Department Bioanalytical Ecotoxicology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
Institute for Environmental Research, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany.
Environ Health Perspect. 2021 Apr;129(4):47006. doi: 10.1289/EHP7773. Epub 2021 Apr 7.
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.
In this study, we aimed to investigate the predictability of chemical mixture effects on the whole-transcriptome scale.
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.
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.
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.
人类和环境生物不断暴露于复杂的化学物质混合物中。因此，扩展我们对这些化学物质联合效应的了解对于评估这些暴露的潜在后果至关重要。在这种情况下，通过组学技术获得的综合分子读数正在加深我们对化学暴露引起的多种效应的理解。对于那些不会立即导致死亡的化学浓度引起的效应，情况尤其如此，因为这通常是环境暴露的情况。然而，化学暴露引起的组学特征很少在混合物背景下得到系统考虑。
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效应的可预测性。
我们预测并测量了一种合成混合物对斑马鱼胚胎的毒基因组效应。该混合物包含了敌草隆、双氯芬酸和萘普生这三种化合物。为了预测混合物暴露的浓度和时间分辨的全转录组反应，我们采用了混合物浓度加和的概念。预测是基于之前的研究中获得的各个混合物成分的转录组图谱。最后，进行了浓度和时间分辨的混合物暴露和随后的毒基因组测量，并将结果与预测进行了比较。
将预测与观察结果进行比较表明，浓度加和的概念为混合物暴露引起的全转录组效应提供了合理的估计。虽然偶尔会观察到非加和效应，但对于具有预期相似作用模式的混合物成分，以及具有不同作用模式的混合物成分，都发现了组合效应，即多成分驱动的效应。
总的来说，这项研究表明，使用浓度和时间分辨的方法，可以在全转录组水平上预测化学物质联合效应的发生和大小。这使得在分子水平上对混合物暴露的效应评估得到改善，这不仅在风险评估方面具有重要意义，而且在药理学应用方面也具有重要意义。https://doi.org/10.1289/EHP7773.
