title: Inflammatory effects of phthalates in neonatal neutrophils.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Vetrano
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
authors.forename: Faith
authors.initials: F
authors.lastname: Archer
authors.forename: Kirin
authors.initials: K
authors.lastname: Syed
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Gray
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
authors.forename: Nkiru
authors.initials: N
authors.lastname: Nwebube
authors.forename: Barry
authors.initials: B
authors.lastname: Weinberger
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007231:Infant, Newborn; D007249:Inflammation / Q000139:chemically induced*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D016877:Oxidants / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D010968:Plasticizers / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016877:Oxidants; D047495:PPAR gamma; D010795:Phthalic Acids; D010968:Plasticizers; C032279:phthalic acid; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate
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