Phthalates and Phthalate Alternatives Have Diverse Associations with Oxidative Stress and Inflammation in Pregnant Women

Exposure to environmental chemicals such as phthalates has been linked to numerous adverse pregnancy outcomes, potentially through an oxidative stress mediated mechanism. Most research examined urinary 8-iso-prostaglandin F_2α (8-iso-PGF_2α) as the oxidative stress biomarker. However, 8-iso-PGF_2α also originates from enzymatic sources linked to inflammation. Therefore, associations between phthalates and 8-iso-PGF_2α could have been misinterpreted. To clarify this, the 8-iso-PGF_2α/prostaglandin F_2α ratio approach was used to quantitatively distinguish between inflammation or oxidative stress derived 8-iso-PGF_2α and estimate their associations with phthalate metabolites in a cohort of 758 pregnant women from The Infant Development and Environment Study (TIDES). Most urinary phthalate metabolites were associated with a significant increase in 8-iso-PGF_2α. For example, a 22.4% higher 8-iso-PGF_2α concentration (95% confidence interval = 14.4, 30.9) was observed with an interquartile range increase in mono- n-butyl phthalate. For most metabolites, associations were observed solely with oxidative stress derived 8-iso-PGF_2α. In contrast, monocarboxy-isononyl phthalate and monoisononyl phthalate (MNP) were associated with both sources of 8-iso-PGF_2α. Metabolites of the phthalate alternative 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH), were only associated with inflammation-derived 8-iso-PGF2_α, which is interesting because DINCH metabolites and MNP have structural similarities_.In conclusion, phthalates metabolites are not exclusively associated with oxidative stress derived 8-iso-PGF_2α. Depending on the metabolite structure, some are also associated with inflammation derived sources, which provides interesting insights in the toxicology of phthalates.