Choice of experimental model determines translational impact: The link between bisphenol A and cardiotoxicity.
Choice of experimental model determines translational impact: The link between bisphenol A and cardiotoxicity.
复制标题
实验模型的选择决定了转化影响：双酚 A 与心脏毒性之间的联系。
DOI：
10.1016/j.fct.2023.113667
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Posnack,NikkiGillum
中科院分区：
文献类型：
--
作者：
Cooper,BlakeL;Posnack,NikkiGillum
双酚类化学物质在我们的环境中几乎无处不在，它们与不良健康后果的关系已引起人们的极大关注。在本期《食品与化学毒理学》中，我们怀着极大的兴趣阅读了Ma等人的研究，该研究报告了急性双酚A(BPA)暴露通过延迟复极而干扰心脏电生理(Ma等人，2023)。利用分离的(雌性)犬心室肌细胞，作者报告了BPA表现出非单调的剂量反应，其中低纳摩尔浓度(1 nM BPA，类似于环境暴露)可使心脏动作电位时程延长约10%。此外，作者发现，当较低的微摩尔浓度(1 PM)或较高的微摩尔浓度(1μM)对犬心肌细胞施加双酚A时，对心脏动作电位时程的影响可以忽略不计。包括双酚A在内的内分泌干扰化学物质表现出这种非常规的剂量-反应关系并不少见(Vandenberg，2014)。然而，在这项新的研究中，当测量结果归一化到各自的对照时，双酚A对动作电位时程延长的剂量依赖效应更加明显--因为在1 NM或1μM双酚A处理的心肌细胞之间的原始平均APD50和APD90值令人惊讶地相似(图1C，F)。结果表明，低纳摩尔浓度的双酚A可迅速抑制两种电流：外向钾电流(-25%)和内向钙电流(-9%)。后续的计算模拟表明，在低纳摩尔浓度下，BPA对IKR的抑制作用占主导地位，从而减缓复极并延长时程。不幸的是，膜片钳研究仅限于1 nM双酚A浓度，因此，尚不清楚这些抑制效应在低或高双酚A剂量下如何改变。尽管这项新研究没有报道半数抑制浓度(IC50)，但先前的研究报告了iKR的半数抑制浓度(IC50)为100μM bpa，IC50=7-31μM bpa，IC50为27 nM bpa(Hyun等人，2021年；梁等人，2014年；Prudencio等人，2021年)。由于这些先前的研究注意到电流抑制的单调的剂量反应，所以很可能所报道的BPA效力的差异可能归因于不同类型的细胞(例如，转基因细胞系、人诱导的多能干细胞来源的心肌细胞、大鼠或犬的心肌细胞)。在选择毒性研究的实验模型时，重要的是要考虑到心脏电生理学中特定物种的差异和与人类相关的翻译价值(Odning等人，2021年)--这项新研究的作者显然考虑到了这一点。
Bisphenol chemicals are nearly ubiquitous in our environment, and much attention has been given to their association with adverse health outcomes. In this issue of Food and Chemical Toxicology, we read with great interest the study by Ma et al., which reported that acute bisphenol A (BPA) exposure disturbs cardiac electrophysiology by delaying repolarization (Ma et al., 2023). Using isolated (female) canine ventricular cardiomyocytes, the authors report that BPA exhibits a non-monotonic dose response, wherein a low nanomolar concentration (1 nM BPA, akin to an environmental exposure) prolongs the cardiac action potential duration (APD) by approximately 10%. Further, the authors found negligible effects on the cardiac APD when either a lower picomolar concentration (1 pM) or higher micromolar concentration (1 μM) of BPA was applied to canine cardiomyocytes. It is not uncommon for endocrine-disrupting chemicals, including BPA, to display such unconventional dose-response relationships (Vandenberg, 2014). Although, in this new study, the dose-dependent effect of BPA on APD lengthening was more noticeable when measurements were normalized to each respective control–as the raw average APD50 and APD90 values were surprisingly comparable between cardiomyocytes treated with either 1 nM or 1 μM BPA (Figure 1C, F).The presented mechanistic studies by Ma et al. demonstrated that a low nanomolar concentration of BPA rapidly inhibits two currents: the outward IKr potassium current (-25%) and the inward ICaL calcium current (-9%). Follow-up computational modeling suggested that the inhibitory effect of BPA on IKr dominates at low nanomolar concentrations, which slows repolarization and prolongs the APD. Unfortunately, patch-clamp studies were limited to only the 1 nM BPA concentration, thus, it remains unclear how these inhibitory effects may change at lower or higher BPA doses. Although the half maximal inhibitory concentration (IC50) was not reported in this new study, previous studies reported an IC50> 100 μM BPA for IKr, an IC50= 7-31 μM BPA for ICaL, and a median inhibitory concentration of 27 nM BPA for ICaL (Hyun et al., 2021; Liang et al., 2014; Prudencio et al., 2021). Since these previous studies noted a monotonic dose response on current inhibition, it is plausible that the reported differences in BPA potency may be attributed to the use of different cell types (ie, transfected cell lines, human induced pluripotent stem cell-derived cardiomyocytes, rat or canine ventricular cardiomyocytes). When selecting an experimental model for toxicity studies, it is important to account for speciesspecific differences in cardiac electrophysiology and the human-relevant translational value (Odening et al., 2021)–which was clearly considered by the authors of this new study.