Superfund Research Program

Placental-Uterine and Prostate Effects of Organochlorines

Project Leader: Kathleen T. Shiverick
Grant Number: P42ES007375
Funding Period: 1995-2006

Project-Specific Links

Final Progress Reports

Year:   1999 

This study has investigated cellular and molecular mechanisms whereby benzo(a)pyrene (BaP), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and several prototype PCB congeners may contribute to uterine and placental disease pathology using human uterine and placental cell lines. Previous studies reported that BaP, but not TCDD, markedly inhibited cell attachment and invasion in human uterine RL95 endometrial cells. The effects of BaP and TCDD were evaluated on the level and localization of the cell adherens junction proteins B-catenin, cadherin and vinculin, as well as the cytoskeletal protein actin, using Western immunoblot analysis and immunofluorescent microscopy. BaP, but not TCDD, is associated with selective alterations in the cell membrane localization and levels of EGF receptors, cadherin and B-catenin adherens junction proteins, as well as the subcortical filamentous actin in RL95 cells. Experiments are in progress to characterize BaP and TCDD effects on cell attachment/invasion and on cell adhesion/cytosleletal proteins in two other human endometrial cell lines that have differtial expression of estrogen receptors. A second effort has been initiated to determine whether the antiproliferative effects of BaP and organochlorines on the human placental JEG-3 cell line involve activation of apoptotic programmed cell death. Exposure of JEG-3 cells for 2-5 days to BaP, 3,4,3',4'-tetrachlorobiphenyl and 2,4,5, 2',4',5'-hexachlorbiphenyl markedly inhibits cell DNA synthesis and proliferation. Experiments characterized the morphologic presence of apoptotic cell bodies, DNA fragmentation using agarose gels electrophoresis, and quantitated levels of the apoptotic effector proteins Bcl-2 and Bax by Western blot analysis. BaP inhibition of cell proliferation does not appear to involve apoptotic cell death, but may involve cell cycle arrest and be mediated by both Ah receptor-dependent and -independent mechanisms.