The exposure-dependent increases in 8-iso-PGF2α and the significance of decoding its sources to identify a specific indicator of oxidative stress or inflammation

F 2 -isoprostanes, 8-iso-PGF2α, have been quantified as biomarkers of oxidative stress in over 1000 distinct experimental and human conditions. However, it has been shown that in addition to the free radical mediated pathway, the inflammation-induced prostaglandin-H-synthase enzymes are a major source of the F 2 -isoprostane generation. Accounting for the inflammatory source, F 2 -isoprostanes can be utilized for either a specific biomarker of oxidative stress or a biomarker of inflammation. To distinguish between F 2 -isoprostanes generated from inflammation vs. oxidative stress, the 8-iso-PGF 2α /PGF 2α ratio was implemented. With this measure, we have verified that exposure to the classic free radical toxicant carbon tetrachloride in rats predominantly causes an increase in chemical 8-iso-PGF 2α (86.6 ± 8.0 % of total at 1200 mg/kg). In contrast, exposure to lipopolysaccharide also induces the formation of F 2 -isoprostanes; however, the predominant mechanism for this exposure is due to increased enzymatic 8-iso-PGF 2α (59.5 ± 7.0 % of total at 0.5 mg/kg). Surprisingly, in human tobacco smokers, we also found that enzymatic lipid peroxidation is the primary source of F 2 -isoprostanes (Hedges’ g = 0.59 for enzymatic vs. 0.35 for chemical 8-iso-PGF 2α ). This distribution was independent of sex and age. Another source associated with elevated levels of 8-iso-PGF 2α in humans is increased urinary phthalate metabolites and most research has concluded oxidative stress mediated phthalate exposure. In a large population of pregnant women, (N ~ 700), we observed compound dependent associations with lower molecular weight phthalate metabolites being associated with higher levels of chemical 8-iso-PGF 2α whereas specific higher, branched chain metabolites are associated with elevated levels of enzymatic 8-iso-PGF 2α . Our experimental and human data show the exposure dependent changes in 8-iso-PGF 2α and the importance of distinguishing its sources to make it a specific biomarker of oxidative stress or inflammation. Without this additional step of 8-iso-PGF2α / PGF2α ratio determination, data can be greatly misinterpreted.