Exploring toxicity of perfluorinated compounds through complex network and pathway modeling.

Perfluorinated compounds (PFCs) have serious impacts on human health, which could interfere with the body's signal pathways and affect the normal hormone balance of humans. PFCs were reported to bind to many proteins causing a series of biological effects. It was quite possible that the in vivo action of PFCs was not a single target or a single pathway, suggesting the toxic effect was due to the disturbance of protein or gene network, not limited to the modification of a single target protein or gene. Thus, a PFCs-targets interaction network was constructed and the significant differences in the characteristics of complex networks between the branched PFCs and linear PFCs were observed. A molecular dynamics simulation proved that binding ability of the branched PFCs to the target protein was much weaker than that of the linear PFCs, explaining why the branched PFCs presented significantly difference from the linear PFCs in terms of complex network characteristics. In addition, four target genes were identified as the central node genes of the network. The four target genes were proved to present certain influences on some diseases, which suggested a high correlation between PFCs to these diseases, including obesity, hepatocellular carcinoma and diabetes. The present work was helpful to develop new approaches to identify the key toxic targets of compounds and to explore the toxicity effects on pathways. AbbreviationsARandrogen receptorBPAbisphenol AESR1estrogen receptor 1ESR2estrogen receptor 2GLTPglycolipid transfer proteinHbFthe fetal hemoglobinHBG1hemoglobin subunit γ-1hERαhuman ERαHSD17B1hydroxysteroid 17-ß dehydrogenase 1KEGGKenya encyclopedia of genes and genomesMDmolecular dynamics simulationPFCsperfluorinated compoundsPFOAperfluorooctanoic acidPFOSperfluorooctane sulfonatePOPspersistent organic pollutantsRMSDroot-mean-square deviationSHBGsex hormone binding globulinSPC/Eextended simple point charge modelTRthyroid hormone receptorCommunicated by Ramaswamy H. Sarma.