Associations of circulating levels of phthalate metabolites with cytokines and acute phase reactants in a Spanish human cohort

Pilar Requena, Celia Pérez-Díaz, Vicente Mustieles, Francisco M Peinado, Josefa León, Francisco M Pérez-Carrascosa, Hanne Frederiksen, Inmaculada Salcedo-Bellido, Rocío Barrios-Rodríguez, Juan Pedro Arrebola*

*Corresponding author for this work
1 Citation (Scopus)


The associations between human phthalate exposure and the onset of chronic diseases with an immunological component (e.g., metabolic syndrome, cancer) remain unclear, partly due to the uncertainties in the underlying mechanisms. This study investigates cross-sectional associations of the concentrations of 10 phthalate metabolites with 19 cytokines and acute phase proteins in 213 serum samples of Spanish adults. The associations were explored by Spearman's correlation, multivariable linear regression, and weighted quantile sum regression analyses. In the multivariable analyses, levels of plasminogen activator inhibitor (PAI)-1 were positively associated with mono-n-butyl phthalate (fold-change per one IQR increase in phthalate levels, 95% Confidence Interval: 1.65, 1.45-1.88) and mono-iso-butyl phthalate (3.07, 2.39-3.95), mono-ethyl phthalate (2.05, 1.62-2.61), as well as categorized mono-iso-decyl and mono-benzyl phthalates. The same phthalates also were significantly associated with leptin, interleukin (IL)-18 and monocyte chemoattractant protein-1. Moreover, the proinflammatory markers IL-1β, IL-17, IL-8, IL-6, IL-12, tumor necrosis factor, and lipopolysaccharide-binding protein showed positive and negative associations with, respectively, mono-(2-ethyl-hexyl) and mono-methyl phthalates. Finally, phthalate mixtures were positively associated with PAI-1, leptin, IL-18, IL-12, IL-8 and IL-1β. Despite the cross-sectional design limitation, these associations point to relevant subclinical immuno-inflammatory actions of these pollutants, warranting confirmation in future studies.

Original languageEnglish
Article number114470
JournalEnvironmental Research
Issue numberPt 2
Number of pages11
Publication statusPublished - Jan 2023


  • Acute phase protein
  • Adipokine
  • Cytokine
  • Human biomonitoring
  • Phthalate
  • Plasminogen activator inhibitor-1


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