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

• Published in: Scientific reports 2017-01, Vol.7 (1), p.39885, Article 39885
• Main Authors: Kalkunte, Satyan, Huang, Zheping, Lippe, Eliana, Kumar, Sunil, Robertson, Larry W., Sharma, Surendra
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/21; 13/31; 64; 64/60; 692/420; 82; 82/29; Angiogenesis; Aorta; Aroclor 1254; Cell lines; Environmental effects; Fetuses; Humanities and Social Sciences; Interleukin 10; Intrauterine exposure; multidisciplinary; Notch protein; Pattern formation; PCB; Placenta; Polychlorinated biphenyls; Pregnancy; Pregnancy complications; Science; Science (multidisciplinary); Secretase; Toxicants; Trophoblasts; Vascular endothelial growth factor
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39885

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.