Phthalate plasticizers are ubiquitous toxicants in the neonatal ICU. These compounds leech into the circulation of neonates in high concentrations from PVC-containing medical devices. They increase and prolong inflammatory responses in neonates, who are already susceptible to chronic inflammation because of immaturity of signaling pathways controlling the resolution of inflammation. Therefore, phthalate exposure likely contributes to the high incidence of severe complications associated with persistent inflammation, such as bronchopulmonary dysplasia. Since phthalate-containing medical devices are essential for neonatal survival, the use of dietary supplementation to counteract phthalate toxicity may offer a practical alternative to limiting their use. It has been shown that phthalate-mediated activation of neonatal neutrophils is reduced by synthetic agonists of peroxisome proliferator activated receptor-(PPAR-?), suggesting that phthalates act by competitively inhibiting activity of this transcription factor, which is a key pathway mediating the down regulation of inflammatory activity in neutrophils. Endogenous PPAR-? ligands, such as ?-3 polyunsaturated fatty acids (PUFA) and nitrated fatty acids, are known to attenuate neutrophil activity. Taken together, these findings suggest that dietary PPAR-? agonists may attenuate the inflammatory toxicity of phthalates. It is hypothesized that PPAR-? activity is developmentally impaired in neonatal neutrophils and that exposure to phthalates further delays the resolution of inflammatory responses in these cells. Activation of PPAR-? via its natural ligands, ?-3 fatty acids and nitrated fatty acids, may ameliorate these effects. In these studies, the effects of phthalates and fatty acids on PPAR-? signaling will be characterized in neonatal neutrophils, and with adult cells. The potential roles of these dietary PPAR-? agonists in ameliorating the inflammatory effects of phthalates will be quantified. Finally, specific mechanisms underlying differential susceptibility of adults and neonates to PPAR ligands will be identified. The American Academy of Pediatrics, U.S. FDA, and the Center for the Evaluation of Risks to Human Reproduction have noted an urgent public health need for data on the toxicity of phthalates in human neonates, and on the role of PPAR signaling in these effects. These findings will address this need, and may suggest novel nutritional interventions to prevent chronic inflammatory conditions associated with exposure to phthalates in neonates.

Public Health Relevance

Hospitalized newborns are exposed to high levels of phthalate plasticizers from intravenous catheters and tubing, and these compounds may contribute to inflammatory diseases in this population. Specific dietary fatty acids (e.g., ?-3 polyunsaturated fatty acids) and their derivatives (e.g., nitrated fatty acids) decrease inflammatory responses. In these studies, we will investigate whether fatty acids ameliorate the toxicity of phthalates, suggesting practical nutritional approaches to reducing the high burden of inflammatory disease attributable to phthalate exposure in hospitalized neonates.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZES1-LWJ-J (DI))
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Gray, Kimberly A
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Rbhs-Robert Wood Johnson Medical School
Schools of Medicine
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