title: Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects.
abstract: The intrauterine environment is particularly vulnerable to environmental exposures. We previously established a mouse model that provided evidence for pregnancy complications and placental anti-angiogenesis in response to Aroclor 1254 (A-1254), a mixture of polychlorinated biphenyls (PCBs). Importantly, these effects were observed in IL-10-/-, but not wild type, mice, suggesting that IL-10 deficiency predisposes to pregnancy disruptive effects of environmental toxicants. However, the mechanisms by which PCBs cause anti-angiogenic effects are unclear. Here, we evaluated PCB-mediated anti-angiogenic effects by diverse but complementary approaches, including HUVEC-mediated trophoblast invasion in nude mice, in vitro three-dimensional capillary tube formation involving HUVEC and/or HTR8 trophoblasts, and aortic ring endothelial cell outgrowth/sprouting. Taken together, our data suggest that PCBs act as potent anti-angiogenic agents. Importantly, we show that treatment of pregnant IL-10-/-mice with A-1254 resulted in placental activation of the Notch/Delta-like ligand (Dll) pathway, a master regulator of cell-cell interaction and vascular patterning. Similar results were obtained with HUVEC and HTR8 trophoblasts. Rescue of A-1254-induced disruption of HUVEC-based tube formation by γ-secretase inhibitor L1790 confirmed the critical role of the Notch/Dll pathway. Our data suggest that PCBs impart pregnancy disruptive functions by activating the Notch/Dll pathway and by inducing anti-angiogenic effects at the maternal-fetal interface.
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Satyan
authors.initials: S
authors.lastname: Kalkunte
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Zheping
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Eliana
authors.initials: E
authors.lastname: Lippe
authors.affiliation: Division of Reproductive and Cyto-Toxicology, National Institute of Occupational Health (Indian Council of Medical Research), Ahmedabad, Gujarat, India.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Occupational &Environmental Health, College of Public Health, The University of Iowa, Iowa City, IA, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
authors.affiliation: Department of Pediatrics, Women and Infants Hospital of Rhode Island-Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
authors.forename: Surendra
authors.initials: S
authors.lastname: Sharma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D002135:Calcium-Binding Proteins; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced / Q000378:metabolism*; D000074562:Receptor, Notch4 / Q000378:metabolism*; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000074562:Receptor, Notch4; D020111:Chlorodiphenyl (54% Chlorine); D016753:Interleukin-10; C073572:Notch4 protein, mouse; D011078:Polychlorinated Biphenyls; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2