Differential effects of phthalate esters on transcriptional activities via human estrogen receptors alpha and beta, and androgen receptor.
Some phthalates are suspected to disrupt the endocrine system, especially by mimicking estrogens. In this study, we characterized the activities of human estrogen receptor alpha (hERalpha), human estrogen receptor beta (hERbeta), and human androgen receptor (hAR) in the presence of 22 phthalates including 3 of their metabolites using highly sensitive reporter gene assays. Of the 22 compounds tested, several phthalate diesters with alkyl chains ranging in length from C3 to C6 exhibited not only hERalpha-mediated estrogenic activity, but also hERbeta-mediated antiestrogenic activity in a dose-dependent manner. In addition, we found that some phthalate diesters possess hAR-mediated antiandrogenic activity. However, the phthalates having side chains with very short length (diethyl) or very long length (diheptyl), and three metabolites (monoesters) were found to have no effect on the activities of the three receptors. These results indicate that several phthalate esters simultaneously act as agonists and/or antagonists via one or more hormonal receptors, and interaction of phthalate esters with the estrogen and androgen receptors requires certain size and bulkiness with alkyl groups.
Takeuchi
Shinji
S
Hokkaido Institute of Public Health, Kita-19, Nishi-12, Kita-ku, Sapporo 060-0819, Japan.
Iida
Mitsuru
M
Kobayashi
Satoshi
S
Jin
Kazuo
K
Matsuda
Tadashi
T
Kojima
Hiroyuki
H
D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000633:toxicity; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D006801:Humans; D010795:Phthalic Acids / Q000633:toxicity*; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects*
D059002:Androgen Receptor Antagonists; D000728:Androgens; D004952:Esters; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D010795:Phthalic Acids; D011944:Receptors, Androgen