High-throughput imaging-based methods for predicting cell-type-specific toxicity of xenobiotics with diverse chemical structures

Abstract

The present invention provides methods for the prediction of in vivo cell-specific toxicity of a compound that combines high-throughput imaging of cultured cells, quantitative phenotypic profiling, and machine learning methods. More particularly, the invention provides a method for the prediction of in vivo renal proximal tubular-, bronchial-epithelial-, and alveolar-cell-specific toxicities of asoluble or particulate compound that comprises contacting cultured human kidney and pulmonary cells with the compound at a range of concentrations, then labelling the cells with DNA, yH2AX and actin markers and obtaining textural features, spatial correlation features, ratios of the markers, intensity features, cell count and morphology, estimating dose response curves and performing automatic classification of the compound using a random-forest algorithm.

Description

field of invention [0001] The present invention provides a method for predicting in vivo cell-specific toxicity of compounds by high-throughput imaging of co-cultured cells. More specifically, the present invention provides methods for predicting in vivo proximal tubular, bronchial epithelial, and alveolar cell-specific toxicity of soluble or particulate compounds combined with high-throughput imaging of cultured human kidney and lung cells. Background of the invention [0002] The kidneys and lungs play important roles in metabolizing and / or eliminating xenobiotics from plasma. Exotic compounds derived from medicines, food or the environment are transported and metabolized by renal proximal tubular cells (PTC), bronchial epithelial cells (BEC) and alveolar cells (AVC). After ingestion, xenobiotics and their metabolites / intermediates may damage PTC, BEC, and AVC; and cause acute kidney / lung injury or chronic kidney / lung disease. Therefore, accurate methods to predict the s...

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Problems solved by technology

Second, most of these assays are based only on the half-maximal inhibitory concentration (IC 50 ), minimum effective concentration (MEC) or other concentration-based parameters or cell death readout (O'Brien et al., Arch Toxicol 80:580–604 (2006); Abraham et al.J BiomolScreen 13:527–537( 2008); Tolosa et al,.Toxicol Sci127:187–198(2012))

Due to these two limitations, most of these previous works either failed to evaluate or achieved very poor performance in predicting organ-specific toxicity

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