在人脐静脉内皮细胞和出生后暴露的小鼠模型中，探索氧化应激和内皮功能障碍作为双酚S暴露与血管疾病之间联系的机制。
Exploring oxidative stress and endothelial dysfunction as a mechanism linking bisphenol S exposure to vascular disease in human umbilical vein endothelial cells and a mouse model of postnatal exposure.
作者信息
Easson Sarah, Singh Radha Dutt, Connors Liam, Scheidl Taylor, Baker Larissa, Jadli Anshul, Zhu Hai-Lei, Thompson Jennifer
机构信息
Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 1N4, Canada.
Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta T2N 1N4, Canada; Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada.
出版信息
Environ Int. 2022 Dec;170:107603. doi: 10.1016/j.envint.2022.107603. Epub 2022 Oct 26.
BACKGROUND
Structural analogues used to replace bisphenol A (BPA) since the introduction of new regulatory restrictions are considered emerging environmental toxicants and remain understudied with respect to their biological actions and health effects. Studies reveal a link between BPA exposure and vascular disease in human populations, whereas the vascular effects of BPA substitutes remain largely unknown.
OBJECTIVES
To determine the effect of BPS, a commonly used BPA substitute, on redox balance, nitric oxide (NO) availability and microvascular NO-dependent dilation.
METHODS
In human umbilical vein endothelial cells (HUVEC), production of reactive oxygen species (ROS) and NO after exposure to BPS was measured using fluorescent probes for DCFDA and DAF-FM diacetate, respectively. The contribution of endothelial NO synthase (eNOS) uncoupling to ROS generation was determined by measuring ROS in the presence or absence of an eNOS inhibitor (L-NAME) or eNOS co-factor, BH4, while the contribution of mitochondria-derived ROS was determined by treating cells with mitochondria-specific antioxidants prior to BPS exposure. Bioenergetic profiles were assessed using Seahorse extracellular flux analysis and mitochondria membrane polarization was measured with TMRE and JC-1 assays. In a mouse model of low dose BPS exposure, NO-mediated endothelial function was assessed in pressurized microvessels by inducing endothelium-dependent dilation in the presence or absence of L-NAME.
RESULTS
BPS exposure (≥25 nM) reduced NO and increased ROS production in HUVEC, the latter corrected by treating cells with L-NAME or BH4. BPS exposure led to a loss of mitochondria membrane potential but had no impact on bioenergetic parameters except for a decrease in the spare respiratory capacity. Treatment of HUVEC with mitochondria-specific antioxidants abolished the effect of BPS on NO and ROS. NO-mediated vasodilation was impaired in male mice exposed to BPS.
DISCUSSION
Exposure to BPS may promote cardiovascular disease by perturbing NO-mediated vascular homeostasis through the induction of oxidative stress.
背景
自新的监管限制出台以来，用于替代双酚A（BPA）的结构类似物被视为新兴环境毒物，其生物学作用和健康影响仍未得到充分研究。研究表明，人群中BPA暴露与血管疾病之间存在联系，而BPA替代品对血管的影响在很大程度上仍不清楚。
目的
确定常用的BPA替代品双酚S（BPS）对氧化还原平衡、一氧化氮（NO）可用性和微血管NO依赖性舒张的影响。
方法
在人脐静脉内皮细胞（HUVEC）中，分别使用DCFDA和DAF-FM二乙酸荧光探针测量暴露于BPS后活性氧（ROS）和NO的产生。通过在存在或不存在内皮型一氧化氮合酶（eNOS）抑制剂（L-NAME）或eNOS辅因子BH4的情况下测量ROS来确定eNOS解偶联对ROS产生的贡献，而线粒体衍生ROS的贡献则通过在BPS暴露前用线粒体特异性抗氧化剂处理细胞来确定。使用海马细胞外通量分析评估生物能量谱，并使用TMRE和JC-1测定法测量线粒体膜电位。在低剂量BPS暴露的小鼠模型中，通过在存在或不存在L-NAME的情况下诱导内皮依赖性舒张来评估加压微血管中NO介导的内皮功能。
结果
BPS暴露（≥25 nM）降低了HUVEC中的NO并增加了ROS产生，后者通过用L-NAME或BH4处理细胞得到纠正。BPS暴露导致线粒体膜电位丧失，但除了备用呼吸能力降低外，对生物能量参数没有影响。用线粒体特异性抗氧化剂处理HUVEC消除了BPS对NO和ROS的影响。暴露于BPS的雄性小鼠中NO介导的血管舒张受损。
讨论
暴露于BPS可能通过诱导氧化应激扰乱NO介导的血管稳态，从而促进心血管疾病。
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