Health effects of PFASs on five major human cancers: A network toxicology perspective on molecular pathogenesis.

Cohort studies and animal experiments showing the burgeoning human cancer risks associated with per- and polyfluoroalkyl substances (PFASs) have garnered increasing concern. However, research detailing the carcinogenic mechanisms of PFASs specifically remains limited. Based on network toxicology, and high-throughput sequencing data, we analyzed the carcinogenic effects of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in the top five major human cancer types (over 1 million new cases per year): gastric, colorectal, liver, kidney, and breast cancer. A total of 24 pathways associated with PFOS carcinogenesis were enriched, of which 9 pathways were found in different cancers. Notably, Ribosome pathways are enriched in rectal cancer, liver cancer, and kidney cancer. As for PFOA, 32 pathways associated with PFOS carcinogenesis were enriched, of which 10 pathways were found in different cancers, notably the peroxisome proliferator-activated receptor (PPAR) signaling pathway is enriched in all five major human cancers. PFOA-induced cancer mainly through the PPAR pathway, while PFOS-induced cancer by disturbing reactive oxygen species and ribosomes. These results indicated that although PFOA and PFOS have analogous structures, they have different mechanisms. This work provides a solid basis for health assessment of PFASs and determining potential pathways before verifying the mechanism of PFASs-induced cancer.