Data from: Quantifying liver-toxic responses from dose-dependent chemical exposures using a rat genome-scale metabolic model

Because the liver plays a vital role in the clearance of exogenous
chemical compounds, it is susceptible to chemical-induced toxicity.
Animal-based testing is routinely used to assess the hepatotoxic potential
of chemicals. While large-scale high-throughput sequencing data can
indicate the genes affected by chemical exposures, we need system-level
approaches to interpret these changes. To this end, we developed an
updated rat genome-scale metabolic model to integrate large-scale
transcriptomics data and utilized a chemical structure similarity-based
ToxProfiler tool to identify chemicals that bind to specific toxicity
targets to understand the mechanisms of toxicity. We used high-throughput
transcriptomics data from a 5-day in vivo study where rats were exposed to
different non-toxic and hepatotoxic chemicals at increasing concentrations
and investigated how liver metabolism was differentially altered between
the non-toxic and hepatotoxic chemical exposures. Our analysis indicated
that the genes identified via toxicity target analysis and those mapped to
the metabolic model showed a distinct gene expression pattern, with the
majority showing upregulation for hepatotoxicants compared to non-toxic
chemicals. Similarly, when we mapped the metabolic genes at the pathway
level, we identified several pathways in carbohydrate, amino acid, and
lipid metabolism that were significantly upregulated for hepatotoxic
chemicals. Furthermore, using our system-level integration of gene
expression data with the rat metabolic model, we could differentiate
metabolites in these pathways that were systematically elevated or
suppressed due to hepatotoxic versus non-toxic chemicals. Thus, using our
combined approach, we were able to identify a set of potential gene
signatures that clearly differentiated liver toxic responses from
non-toxic chemicals, which helped us identify potential metabolic pathways
and metabolites that are systematically associated with the toxicant
exposure.