Effect of organochlorine pesticides on human androgen receptor activation in vitro.
Many persistent organochlorine pesticides (OCs) have been implicated in adverse effects, that is, reproductive and developmental effects, in man and in wildlife alike. It has been hypothesized that these so-called xeno-hormones could be responsible for the increased incidence in various male sexual differentiation disorders such as hypospadias, cryptorchidism, low sperm counts and quality. In this report, OCs, called endocrine disrupters, were tested for their interaction with the androgen receptor. The stable prostatic cell line PALM, which contains a human androgen receptor (hAR) expression vector and the reporter MMTV-luciferase, was used to characterize the response of hAR to OC and was compared with synthetic androgen compound R1881. We found that all the OC pesticides tested were able to shift the agonist [(3)H]-R1881 from its binding site to the AR in competitive binding assays. In addition, these compounds antagonize-in a dose-dependent manner-the AR-mediated transcription by synthetic AR ligand R1881. None of the pesticides reacted as agonists. These results demonstrate that OC endocrine activities in vivo probably result from direct and specific binding to the AR ligand-binding domain. Although the antagonistic potential of OC pesticides is lower than that of hydroxyflutamide, they are capable of disrupting the male hormone signaling pathway. Because these chemicals are extremely persistent and tend to bioaccumulate, these results support the hypothesis that the recent increase in the incidence of male sexual disorders could be due to long exposure to ubiquitous OC pesticides found in the environment.
Lemaire
Géraldine
G
Laboratoire de Pharmaco-Toxicologie Cellulaire et Moléculaire, INRA, 06606 Antibes, France. lemaireg@yahoo.com
Terouanne
Béatrice
B
Mauvais
Pascale
P
Michel
Serge
S
Rahmani
Roger
R
D000726:Androgen Antagonists / Q000378:metabolism / Q000633:toxicity*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005485:Flutamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D015741:Metribolone / Q000378:metabolism / Q000633:toxicity*; D011944:Receptors, Androgen / Q000378:metabolism*; D045165:Testosterone Congeners / Q000378:metabolism / Q000633:toxicity*
D000726:Androgen Antagonists; D007306:Insecticides; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D015741:Metribolone; C014290:hydroxyflutamide; D005485:Flutamide