Polychlorinated biphenyls interfere with androgen-induced transcriptional activation and hormone binding.
Polychlorinated biphenyls (PCBs) are ubiquitous highly persistent manufactured chemicals known to bioaccumulate in the food chain. Exposure to PCBs has been implicated in a wide range of human health effects, including altering normal endocrine processes and reproductive function. However, very little is understood regarding the specific mechanisms by which PCBs may exert their effects in biological systems. We have examined the ability of PCBs to interfere with transcriptional activation of the androgen receptor (AR) and glucocorticoid receptor (GR) in an in vitro transcription-based reporter assay system. Four Aroclor PCB mixtures were found to antagonize AR-mediated transcription in the presence of the natural AR ligand dihydrotestosterone (DHT). The antagonistic activity of Aroclor mixtures increased in the following order: 1260 < 1242 < 1254 < 1248. These Aroclor mixtures had no discernible effect on GR activity. Aroclor 1254 in the absence of DHT exhibited weak agonistic responses in a dose-dependent manner with AR. Within a series of individual congeners, congeners 42, 128, and 138 are shown to antagonize AR activity. These congeners all share a common core chlorine substitution pattern. Ligand-binding studies demonstrate that endocrine activities of PCB mixtures and congeners on AR are likely due to direct and specific binding to AR ligand-binding domain.
Portigal
Cheryl L
CL
The Prostate Centre at Vancouver General Hospital, Jack Bell Research Centre, 2660 Oak Street, Vancouver, British Columbia, V6H 3Z6, Canada.
Cowell
Simon P
SP
Fedoruk
Matthew N
MN
Butler
Christopher M
CM
Rennie
Paul S
PS
Nelson
Colleen C
CC
D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D001140:Aroclors / Q000633:toxicity; D003907:Dexamethasone / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000037:antagonists & inhibitors; D008297:Male; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D011944:Receptors, Androgen / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects
D059002:Androgen Receptor Antagonists; D000728:Androgens; D001140:Aroclors; D005938:Glucocorticoids; D008024:Ligands; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D013196:Dihydrotestosterone; D003907:Dexamethasone; D011078:Polychlorinated Biphenyls; D008156:Luciferases