Abstract

Background:

Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data.

Objectives:

Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro.

Methods:

In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration–response ($10\text{\hspace{0.17em}nM}–100\mathrm{\mu }\mathrm{M}$) for effects in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs). Functional phenotypic end points included effects on beating parameters and intracellular ${\mathrm{Ca}}^{2+}$ flux in CMs and inhibition of tubulogenesis in ECs. High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress.

Results:

Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs. Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity.

Discussion:

Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches. This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites. https://doi.org/10.1289/EHP7030

中文翻译：

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多氯联苯及其主要代谢产物的心血管作用。

摘要

背景：

异源生物的代谢非常复杂，而对于化学物质的生物活化和解毒过程的解释仍然是体外新方法方法数据决策中最具挑战性的方面。

目标：

考虑到人类器官型培养物模型的生理相关性及其在高通量筛选中的效用，我们假设化学物及其主要代谢物的多维化学生物学特征分析是体外母体分子与代谢物的毒理学表征的明智选择。

方法：

在这项研究中，我们测试了25种多氯联苯（PCB 3、11、52、126、136和153及其相关代谢物（羟基化，甲氧基化，硫酸化和醌））的浓度响应（$10\text{\hspace{0.17em}纳米}–100\mathrm{\mu }\mathrm{中号}$）对人类诱导的多能干细胞（iPSC）衍生的心肌细胞（CMs）和内皮细胞（EC）（iPSC衍生的HUVEC）的影响。功能性表型终点包括对跳动参数和细胞内的影响${\mathrm{钙}}^{2+}$CMs中的流量变化和ECs中的肾小管生成抑制作用。高内涵成像用于评估细胞毒性，线粒体完整性和氧化应激。

结果：

总共19种理化指标和36种体外表型的数据集成表明，氯化状态和代谢物类别是PCBs体外心血管效应的有力预测指标。PCB的氧化，特别是二羟基化和醌代谢物的氧化，具有最明显的作用，而PCB的硫酸化和甲氧基化则导致生物活性降低。

讨论：

风险特征分析表明，尽管体外获得的有效浓度超过了普通人群中测得的水平，但由于人群易感性方面的潜在差异以及需要使用交叉读取方法填补数据空白的需要，因此不能排除风险。这项研究表明了一种如何利用体外数据来表征多氯联苯及其代谢物对人类健康的危害的策略。https://doi.org/10.1289/EHP7030