Angiogenic Activity and Mechanism for Bisphenols on Endothelial Cell and Mouse: Evidence of a Structural-Selective Effect

Bisphenols at environmentallyrelevant concentrations distinctlyinduce abnormal angiogenesis via disruption of different nuclear receptor-mediatedphosphatidylinositol 3-kinase pathways. Increasedepidemiological evidence indicates the association ofbisphenol exposure with human vascular disorders, while the underlyingmechanism has not been clarified. Here, we sought to unveil the potentialangiogenic effect and the underlying mechanism of bisphenols withdifferent structural features using endothelial cells treated withan environmentally relevant concentration of bisphenols (range: 1nM to 10 & mu;M) and a C57BL/6 mouse model fed with doses of 0.002,0.02, 2, and 20 mg/kg BW/day for 5 weeks. Bisphenol A (BPA) and bisphenolS (BPS) at a 1 nM level significantly increased tube formation by45.1 and 30.2% and induced the microvessel sprouting, while tube lengthand microvessel sprouting were significantly inhibited by 37.2 and55.7% after exposure to tetrabromobisphenol S (TBBPS) at 1 & mu;M,respectively. Mechanistically, TBBPA and TBBPS significantly inhibitedthe interaction between phosphatidylinositol 3-kinase (PI3K) and thyroidreceptor (TR), while BPA and BPS favored the interaction between PI3Kand estrogen receptor (ER), resulting in abnormal PI3K signaling withconsequent distinct angiogenic activity. BPA- and BPS-induced pro-angiogeniceffects and TBBPS showed anti-angiogenic effects due to their distinctdisruption on the TR/ER-PI3K pathway. Our work provided new evidenceand mechanistic insight on the angiogenic activity of bisphenols andexpanded the scope of endocrine disruptors with interference in vascularhomeostasis.

Automated summary

Bisphenols at environmentally-relevant concentrations can induce abnormal angiogenesis through disruption of different nuclear receptor-mediated phosphatidylinositol 3-kinase pathways. Bisphenol A (BPA) and bisphenol S (BPS) promote angiogenesis, while tetrabromobisphenol S (TBBPS) inhibits angiogenesis. The different effects are attributed to their distinct interactions with phosphatidylinositol 3-kinase (PI3K) and thyroid receptor (TR) or estrogen receptor (ER).