Abstract

Background:

Humans and environmental organisms are constantly exposed to complex mixtures of chemicals. Extending our knowledge about the combined effects of chemicals is thus essential for assessing the potential consequences of these exposures. In this context, comprehensive molecular readouts as retrieved by omics techniques are advancing our understanding of the diversity of effects upon chemical exposure. This is especially true for effects induced by chemical concentrations that do not instantaneously lead to mortality, as is commonly the case for environmental exposures. However, omics profiles induced by chemical exposures have rarely been systematically considered in mixture contexts.

Objectives:

In this study, we aimed to investigate the predictability of chemical mixture effects on the whole-transcriptome scale.

Methods:

We predicted and measured the toxicogenomic effects of a synthetic mixture on zebrafish embryos. The mixture contained the compounds diuron, diclofenac, and naproxen. To predict concentration- and time-resolved whole-transcriptome responses to the mixture exposure, we adopted the mixture concept of concentration addition. Predictions were based on the transcriptome profiles obtained for the individual mixture components in a previous study. Finally, concentration- and time-resolved mixture exposures and subsequent toxicogenomic measurements were performed and the results were compared with the predictions.

Results:

This comparison of the predictions with the observations showed that the concept of concentration addition provided reasonable estimates for the effects induced by the mixture exposure on the whole transcriptome. Although nonadditive effects were observed only occasionally, combined, that is, multicomponent-driven, effects were found for mixture components with anticipated similar, as well as dissimilar, modes of action.

Discussion:

Overall, this study demonstrates that using a concentration- and time-resolved approach, the occurrence and size of combined effects of chemicals may be predicted at the whole-transcriptome scale. This allows improving effect assessment of mixture exposures on the molecular scale that might not only be of relevance in terms of risk assessment but also for pharmacological applications. https://doi.org/10.1289/EHP7773

中文翻译：

---

斑马鱼胚胎中化学混合物暴露引起的全转录组预测和组合效应的测量

摘要

背景：

人类和环境生物不断暴露于复杂的化学品混合物中。因此，扩展我们关于化学品综合影响的知识对于评估这些暴露的潜在后果至关重要。在这种情况下，通过组学技术检索的综合分子读数正在促进我们对化学暴露影响的多样性的理解。对于不会立即导致死亡的化学浓度引起的影响尤其如此，环境暴露通常就是这种情况。然而，在混合环境中很少系统地考虑由化学暴露引起的组学特征。

目标：

在这项研究中，我们旨在研究化学混合物对全转录组规模的影响的可预测性。

方法：

我们预测并测量了合成混合物对斑马鱼胚胎的毒理学影响。该混合物含有化合物敌草隆、双氯芬酸和萘普生。为了预测浓度和时间分辨的全转录组对混合物暴露的反应，我们采用了浓度添加的混合物概念。预测是基于在先前研究中获得的单个混合物组分的转录组谱。最后，进行浓度和时间分辨的混合物暴露和随后的毒理学测量，并将结果与​​预测进行比较。

结果：

这种预测与观察的比较表明，浓度添加的概念为混合物暴露对整个转录组的影响提供了合理的估计。尽管仅偶尔观察到非加性效应，但对于具有预期相似和不同作用模式的混合物成分，发现了组合效应，即多组分驱动效应。

讨论：

总体而言，这项研究表明，使用浓度和时间分辨方法，可以在全转录组尺度上预测化学物质组合效应的发生和大小。这允许在分子尺度上改进混合物暴露的效果评估，这可能不仅与风险评估相关，而且与药理学应用相关。https://doi.org/10.1289/EHP7773