Transcriptional activation of the human estrogen receptor by DDT isomers and metabolites in yeast and MCF-7 cells.
In this study, we determined whether the DDT isomers p,p'-DDT [1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane], o,p'-DDT [1,1,1-trichloro-2(p-chlorophenyl)-2-(o-chlorophenyl)ethane], and their metabolites p,p'-DDD [1,1-dichloro-2,2-bis(p-chlorophenyl)ethane], o,p'-DDD [1,1-dichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)ethane], p,p'-DDE [1,1,-dichloro-2,2-bis(p-chlorophenyl)ethylene], o,p'-DDE [1,1-dichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)ethylene], and p,p'-DDA [2,2-bis(p-chlorophenyl)acetic acid], could bind to and transcriptionally activate the human estrogen receptor (hER). Novel results from competitive binding assays showed that o,p'-DDD, o,p'-DDE, and p,p'-DDT, as well as the established environmental estrogen o,p'-DDT, were able to bind specifically to the hER with approximately 1000-fold weaker affinities for the hER than that of estradiol. In contrast, only o,p'-DDT, but not p,p'-DDT, bound to the rat estrogen receptor. Moreover, two yeast expression-reporter systems, constructed to test if the DDT isomers and metabolites could transcriptionally activate the hER, demonstrated that an o,p'-DDT metabolite could transactivate the hER or LexA-hER fusion protein with just a 140- to 300-fold weaker potency than that of estradiol. The DDT isomers and metabolites that bound the hER in vitro triggered estrogen receptor-mediated transcription of the lacZ reporter gene in the yeast systems. Furthermore, the DDT isomers and metabolites that transactivated the hER elicited an additive response when given together or with estradiol. The DDT isomers and metabolites that triggered transcription of the yeast expression-reporter systems also stimulated two estrogenic endpoints in estrogen-responsive MCF-7 cells: the induction of the progesterone receptor and the down-regulation of the hER. Thus, in MCF-7 cells and in yeast expression-reporter systems, certain DDT isomers and metabolites act directly as agonists and transactivate the hER at concentrations found in human tissues.
Chen
C W
CW
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, NY 14642, U.S.A.
Hurd
C
C
Vorojeikina
D P
DP
Arnold
S F
SF
Notides
A C
AC
D000818:Animals; D002460:Cell Line; D003634:DDT / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D010957:Plasmids; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*; D015003:Yeasts / Q000235:genetics
D011960:Receptors, Estrogen; D003634:DDT