Inflammatory effects of phthalates in neonatal neutrophils

TitleInflammatory effects of phthalates in neonatal neutrophils
Publication TypeJournal Article
Year of Publication2010
AuthorsVetrano A.M, Laskin D.L, Archer F., Syed K., Gray J.P, Laskin J.D, Nwebube N., Weinberger B.
JournalPediatr ResPediatr Res
Date PublishedAug
ISBN Number1530-0447 (Electronic)<br/>0031-3998 (Linking)
Accession Number20453712
Keywords*Neutrophils/drug effects/immunology, Adult, Apoptosis/drug effects, Chemotaxis/drug effects, Diethylhexyl Phthalate/analogs & derivatives/metabolism/pharmacology, Humans, Hydrogen Peroxide/metabolism, Infant, Newborn, Inflammation/*chemically induced, Oxidants/metabolism, Phthalic Acids/*pharmacology, Plasticizers/metabolism/pharmacology, PPAR gamma/metabolism, Signal Transduction/drug effects

Hospitalized infants are exposed to numerous devices containing the plasticizer di-(2-ethylhexyl) phthalate. Urinary levels of the phthalate metabolite, mono-(2-ethylhexyl) phthalate (MEHP), are markedly elevated in premature infants. Phthalates inactivate peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear transcription factor that mediates the resolution of inflammation, a process impaired in neonates. We speculate that this increases their susceptibility to MEHP, and this was analyzed. MEHP inhibited neutrophil apoptosis; neonatal cells were more sensitive than adult cells. In neonatal, but not in adult neutrophils, MEHP also inhibited chemotaxis, stimulated oxidative metabolism, and up-regulated expression of NADPH oxidase-1. In both adult and neonatal neutrophils, MEHP stimulated IL-1beta and VEGF production, whereas IL-8 production was stimulated only in adult cells. In contrast, MEHP-inhibited production of MIP-1beta by adult cells, and Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) by neonatal neutrophils. The effects of MEHP on apoptosis and oxidative metabolism in neonatal cells were reversed by the PPAR-gamma agonist, troglitazone. Whereas troglitazone had no effect on MEHP-induced alterations in inflammatory protein or chemokine production, constitutive IL-8 and MIP-1beta production was reduced in adult neutrophils, and RANTES and MIP-1beta in neonatal cells. These findings suggest that neonatal neutrophils are more sensitive to phthalate-mediated inhibition of PPAR-gamma, which may be related to decreased anti-inflammatory signaling.