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Published on: August 12, 2020
Inflammatory effects of phthalates in neonatal neutrophils
Anna M Vetrano1, Debra L Laskin, Faith Archer
1Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
Insights
Neonatal infants exposed to phthalates show increased susceptibility to inflammation due to inhibited peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This phthalate metabolite, mono-(2-ethylhexyl) phthalate (MEHP), impairs crucial immune cell functions in newborns.
Area of Science:
- Environmental toxicology
- Neonatal immunology
- Inflammation research
Background:
- Hospitalized infants are frequently exposed to di-(2-ethylhexyl) phthalate, a common plasticizer.
- Elevated urinary levels of the phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) are observed in premature infants.
- Phthalates are known to inactivate peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a key regulator of inflammation.
Purpose of the Study:
- To investigate the heightened susceptibility of neonates to MEHP.
- To analyze the impact of MEHP on neutrophil function in neonatal versus adult cells.
- To explore the role of PPAR-gamma in mediating the effects of MEHP.
Main Methods:
- Comparative analysis of MEHP effects on neonatal and adult neutrophils.
- Assessment of neutrophil apoptosis, chemotaxis, oxidative metabolism, and inflammatory marker production.
- Evaluation of the modulatory effects of the PPAR-gamma agonist troglitazone.
Main Results:
- MEHP inhibited neutrophil apoptosis, with greater sensitivity in neonatal cells.
- Neonatal neutrophils exhibited MEHP-induced inhibition of chemotaxis and increased oxidative metabolism.
- MEHP altered the production of various inflammatory cytokines and chemokines, with differential effects in neonatal and adult cells.
- Troglitazone reversed MEHP's effects on apoptosis and oxidative metabolism in neonatal cells.
Conclusions:
- Neonatal neutrophils are more sensitive to phthalate-mediated PPAR-gamma inhibition.
- Impaired anti-inflammatory signaling in neonates may contribute to their increased susceptibility to phthalates.
- Phthalate exposure in early life may have significant implications for immune system development and function.
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.
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