Bisphenols and brominated bisphenols induced endothelial dysfunction via its disruption of endothelial nitric oxide...

Emerging literatures have concentrated on the association between cardiovascular diseases risk of typical endocrine disruptor bisphenols, which also put forward the further studies need respect to the potential mechanism. Herein, we investigated the endothelial dysfunction effects of bisphenols and brominated bisphenols involved in aortic pathological structure, endothelial nitric oxide synthase (eNOS) protein phosphorylation, synthase activity and nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) and C57BL/6 mice. Bisphenol A (BPA) and bisphenol S (BPS) increased NO production by 85.7% and 68.8% at 10^-6 M level in vitro and 74.3%, 41.5% in vivo, respectively, while tetrabromobisphenol S (TBBPS) significantly inhibited NO by 55.7% at 10^-6 M in vitro and 28.9% in vivo at dose of 20 mg/kg BW/d. Aortic transcriptome profiling revealed that the process of 'regulation of NO mediated signal transduction' was commonly induced. The mRNA and protein expression of phosphorylated eNOS at Ser¹¹⁷⁷ were promoted by BPA and BPS but decreased by TBBPA and TBBPS in HUVECs. Phosphorylation and enzymatic activity of eNOS were significantly increased by 43.4% and 13.8% with the treatment of BPA and BPS at 10^-7 M, but decreased by 16.9% after exposure to TBBPS at 10^-6 M in vitro. Moreover, only TBBPS was observed to increase aorta thickness significantly in mice and induce endothelial dysfunction. Our work suggests that bisphenols and brominated bisphenols may exert adverse outcome on vascular health differently in vitro and in vivo, and emphasizes areas of public health concern similar endocrine disruptors vulnerable on the vascular endothelial function.