Abstract
The kidney is a major target for xenobiotics, which include drugs, industrial chemicals, environmental toxicants and other compounds. Accurate methods for screening large numbers of potentially nephrotoxic xenobiotics with diverse chemical structures are currently not available. Here, we describe an approach for nephrotoxicity prediction that combines high-throughput imaging of cultured human renal proximal tubular cells (PTCs), quantitative phenotypic profiling, and machine learning methods. We automatically quantified 129 image-based phenotypic features, and identified chromatin and cytoskeletal features that can predict the human in vivo PTC toxicity of 44 reference compounds with ~82 % (primary PTCs) or 89 % (immortalized PTCs) test balanced accuracies. Surprisingly, our results also revealed that a DNA damage response is commonly induced by different PTC toxicants that have diverse chemical structures and injury mechanisms. Together, our results show that human nephrotoxicity can be predicted with high efficiency and accuracy by combining cell-based and computational methods that are suitable for automation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1638-y) contains supplementary material, which is available to authorized users.
Highlights
The kidney plays an important role in the filtration and active elimination of xenobiotics from the plasma (Tiong et al 2014)
To make our computational models more comprehensive, we increased the number of reference xenobiotic compounds to 44 (Supplementary Material 1—Table S1), among which 38 compounds were previously used in our IL-6/8-based models (Li et al 2013, 2014; Su et al 2014; Kandasamy et al 2015)
These reference compounds included commonly used industrial chemicals, antibiotics, antivirals, chemotherapy drugs, mycotoxins, agricultural chemicals and other compounds (Fig. 1a). They were divided into two groups based on their known in vivo toxicity from published clinical and/or animal studies [detailed information for most of the compounds can be found in our previous reports (Li et al 2014; Kandasamy et al 2015)]
Summary
The kidney plays an important role in the filtration and active elimination of xenobiotics from the plasma (Tiong et al 2014). Foreign compounds originating from medicine, food, or the environment are actively transported and metabolized by the renal proximal tubular cells (PTCs; Commandeur and Vermeulen 1990). Animal testing is a standard approach, but suffers from the problems of long turnaround time, low throughput, and sometimes poor prediction of human toxicity (Krewski et al 2010). This approach is especially unsuitable for evaluating the large numbers of existing and ever-increasing numbers of novel synthetic compounds, such as chemicals and nanoparticles. The current interest in alternatives to animal testing is
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