface; D011944:Receptors, Androgen; D003633:Dichlorodiphenyl Dichloroethylene; D007334:Insulin-Like Growth Factor I; D003634:DDT; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen
keywords: Androgen receptor; LNCaP; PSA screen; Prostate-specific antigen; p,p′-DDE; p,p′-DDT