Research Projects
The Friday Evening Post article on Smoking and Fertility
Placental, Uterine and Prostate Effects of Organochlorine Environmental Contaminants
| This study evaluates the usefulness of established human uterine, placental and prostate cell lines as in vitro models for investigation of potential mechanisms of cellular and molecular toxicity. Our goal is to identify the molecular and cellular endpoints which are the most sensitive biomarkers of exposure and toxic effects following treatment with TCDD, benzo(a)pyrene (BaP) and several proto-tyep PCB congeners in order to evaluate AhR-dependent and -independent processes, respectively. The overall hypothesis is that TCDD, BaP and PCBs alter uterine and placental functions by dysregulation of autocrine and paracrine growth regulatory networks which are recongnized to be important for proliferation, invasiveness and endocrine function. |  |
The gene products include the growth factors EGF and its receptor, TGFs-a, b1 and b2, they cytokine IL-1b and the inhibitor plasminogen activator protease, PAI. A major goal is to develop in vitro models to reproduce some of the in vivo events involved in uterine disease and in the development and function of human placenta. Overall dose-response relationships are evaluated for effects on 1) proliferation and growth regulatory genes, 2) cell migration/invasion and regulatory genes, and 3) CYP1A1 induction which is a well characterized response. Three in vitro models have been developed
1. Uterine Cells: The human uterine endometrial cell adenocarcinoma RL95-2 cell line has proven useful in evaluating two separate aspects of uterine function: a) expression of proinflammatory cytokines as a potential mitigating factor in endometriosis and uterine disease; b) model of uterine epithelial oranization of cell adhesion and cytoskeletal proteins which is an essential feature of receptivity for adhesion of a placental trophoblast cell and an intitial step in implantation of a blastocyst.
2. Placental Cells: Placental function has been studied using two human trophoblasitc choriocarcinoma cell lines, JEG-3 and BeWo, which represent distinct stages of differentiation and supopulations of trophoblast cells in terms of proliferation and endocrine function. Our previous studies with primary cultures of placental cells showed a BaP-mediated loss of EGF-R which has been replicated int he JEG-3 and BeWo cells.
3. Prostate Cells: The human prostate adenocarcinoma LNCaP cell line has been studied as a potential model for evaluating mechanisms of male reproductive toxicity. This the only established androgen-dependent human prostate cell line and serves as a model for evaluating growth regulation and potential therapeutic approaches.
Effects of Dietary Isoflavonoids on Prostate Cancer Proliferation and Tumorigenesis
Prostate cancer has become the most commonly diagnosed cancer and the second leading cause of cancer death among males in the US, with 317,000 new cases and 40,000 deaths per year. Androgens play a permissive role in prostate cancer development with androgen ablation therapy exerting beneficial effects in patiens with advanced prostatic cancer. Epidemiological studies have shown that men and women who consume a traditional diet high in soy products have a low incidence of the hormone-dependent cancers of the prostate and breast. Chemoprevention, as opposed to chemotherapy, has been proposed as an approach to reduce the risk of, as well as death from, cancer. In this regard, isoflavones represent a class of naturally occurring plant compounds, especially rich in soy products, that humans consume in gram quantities daily. The major forms of soybean isoflavonoids detected in humans are daidzein and genistein, with lesser amounts of biochanin A and coumestrol. Several of the isoflavone compounds have been shown to inhibit the growth of human prostate cancer cells in culture, as well as the proliferation of a number of other human cancer cell types.
Soy diets and some of the isoflavonoid compounds have been shown to delay the appearance and growth of tumors rather than their formation, and thus likely inhibit the growth of latent tumors. This study evaluates a series of isoflavones for inhibitory effects on human prostate cancer cells. Of particular interest is whether the respective isoflavones have additive or synergistic effects on cell proliferation. The goal is to determine enpoints which are the most sensitive biomarkers for exposure to each isoflavonoid compound. These studies establish dose-response relationships for further evaluation of altered expression of genes important in the prostate growth regulatory networks. We compare hormone-sensitive and hormone-independent prostate cancer cells with a more normal non-tumorigenic prostate cell line which will allow for the identification of similar or related mechanisms. The identification of genes altered by dietary chemoprotective agents will allow for a more targeted apporach to the development of rational therapeutic regimens and diagnostic tests.
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