Zhou Michael, Ford Breanna, Lee Douglas, Tindula Gwen, Huen Karen, Tran Vy, Bradman Asa, Gunier Robert, Eskenazi Brenda, Nomura Daniel K, Holland Nina
School of Public Health, Center for Environmental Research and Children's Health, University of California, Berkeley, Berkeley, CA, United States.
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, United States.
Front Public Health. 2018 Oct 22;6:298. doi: 10.3389/fpubh.2018.00298. eCollection 2018.
Phthalates are known endocrine disruptors and found in almost all people with several associated adverse health outcomes reported in humans and animal models. Limited data are available on the relationship between exposure to endocrine disrupting chemicals and the human metabolome. We examined the relationship of metabolomic profiles in plasma and urine of 115 pregnant women with eleven urine phthalate metabolites measured at 26 weeks of gestation to identify potential biomarkers and relevant pathways. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 415 metabolites in plasma and 151 metabolites in urine samples. We have chosen metabolites with the best defined peaks for more detailed analysis (138 in plasma and 40 in urine). Relationship between urine phthalate metabolites and concurrent metabolomic markers in plasma and urine suggested potential involvement of diverse pathways including lipid, steroid, and nucleic acid metabolism and enhanced inflammatory response. Most of the correlations were positive for both urine and plasma, and further confirmed by regression and PCA analysis. However, after the FDR adjustment for multiple comparisons, only 9 urine associations remained statistically significant (-values 0.0001-0.0451), including Nicotinamide mononucleotide, Cysteine T2, Cystine, and L-Aspartic acid. Additionally, we found negative associations of maternal pre-pregnancy body mass index (BMI) with more than 20 metabolomic markers related to lipid and amino-acid metabolism and inflammation pathways in plasma ( = 0.01-0.0004), while Mevalonic acid was positively associated ( = 0.009). Nicotinic acid, the only significant metabolite in urine, had a positive association with maternal BMI ( = 0.002). In summary, when evaluated in the context of metabolic pathways, the findings suggest enhanced lipid biogenesis, inflammation and altered nucleic acid metabolism in association with higher phthalate levels. These results provide new insights into the relationship between phthalates, common in most human populations, and metabolomics, a novel approach to exposure and health biomonitoring.
邻苯二甲酸盐是已知的内分泌干扰物，几乎在所有人身上都能发现，在人类和动物模型中已有多项相关不良健康后果的报道。关于接触内分泌干扰化学物质与人类代谢组之间的关系，现有数据有限。我们研究了115名孕妇在妊娠26周时血浆和尿液中的代谢组学特征与11种尿液邻苯二甲酸盐代谢物之间的关系，以确定潜在的生物标志物和相关途径。通过选择反应监测液相色谱和三重四极杆质谱法进行靶向代谢组学分析，以测量血浆中的415种代谢物和尿液样本中的151种代谢物。我们选择了峰定义最佳的代谢物进行更详细的分析（血浆中138种，尿液中40种）。尿液邻苯二甲酸盐代谢物与血浆和尿液中同时存在的代谢组学标志物之间的关系表明，包括脂质、类固醇和核酸代谢以及增强的炎症反应在内的多种途径可能参与其中。大多数相关性在尿液和血浆中均为阳性，并通过回归和主成分分析得到进一步证实。然而，在对多重比较进行错误发现率（FDR）调整后，只有9种尿液关联仍具有统计学意义（P值为0.0001 - 0.0451），包括烟酰胺单核苷酸、半胱氨酸T2、胱氨酸和L - 天冬氨酸。此外，我们发现孕妇孕前体重指数（BMI）与血浆中20多种与脂质和氨基酸代谢以及炎症途径相关的代谢组学标志物呈负相关（P = 0.01 - 0.0004），而甲羟戊酸呈正相关（P = 0.009）。尿液中唯一显著的代谢物烟酸与孕妇BMI呈正相关（P = 0.002）。总之，在代谢途径的背景下进行评估时，研究结果表明，邻苯二甲酸盐水平较高与脂质生物合成增强、炎症以及核酸代谢改变有关。这些结果为大多数人群中常见的邻苯二甲酸盐与代谢组学（一种新型的暴露和健康生物监测方法）之间的关系提供了新的见解。
