Large-Scale Transcriptional Profiling of Molecular Perturbations Reveals Cell Line Specific Responses and Implications for Environmental Screening

Cell-based bioassays represent nearly half of all high-throughput screens currently conducted for risk assessment of environmental chemicals. However, there has long been a concern about the sensitivity and heterogeneity among cell lines, which were explored only in a limited manner. Here, we address this question by conducting a large-scale transcriptome analysis of the responses of discrete cell lines to specific molecules. We report the collections of >223 300 gene expression profiles from a wide array of cell lines exposed to 2243 compounds. Our results demonstrate distinct responses among cell lines at both the gene and the pathway levels. Temporal variations for a very large proportion of compounds occur as well. High sensitivity and/or heterogeneity is either cell line-specific or universal depending on the modes of action of the compounds. Among 12 representative pathways analyzed, distinct cell-chemical interactions exist. On one hand, lung carcinoma cells are always best suited for glucocorticoid receptor agonist identification, while on the other hand, high sensitivity and heterogenic features are universal for histone deacetylase inhibitors and ATPase inhibitors. Our data provide novel insights into the understanding of cell-specific responses and interactions between cells and xenobiotics. The findings have substantial implications for the design, execution, and interpretation of highthroughput screening assays in (eco)toxicology.

Automated summary

There are significant differences in responses among cell lines, including sensitivity and heterogeneity to different compounds, and temporal variations also occur with exposure. There are specific interactions between cells and chemicals, such as lung carcinoma cells being best suited for glucocorticoid receptor agonist identification, while histone deacetylase inhibitors and ATPase inhibitors exhibit universal high sensitivity and heterogenic features.