High-Throughput Transcriptomics Differentiates Toxic versus Non-Toxic Chemical Exposures Using a Rat Liver Model

Abstract

To address the challenge of limited throughput with traditional toxicity testing, a newly developed high-throughput transcriptomics (HTT) platform, together with a 5-day in vivo rat model, offers an alternative approach to estimate chemical exposures and provide reasonable estimates of toxicological endpoints. This study contains an HTT analysis of 18 environmental chemicals with known liver toxicity. They were evaluated using male Sprague Dawley rats exposed to various concentrations daily for five consecutive days via oral gavage, with data collected on the sixth day. Here, we further explored the 5-day rat model to identify potential gene signatures that can differentiate between toxic and non-toxic liver responses and provide us with a potential histopathological endpoint of chemical exposure. We identified a distinct gene expression pattern that differentiated non-hepatotoxic compounds from hepatotoxic compounds in a dose-dependent manner, and an analysis of the significantly altered common genes indicated that toxic chemicals predominantly upregulated most of the genes and several pathways in amino acid and lipid metabolism. Finally, our liver injury module analysis revealed that several liver-toxic compounds showed similarities in the key injury phenotypes of cellular inflammation and proliferation, indicating potential molecular initiating processes that may lead to a specific end-stage liver disease.