Inflammatory effects of phthalates in neonatal neutrophils.
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.
Vetrano
Anna M
AM
Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
Laskin
Debra L
DL
Archer
Faith
F
Syed
Kirin
K
Gray
Joshua P
JP
Laskin
Jeffrey D
JD
Nwebube
Nkiru
N
Weinberger
Barry
B
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
D016877:Oxidants; D047495:PPAR gamma; D010795:Phthalic Acids; D010968:Plasticizers; C032279:phthalic acid; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate
Clin Nephrol. 1993 Jul;40(1):57
8358875
Int J Hyg Environ Health. 2005;208(6):489-98
16325559
Drugs Today (Barc). 2004 May;40(5):423-30
15319797
Arch Toxicol. 2004 Jul;78(7):384-9
15022035
Environ Health Perspect. 2001 Mar;109(3):229-37
11333183
J Pediatr Gastroenterol Nutr. 2004 Oct;39(4):341-5
15448422
Free Radic Biol Med. 2007 Aug 1;43(3):319-31
17602947
Biomarkers. 2006 Jan-Feb;11(1):1-13
16484133
Prog Lipid Res. 2006 Jul;45(4):334-56
16678271
Crit Care Med. 2004 Mar;32(3):826-31
15090969
J Perinatol. 2006 May;26 Suppl 1:S57-62; discussion S63-4
16625227
Br J Haematol. 2000 Jul;110(1):18-28
10930976
J Leukoc Biol. 2001 Dec;70(6):969-76
11739560
N Engl J Med. 1975 Feb 20;292(8):381-6
1110722
Toxicol Sci. 2000 Dec;58(2):339-49
11099646
Clin Chim Acta. 2005 Aug;358(1-2):159-66
15893743
Pediatr Res. 1982 May;16(5):373-6
6285261
Dev Med Child Neurol. 2007 Aug;49(8):587-90
17635203
J Toxicol Environ Health B Crit Rev. 2009 Feb;12(2):157-74
19235623
Environ Health Perspect. 1986 Mar;65:343-50
3709461
Pediatr Res. 2005 Jan;57(1):56-62
15557111
J Immunol Methods. 1997 Mar 28;202(2):133-41
9107302
Eur J Pediatr. 1996 Aug;155 Suppl 2:S14-7
8839740
J Biol Chem. 1998 Oct 2;273(40):25573-80
9748221
J Pediatr Surg. 2005 Jun;40(6):942-7; discussion 947-8
15991175
Int J Pharm. 2003 Aug 27;262(1-2):83-91
12927390
Toxicol Sci. 2000 Dec;58(2):350-65
11099647
Eur J Pediatr. 1988 Jan;147(1):41-6
3422189
Reprod Toxicol. 2006 Oct;22(3):291-399
17068859
Acta Paediatr. 1999 Oct;88(10):1174-5
10565474
Pediatrics. 2003 Jun;111(6 Pt 1):1467-74
12777573
J Exp Med. 1962 Mar 1;115:453-66
13872176
Transfusion. 2006 Aug;46(8):1457-8; author reply 1459
16934089
Pediatr Res. 2007 May;61(5 Pt 1):572-7
17413861
Blood. 1994 Feb 15;83(4):1086-92
7906565
Immunol Rev. 2000 Oct;177:195-203
11138776
Toxicology. 1980;18(1):49-60
7210023
Environ Health Perspect. 2003 Nov;111(14):1783-5
14594632
Biol Neonate. 2000 Nov;78(4):269-76
11093005
Environ Health Perspect. 2006 Nov;114(11):1783-9
17107868
Pediatrics. 2004 May;113(5):e429-34
15121985
Antioxid Redox Signal. 2007 Jan;9(1):49-89
17115887
Int J Biochem Cell Biol. 2003 Dec;35(12):1619-38
12962702
Antioxid Redox Signal. 2004 Feb;6(1):155-67
14713347
Int J Immunopharmacol. 1995 Feb;17(2):103-8
7657403
Clin Immunol. 2005 Feb;114(2):100-9
15639643
Exp Gerontol. 1998 Sep;33(6):525-33
9789730
J Free Radic Biol Med. 1986;2(4):295-8
3294992
Transfusion. 1993 Jul;33(7):598-605
8333024
Gastroenterology. 2009 Feb;136(2):585-95.e5
19013462
Toxicol Sci. 2003 Aug;74(2):297-308
12805656
J Immunol Methods. 1980;36(2):109-17
7430646
Toxicology. 2005 Mar 1;208(1):115-21
15664438
Artif Organs. 2003 Mar;27(3):256-60
12662212