Inflammation Differentiated from Oxidative Stress in Relation to Environmental Phthalate Exposure: Evidence from Human and Animal Studies

Abstract

Exposure to phthalates has been linked to many adverse birth outcomes including preterm birth and preeclampsia. One mechanism behind these associations may be oxidative stress, which is best estimated using biomarkers such as 8-iso-prostaglandin F2α(8-iso-PGF2α). Previously observed associations with 8-iso-PGF2αmay be confounded due to simultaneous generation of this marker by an inflammation-driven mechanism. In this study, we reexamined the association between phthalate exposure and elevated oxidative stress using the ratio between 8-iso-PGF2αand PGF2α, which allows for the quantitative distinction of the two sources of 8-iso-PGF2α, i.e., oxidative stress or inflammation,and thus clarifies the true mechanism of the association. We investigated the association between phthalate metabolites and oxidative stress vs. inflammation in The Infant Development and the Environment Study. In 761 urine specimens collected during the 3rdtrimester we analyzed phthalate metabolites as well 8-iso-PGF2α and PGF2α using mass spectrometry. Most phthalates were associated with increased oxidative stress. For example, an interquartile range difference in mono-n-butyl phthalate was associated with a 22% (95% confidence interval=14, 31) increase in the oxidative stress pathway in covariate-adjusted models. Detection of phthalate replacement metabolites such as di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) was associated with an increase in the inflammation pathway. We also examined these associations in an animal model, in which adult rats were administered di-butyl phthalate (DBP) or di-2-ethylhexyl phthalate (DEHP) and urine samples collected 7 hours after dosing were analyzed by mass spectrometry for the same biomarkers. We observed a similar increase in the oxidative stress pathway in response to DBP exposure. These findings have important implications for developing interventions to prevent adverse birth outcomes when intervening on exposure is difficult or impossible.