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.
AbbreviationsAR
androgen receptor
BPAbisphenol A
ESR1estrogen receptor 1
ESR2estrogen receptor 2
GLTPglycolipid transfer protein
HbFthe fetal hemoglobin
HBG1hemoglobin subunit γ-1
hERαhuman ERα
HSD17B1hydroxysteroid 17-β dehydrogenase 1
KEGGKenya encyclopedia of genes and genomes
MDmolecular dynamics simulation
PFCsperfluorinated compounds
PFOAperfluorooctanoic acid
PFOSperfluorooctane sulfonate
POPspersistent organic pollutants
RMSDroot-mean-square deviation
SHBGsex hormone binding globulin
SPC/Eextended simple point charge model
TRthyroid hormone receptor

androgen receptor
bisphenol A
estrogen receptor 1
estrogen receptor 2
glycolipid transfer protein
the fetal hemoglobin
hemoglobin subunit γ-1
human ERα
hydroxysteroid 17-β dehydrogenase 1
Kenya encyclopedia of genes and genomes
molecular dynamics simulation
perfluorinated compounds
perfluorooctanoic acid
perfluorooctane sulfonate
persistent organic pollutants
root-mean-square deviation
sex hormone binding globulin
extended simple point charge model
thyroid hormone receptor
Communicated by Ramaswamy H. Sarma