Protective Effects of Fatty Acids in Phthalate-Induced Inflammation in Neonates

描述（由申请方提供）：邻苯二甲酸酯增塑剂是新生儿ICU中普遍存在的毒物。这些化合物从含PVC的医疗器械中以高浓度渗入新生儿的循环中。它们增加并延长新生儿的炎症反应，由于控制炎症消退的信号通路不成熟，新生儿已经对慢性炎症易感。因此，邻苯二甲酸酯暴露可能导致与持续性炎症相关的严重并发症（如支气管肺发育不良）的高发生率。由于含邻苯二甲酸酯的医疗器械对新生儿的生存至关重要，因此使用膳食补充剂来抵消邻苯二甲酸酯毒性可能会提供一种限制其使用的实用替代方案。研究表明，过氧化物酶体增殖物激活受体（PPAR-？）的合成激动剂可降低邻苯二甲酸酯介导的新生儿中性粒细胞活化，这表明邻苯二甲酸酯通过竞争性抑制该转录因子的活性而起作用，该转录因子是介导中性粒细胞中炎症活性下调的关键途径。内源性过氧化物酶体增殖物激活受体-？配体，如？3多不饱和脂肪酸（PUFA）和硝化脂肪酸，已知减弱中性粒细胞活性。综上所述，这些研究结果表明，饮食中的过氧化物酶体增殖物激活受体？激动剂可以减弱邻苯二甲酸酯的炎性毒性。据推测，PPAR-？活性在新生儿中性粒细胞中发育受损，并且暴露于邻苯二甲酸酯进一步延迟了这些细胞中炎症反应的消退。激活过氧化物酶体增殖物激活受体-？通过其天然配体，3脂肪酸和硝化脂肪酸，可以改善这些影响。在这些研究中，邻苯二甲酸酯和脂肪酸对PPAR-？信号传导将在新生儿嗜中性粒细胞和成年细胞中表征。这些饮食中的潜在作用？将定量改善邻苯二甲酸酯的炎症作用的激动剂。最后，将确定成人和新生儿对PPAR配体的不同易感性的具体机制。美国儿科学会、美国FDA和人类生殖风险评估中心指出，迫切需要关于邻苯二甲酸酯在人类新生儿中的毒性以及PPAR信号在这些影响中的作用的公共卫生数据。这些发现将满足这一需求，并可能提出新的营养干预措施，以预防与邻苯二甲酸酯暴露相关的新生儿慢性炎症。

DESCRIPTION (provided by applicant): 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.