Investigating fatty liver disease-associated adverse outcome pathways of perfluorooctane sulfonate using a systems toxicology approach

Abstract

Adverse outcome pathway (AOP) frameworks help elucidate toxic mechanisms and support chemical regulation. AOPs link a molecular initiating event (MIE), key events (KEs), and an adverse outcome by key event relationships (KERs), which assess the biological plausibility, essentiality, and empirical evidence involved. Perfluorooctane sulfonate (PFOS), a hazardous poly-fluoroalkyl substance, demonstrates hepatotoxicity in rodents. PFOS may induce fatty liver disease (FLD) in humans; however, the underlying mechanism remains unclear. In this study, we evaluated the toxic mechanisms of PFOS-associated FLD by developing an AOP using publicly available data. We identified MIE and KEs by performing GO enrichment analysis on PFOS- and FLD-associated target genes collected from public databases. The MIEs and KEs were then prioritized by PFOS-gene-phenotype-FLD networks, AOP-helpFinder, and KEGG pathway analyses. Following a comprehensive literature review, an AOP was then developed. Finally, six KEs for the AOP of FLD were identified. This AOP indicated that toxicological processes initiated by SIRT1 inhibition led to SREBP-1c activation, de novo fatty acid synthesis, and fatty acid and triglyceride accumulation, culminating in liver steatosis. Our study provides insights into the toxic mechanism of PFOS-induced FLD and suggests approaches to assessing the risk of toxic chemicals.

Keywords: Adverse outcome pathway; Fatty liver disease; Perfluorooctane sulfonate; SIRT1.