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Citation
Tags
HERO ID
3982742
Reference Type
Journal Article
Title
Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects
Author(s)
Kalkunte, S; Huang, Z; Lippe, E; Kumar, S; Robertson, LW; Sharma, S
Year
2017
Is Peer Reviewed?
1
Journal
Scientific Reports
EISSN:
2045-2322
Volume
7
Page Numbers
Article #39885
Language
English
PMID
28071720
DOI
10.1038/srep39885
Web of Science Id
WOS:000391547100001
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.
Tags
IRIS
•
PCBs
Mechanistic
Supplemental
Litsearches
LitSearch: August 2016-August 2017
PubMed
Toxline
WoS
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