D S Hunter

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (3)20.79 Total impact

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    ABSTRACT: The remarkable frequency of uterine leiomyoma in the human population calls into question the potential for the participation of environmental factors in tumor etiology. Having been implicated in the dramatic rise in hormone-related cancers in recent years, endocrine disruptors are salient suspects in this pathogenesis, although the mechanism by which they might participate is unclear. Investigations using the Eker rat model show that uterine leiomyoma may have an enhanced sensitivity to modulation via the estrogen receptor. This sensitivity could make these tumors a target for disruption by exogenous estrogen receptor ligands. Direct evidence for a pathogenic role of exogenous compounds in leiomyomas is lacking; however, it can be demonstrated that such diverse agents as organochlorine pesticides, dietary flavonoids, botanical extracts, and therapeutic antiestrogens have either estrogen agonist or antagonist function in myometrial tissues. The use of this model will help define the impact of exogenous estrogen receptor modulators on uterine leiomyoma and will permit the evaluation of strategies for therapeutic intervention.
    Environmental Health Perspectives 11/2000; 108 Suppl 5:829-34. DOI:10.1289/ehp.00108s5829 · 7.03 Impact Factor
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    ABSTRACT: Although benign, uterine leiomyomas occur with high frequency and significant morbidity in reproductive-age women, and they present a significant health problem. Leiomyomas develop in the uterine myometrium and are sensitive to ovarian hormones, making them potential target sites for endocrine disruptors. Here we utilize cell lines derived from rat uterine leiomyomas to determine if a panel of 7 organochlorine pesticides have potential agonist activity in myometrial cells using cellular and molecular in vitro assays. The organochlorine pesticides investigated have been previously characterized as having agonist activity in other hormonally responsive tissues, but their effects have not been studied in uterine myometrial cells. In Eker rat leiomyoma-derived cells, HPTE, kepone, and the alpha isomer of endosulfan stimulated proliferation, an effect dampened by the antiestrogen ICI 182,780. In addition, these compounds stimulated transcription of the vitellogenin estrogen-response element via the ER in a transcriptional reporter gene assay and induced the expression of an endogenous estrogen-responsive gene, the progesterone receptor (PR). This contrasted with the agonist profile of methoxychlor, dieldrin, toxaphene, and endosulfan-beta. These compounds, unable to stimulate proliferation of uterine leiomyoma cells, did exhibit agonistic activity in these cells at the transcriptional level in the estrogen-sensitive reporter gene assay, and they were also able to upregulate PR message. These data demonstrate that organochlorine pesticides act as estrogen receptor agonists in Eker rat uterine myometrial cells, and they indicate a need for further investigation of the potential tissue-specific agonist activity of these pesticides and their role in the pathogenesis of uterine leiomyoma.
    Toxicological Sciences 05/2000; 54(2):355-64. DOI:10.1093/toxsci/54.2.355 · 4.48 Impact Factor
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    ABSTRACT: The possible contribution of endocrine disrupters to human disease, particularly those compounds that modulate the estrogen receptor (ER), has recently drawn considerable attention. The tissue specificity of effects mediated by the ER is well recognized, although the mechanism of this specificity is not understood sufficiently to predict the effects of a particular ligand in different target tissues. Although the divergence of ER-mediated effects in the breast, bone, and uterine endometrium has been described, a frequently overlooked site of estrogen action is the smooth muscle of the uterus. The uterine myometrium is the tissue of origin of an extremely common hormone-responsive tumor, uterine leiomyoma, a tumor with a significant impact on women's health and a possible environmental influence. This report describes an in vitro/in vivo system for identifying the effects of ER ligands in the myometrium and elucidating their mechanism of action. Several natural and synthetic xenoestrogens were evaluated at the cellular and molecular level for their ability to mimic estrogen action in uterine myometrial tissues. Diethylstilbestrol, coumestrol, genistein, naringenin, and endosulfan were able to activate the AF2 function of the ER in vitro and demonstrated agonist activity in estrogen-responsive myometrial cells, as determined by induction of proliferation and increased message levels of progesterone receptor. Compounds that could not activate AF2 function (4-hydroxy-tamoxifen, LY117018, and LY317783) did not act as estrogen agonists. For agonists, rank order of potency was predicted by receptor affinity; however, endosulfan displayed a surprising degree of activity, despite negligible receptor binding. Additionally, diethylstilbestrol and tamoxifen demonstrated prototypical agonist and antagonist effects, respectively, in the intact myometrium of sexually mature rats. The results presented here suggest that some exogenous ER ligands may mimic the effects of endogenous estrogens on uterine leiomyoma and may contribute to a complex hormonal milieu that impacts both normal and neoplastic myometrium.
    Cancer Research 08/1999; 59(13):3090-9. · 9.28 Impact Factor

Publication Stats

133 Citations
20.79 Total Impact Points

Institutions

  • 2000
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1999–2000
    • University of Texas MD Anderson Cancer Center
      • Science Park - Research Division
      Houston, TX, United States