Systematic comparison of temporal transcriptional responses to hepatotoxicants in primary human hepatocytes and HepaRG cells using concentration-response modelling of gene co-expression networks

Abstract

Next generation risk assessment of chemicals revolves around the use of mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool to elucidate the underlying mechanisms of adverse effects of xenobiotics. In the present study, two widely used human in vitro hepatocyte culture systems, namely primary human hepatocytes (PHH) and human hepatoma HepaRG cells, were exposed to liver toxicants known to induce liver steatosis, cholestasis or necrosis. Benchmark concentration-response modelling was applied to transcriptomics gene co-expression networks (modules) in order to derive benchmark concentrations (BMCs) and to gain mechanistic insight into the hepatotoxic effects. BMCs derived by concentration-response modelling of gene co-expression modules recapitulated concentration-response modelling of individual genes. Although PHH and HepaRG cells showed overlap in deregulated genes and modules by the liver toxicants, PHH demonstrated a higher responsiveness, based on the lower BMCs of co-regulated gene modules. Such BMCs can be used as point of departure for assessing module-associated cellular (stress) pathways/processes. This approach could serve next generation risk assessment practice to identify early responsive modules at low BMCs. In turn, this can assist in delineating potential hazards of new test chemicals using in vitro systems when BMCs are paired with chemical exposure assessment and used in a subsequent risk assessment.