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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects.

Authors: Kalkunte, Satyan; Huang, Zheping; Lippe, Eliana; Kumar, Sunil; Robertson, Larry W; Sharma, Surendra

Published In Sci Rep, (2017 Jan 10)

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.

PubMed ID: 28071720 Exiting the NIEHS site

MeSH Terms: Adaptor Proteins, Signal Transducing; Angiogenesis Inhibitors/toxicity*; Animals; Calcium-Binding Proteins; Chlorodiphenyl (54% Chlorine)/toxicity*; Disease Models, Animal; Female; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-10/genetics; Intracellular Signaling Peptides and Proteins/metabolism*; Membrane Proteins/metabolism*; Mice; Mice, Inbred C57BL; Mice, Knockout; Polychlorinated Biphenyls/toxicity*; Pregnancy; Pregnancy Complications/chemically induced; Pregnancy Complications/metabolism*; Receptor, Notch4/metabolism*; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2/metabolism*

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