Integrating Time-Resolved nrf2 Gene-Expression Data into a Full GUTS Model as a Proxy for Toxicodynamic Damage in...

The immense production of the chemical industry requires an improved predictive risk assessment that can handle constantly evolving challenges while reducing the dependency of risk assessment on animal testing. Integrating omics data into mechanistic models offers a promising solution by linking cellular processes triggered after chemical exposure with observed effects in the organism. With the emerging availability of time-resolved RNA data, the goal of integrating gene expression data into mechanistic models can be approached. We propose a biologically anchored TKTD model, which describes key processes that link the gene expression level of the stress regulator nrf2 to detoxification and lethality by associating toxicodynamic damage with nrf2 expression. Fitting such a model to complex data sets consisting of multiple endpoints required the combination of methods from molecular biology, mechanistic dynamic systems modeling, and Bayesian inference. In this study, we successfully integrate time-resolved gene expression data into TKTD models and thus provide a method for assessing the influence of molecular markers on survival. This novel method was used to test whether nrf2 can be applied to predict lethality in zebrafish embryos. With the presented approach, we outline a method to successfully approach the goal of a predictive risk assessment based on molecular data.