Toxicological Sciences 53, 278-288 (2000)
Copyright © 2000 by the Society of Toxicology
Examination of Selected Food Additives and Organochlorine Food Contaminants for Androgenic Activity in Vitro
,1
* Toxicology Research Division, Food Directorate, Health Canada; and
Reproductive Biology Unit, and Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Sir Frederick G. Banting Research Centre, Ottawa, Ontario, Canada
In order to produce a reporter gene assay for androgenic chemicals, a constitutive expression vector coding for the human androgen receptor and a reporter construct containing the firefly luciferase coding sequence under transcriptional control of the androgen responsive MMTV promoter were cotransfected into the androgen-insensitive human PC-3 prostate carcinoma cell line and stable transfectants selected. One colony of transfectants, PC-3 LUCAR+, was characterized further. 5
-Dihydrotestosterone (DHT) enhanced luciferase activity in a linear fashion for up to 3 days of culture. The Kd for DHT activation was within the range of 25.0–60.0 pM (r2 values > 0.95). Flutamide competitively inhibited DHT activation (mean Ki value of 0.89 µM). Progesterone, estradiol, dexamethasone, and hydrocortisone were weak agonists (100-fold less effective than DHT) and diethylstilbestrol was without effect. The effects of organochlorine food contaminants (0, 0.1, 1.0, and 10.0 µM) on luciferase activity in PC-3 LUCAR+ cells were determined after exposure to the chemical for 18 h in the presence and absence of DHT (50 pM). 1,1-dichloro-2,2-bis(p-chlorophenyl)- ethylene (p,p'-DDE) induced luciferase activity in the absence of DHT (100µM p,p'-DDE equivalent to 50 pM DHT), but in the presence of DHT (50 pM), p,p'-DDE acted antagonistically. 2,3,7,8-Tetrachlorodibenzo-p-dioxin, kepone, butylated hydroxyanisole, and butylated hydroxytoluene all partially inhibited activation by DHT (50 pM) but alone had little or no effect. Toxaphene at 10 µM induced luciferase activity in the absence of DHT but decreased cell viability. - and 
-Hexachlorocyclohexanes (HCH) at 10 µM antagonized the DHT effect, but ß-HCH and 
-HCH mirex, photomirex, oxychlordane, cis- and trans-nonachlor were without effect. Thus, of the chemicals tested, some interact with the human androgen receptor in vitro as agonists, others as antagonists, and some as partial agonists/antagonists.
Key Words: androgen; receptor; pesticides; food additives; human.
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