A systems-level integration of liver-kidney transcriptomics and genome-scale metabolic models reveals organ-specific injury mechanisms.

The liver and kidneys are the primary organs that clear chemicals from the body, yet they often exhibit different pathological responses to the same systemic exposure. While high-throughput transcriptomics (HTT) can map broad molecular perturbations, identifying the differential mechanisms that govern organ-specific injury remains a challenge. To address this knowledge gap, we investigated the dose-dependent effects of three peroxisome proliferator-activated receptor alpha agonists-coumarin, fenofibrate, and perfluorooctanoic acid (PFOA)-on liver and kidney metabolism to understand the organ-specific mechanisms of toxicity. We used HTT data from 5-day in vivo rat exposure studies and performed a comparative analysis on the paired liver and kidney data, using gene co-expression and pathway enrichment analyses together with genome-scale models, to investigate their differential sensitivity to chemical exposure. Our results revealed that all three chemicals caused larger gene perturbations in the liver compared to the kidney, in agreement with their well-known hepatotoxicity. Fenofibrate and PFOA triggered a profound upregulation in pathways related to fatty acid metabolism but suppressed several pathways related to amino acid metabolism in both organs. All three chemicals showed a strong upregulated antioxidant response in the liver, indicating an adaptive response to chemical stress, with fenofibrate and PFOA entering uncontrolled endoplasmic reticulum stress, which was also observed for PFOA in the kidney. Our comparative analysis revealed a striking divergence in cellular repair mechanisms in response to stress across both tissues: while the liver strongly upregulated apoptotic and cell-cycle repair pathways, signaling active hepatotoxicity, the kidney consistently downregulated these same vital processes in response to all three chemicals, indicating differential mechanisms that may lead to organ toxicity.