A primary goal of our research is the identification of alterations in gene expression in human reproductive cell lines which are mediated by prototype Superfund chemicals. Our focus is to develop in vitro models to reproduce some of the in vivo events involved in the development and function of human placenta, uterus and prostate. In the present funding period, studies have focused on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo(a)pyrene (BaP), and the polychlorinated biphenyl (PCB) congeners 3,3',4,4'-tetrachlorobiphenyl (TCB) and 2,2'4,4'5,5'- hexachlorobiphenyl (HCB) as prototypes for defining Ah receptor (AhR)- dependent effects. Our hypothesis is that TCDD, PCBs and BaP alter paracrine and autocrine growth regulatory networks which are recognized to be important for proliferation, migration/invasiveness and hormone responsiveness. Dose-response relationships have been established for each gene product to identify which endpoints are the most sensitive biomarkers in relationship to the induction of cytochrome P450 CYPIA1. The next funding period will focus on evaluation of the effects of PCB congeners which are relevant to human exposure and which may have both AhR-dependent and -independent mechanisms of action. The first Specific Aim is to identify mechanisms by which TCDD, PCBs and BaP induce the expression of the pro-inflammatory cytokines in human uterine and placental cell lines which may underlie the promotion of uterine disease and impaired placental development. The second Specific Aim is to characterize the effects of TCDD, PCBs and BaP on the migration/invasive activity of placental and uterine cells relative to changes in cell adhesion molecule interactions with extracellular matrix and cytoskeletal microfilaments.
The Third Aim i s to investigate the potential role of the enzymes prostaglandin H synthase (PGHS)-1 and -2 in the metabolic activation and toxic effects of BaP and PCB compounds. PGHS enzymes, constitutively expressed and induced, may provide an alternative pathway to CYPIAI for peroxidative metabolism and oxidative stress-induced alterations in gene expression.
The final Aim will investigate whether human prostate cell lines are targets for changes in proliferation, migration and growth factor gene expression, which can be mechanisms for the promotion of prostate disease. In summary, this research will identify and validate sensitive biomarkers for exposure, as well as establish molecular and cellular mechanisms for altered uterine, placental and prostate function.
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