Using Transcriptomic Points of Departure to Determine Compound Toxicity

Conventional concepts of points of departure for adverse effects (e.g., NOAEL/LOAEL) do not translate directly to gene expression data. The benchmark dose approach offers a robust alternative method, and has been adapted to transcriptomics.  Benchmark Dose is a data driven mathematical approach to determine a dose at which a significant change in response is detected. It is applicable to continuous data such as gene expression data where changes in the abundance of gene transcripts can be detected for all genes expressed in a cell using fluorescence detection (as in microarray technology) or via counts of sequenced transcripts per gene (as with RNA-Seq or BioSpyder’s TempO-Seq ligation system). 

Chemicals with different potencies lead to apical effects at different exposure levels (i.e., have different points of departure, POD). It has been similarly established that compounds with lower points of departure also induce transcriptomic changes at lower concentrations. This observation has led to the concept of the transcriptomic point of departure as a proxy for compound toxicity. The impact of a compound on the transcriptome can be quantitatively determined and used to compare potency (Figure). We are using this concept with clients in applications related to compound screening and down-selection. There are also potential applications in product stewardship, such as alternatives assessment.