Advancing transcriptomics-based mechanistic assessment of nephrotoxicity in vitro using the human RPTEC/TERT1 TXG-MAPr gene co-expression network

Toxicological Sciences, vol. 209

Abstract

Traditional animal-based chemical safety assessments often fall short in accurately predicting human toxicities, highlighting the need for more human-relevant testing strategies. In response to this challenge, new approach methodologies have emerged, with high-throughput in vitro transcriptomic screening playing a pivotal role in elucidating mechanisms of toxicity. In this study, we developed the first human kidney in vitro toxicogenomic co-expression network using transcriptomic profiles from immortalized human renal proximal tubule epithelial cells (RPTEC/TERT1) exposed to a curated panel of nephrotoxicants. Through weighted correlation network analysis, we identified distinct gene co-expression modules and conducted comprehensive downstream analyses at the module, sample, and transcription factor levels. We integrated these insights into the human in vitro RPTEC/TERT1 TXG-MAPr, an interactive R Shiny platform designed to facilitate the interpretation of gene co-expression networks. Our findings demonstrate that module-based analysis enables the differentiation of distinct mechanisms of action. By linking transcriptional modules to KE within the nephrotoxicity adverse outcome pathway network, we reinforce the potential of gene co-expression network approaches to advance mechanism-based risk assessment and support next-generation chemical safety assessment.

Authors 4

1. Hugo W van Kessel Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University , 2300 RA Leiden,

   Division of Cell Systems and Drug Safety, Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

2. Steven J. Kunnen Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University , 2300 RA Leiden,

   Division of Cell Systems and Drug Safety, Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

3. Giulia Callegaro Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University , 2300 RA Leiden,

   Division of Cell Systems and Drug Safety, Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands

4. Bob van de Water corresponding Aachen Division of Cell Systems and Drug Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University , 2300 RA Leiden,

   Division of Cell Systems and Drug Safety, Leiden University, Leiden Academic Centre for Drug Research, Leiden, The Netherlands