DDT and its metabolites alter gene expressions in human uterine cell lines through estrogen receptor-independent mechanisms

Daniel E. Frigo, Matthew E. Burow, Kamron A. Mitchell, Tung Chin Chiang, John A. McLachlan

    Research output: Contribution to journalReview articlepeer-review

    55 Scopus citations

    Abstract

    Endocrine-disrupting organochlorines, such as the pesticide dichloridiphenyltrichloroethane (DDT), bind to and activate estrogen receptors (ERs), thereby eliciting estrogen-like effects. Although ERs function predominantly through activation of transcription via estrogen-responsive elements, both ERs, α and β, can interact with various transciption factors such as activator protein-1 (AP-1). Additionally, estrogens may regulate early signaling events, suggesting that the biological effects of environmental estrogens may not be mediated through classic ER (α and β) activity alone. We hypothesized that known environmental estrogens, such as DDT and its metabolites, activate AP-1-mediated gene transactivation through both ER-dependent and ER-independent means. Using two Ishikawa human endometrial adenocarcinoma cell line variants that we confirmed to be estrogen responsive [Ishikawa(+)] and estrogen unresponsive [Ishikawa(-)], we generated stably transfected AP-1 luciferase cell lines to identify the role of an estrogen-responsive mechanism in AP-1-mediated gene expression by various stimuli. Our results demonstrate that DDT and dichlorodiphenyldichloroethane (DDD) were the most potent activators of AP-1 activity; 2,2-bis(p-chlorophenyl) acetic acid failed to activate. Although stimulated in both Ishikawa(+) and Ishikawa(-) cells by DDT and its congeners, AP-1 activation was more pronounced in the estrogen-unresponsive Ishikawa(-) cells. In addition, DDT, DDD, and dichlorodiphenyldichloroethylene (DDE) could also stimulate Ap-1 activity in the estrogen-unresponsive human embryonic kidney 293 cells using a different promoter context. Thus, our data demonstrate that DDT and its metabolites activate the AP-1 transcription factor independent of ER (α or β) status.

    Original languageEnglish (US)
    Pages (from-to)1239-1245
    Number of pages7
    JournalEnvironmental health perspectives
    Volume110
    Issue number12
    DOIs
    StatePublished - Dec 1 2002

    Keywords

    • AP-1
    • DDT
    • Early signaling
    • Estrogen receptor
    • Ishikawa cell line
    • Organochlorines

    ASJC Scopus subject areas

    • General Environmental Science
    • Environmental Chemistry
    • Public Health, Environmental and Occupational Health

    Fingerprint

    Dive into the research topics of 'DDT and its metabolites alter gene expressions in human uterine cell lines through estrogen receptor-independent mechanisms'. Together they form a unique fingerprint.

    Cite this