基于脂肪酸代谢的动态变化解析邻苯二甲酯对儿童哮喘发生的影响

Phthalate esters (PAEs) are widely used as plasticizers in many industrial and consumer products, such as plastics, personal-care products, toys, paints and medical devices. They are easily released into the environment due to a lack of covalent bounding of PAEs in products. Human exposure to PAEs occurs through inhalation, absorption, ingestion or dermal contact during their whole lifetime including intrauterine development. Experimental results indicate that chronic exposure to PAEs may be responsible for a number of adverse health effects. Incidence of childhood asthma has risen in recent decades and is one of the most common chronic diseases among children. Epidemiological findings suggest a possible relationship between PAEs pollution and asthma in children. It was reported that PAEs exposure could disrupt fatty acid metabolism, such as increasing fatty acid oxidation, altering the expression of fatty acid transferring proteins. In addition, clinical data have also demonstrated that abnormal metabolism of fatty acid was closely related to the development of asthma disease. Therefore, we speculated that the dysregulation of fatty acid metabolism might play an important role in the development of childhood asthma caused by PAEs exposure. It is a promising strategy of linking PAEs exposure with biological response to integrate global profiling data of free fatty acids (FFAs) and oxylipins (OLs) and biomonitoring data. However, the current analytical methods are difficult to offer a comprehensive coverage of FFAs and OLs. Moreover, urinary monophthalates are commonly used as biomotoring indicators, but they are not enough to characterize the body burden of PAEs, especially for high molecular weight PAEs. This project aims to develop analytical methods of PAEs and its metabolites, FFA, and OLs in serum samples by using ultra performance liquid chromatography or supercritical fluid chromatography coupled with high-resolution mass spectrometry technologies, and further explored the association between low-level environmental PAEs exposure and dysregulation of FFAs and OLs homeostasis in childhood asthma. The results will provide reference data for evaluating health effects of children exposure to PAEs.

邻苯二甲酸酯（PAEs）作为增塑剂广泛添加在多种消费品中，释放到环境中的PAEs可通过呼吸、饮食和皮肤等途径进入体内。流行病学调查发现PAEs暴露水平与儿童哮喘的发生显著相关，进一步研究表明PAEs暴露可影响体内脂肪酸的代谢，因而脂肪酸代谢的动态变化可能是PAEs暴露影响儿童哮喘发生的因素。已有游离脂肪酸（FFAs）及其氧化产物氧脂素（OLs）分析方法的目标物覆盖度不够；以尿液中邻苯二甲酸单酯为暴露标志物开展的高分子量PAEs暴露评估结果存在误差。因此，本项目拟利用超高效液相（和超临界流体）色谱-高分辨质谱技术，构建血清中PAEs及其代谢产物、FFAs和OLs的靶向和非靶向分析方法，实现目标化合物的全景式分析；解析环境低剂量多种PAEs联合暴露引发血清中脂肪酸代谢的动态变化及其对儿童哮喘发生可能的影响，并筛选出潜在生物标志物，为PAEs长期暴露对儿童健康风险的评价提供参考数据。

邻苯二甲酸酯（PAEs）作为增塑剂广泛添加在塑料、个人护理品和医疗用品等多种消费产品中,可通过呼吸、饮食和皮肤接触等途径进儿童入体内，研究发现PAEs暴露水平与儿童哮喘的发生显著相关。PAEs暴露可影响体内脂肪酸代谢，而且异常的脂肪酸代谢与哮喘的发生有着密切的联系。本项目以液相色谱-质谱联用仪为技术平台，构建了PAEs内暴露水平评估和脂肪酸代谢谱表征新方法，进而通过临床样本分析初步揭示了PAEs暴露对儿童哮喘发生的影响。结果发现深圳市1~8岁儿童血清中共检测出了9种PAEs本体及代谢物，PAEs的暴露浓度为749.1±385.2 ng/mL，哮喘儿童血清中DCHP、MMP浓度显著高于对照组(P<0.05)，但DEP浓度低于健康对照组，且BBP、DCHP、MMP的水平与儿童哮喘呈显著正相关关系；儿童血清样品中共检测出41种脂肪酰类化合物，哮喘组与健康对照组、其他呼吸道疾病儿童血清脂肪酸代谢谱无显著差异，但哮喘脂肪酸谱表现出明显的年龄差异，6~8岁学龄儿童抗炎类脂肪酰显著高于对照组和其他呼吸道疾病组，这可能与学龄儿童较为完善的免疫系统有关；非靶向代谢组学分析结果表明哮喘儿童血清中氨基酸和脂质代谢也存在明显异常调控，且3~6岁学龄前儿童表现更为明显；另外，统计分析结果表明显著性差异化合物与PAEs暴露水平之间无显著的剂量-效应关系，表明PAEs暴露引发的代谢异常并未在儿童哮喘发病中发挥主要作用。