Ketema Rahel Mesfin, Ait Bamai Yu, Goudarzi Houman, Yamaguchi Takeshi, Zeng Yi, Yasuda Ayaka, Marsela Megasari, Konno Satoshi, Kishi Reiko, Ikeda Atsuko
Faculty of Health Sciences, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo 060-0812, Japan.
Center for Environmental and Health Sciences, Hokkaido University, Kita 12, Nishi 7, Kita-ku, Sapporo 060-0812, Japan.
Environ Sci Technol. 2025 Apr 22;59(15):7541-7549. doi: 10.1021/acs.est.4c14579. Epub 2025 Apr 8.
Phthalate exposure is linked to asthma and allergic symptoms, yet their individual and combined effects on symptoms and inflammatory biomarkers, type 2 (T2) and non-T2, remain unexplored. This study examined the association of phthalate metabolites with allergic symptoms (wheeze, allergic rhinoconjunctivitis, and eczema), T2 biomarker (fraction of exhaled nitric oxide (FeNO), blood eosinophil count, and total immunoglobulin E (IgE)), and non-T2 biomarker (absolute neutrophil count (ANC)) and also their association with oxidative stress biomarkers, such as 4-hydroxynonenal, hexanoyl-lysine, and 8-hydroxy-2-deoxyguanosine. Ten urinary phthalate metabolites were measured using UPLC-MS/MS in 421 children (aged 9-12 years) from The Hokkaido Cohort, Japan. Symptoms were defined using the International Study of Asthma and Allergies in Childhood questionnaire, and biomarkers were measured in blood. Logistic regression assessed individual metabolites, while quantile-g computation and Bayesian kernel machine regression analyzed mixture effects on binary outcomes. Individual analysis showed that MnBP (mono--butyl phthalate) was positively associated with allergic rhinoconjunctivitis and eosinophil ≥ 300 cells/μL, while ∑DBP (dibutyl phthalate) and OH-MiNP (mono-hydroxy-isononyl phthalate) were linked with FeNO ≥ 35 ppb. DEHP (di(2-ethylhexyl) phthalate) metabolites were associated with a high prevalence of blood eosinophils ≥ 300 cells/μL. We found a positive association between phthalates and oxidative stress markers, but no link was observed between oxidative stress and inflammatory markers. Mixture analysis identified MnBP as a major contributor to the high FeNO level, with di--butyl phthalate (DnBP) and DEHP metabolites contributing to eosinophil count ≥ 300 cells/μL and ANC ≥ 4400 cells/μL. These findings suggest that phthalate exposure from DnBP and DEHP is associated with immune dysregulation by triggering both T2 and non-T2 inflammatory responses.
邻苯二甲酸盐暴露与哮喘和过敏症状有关，但其对症状和炎症生物标志物（2型（T2）和非T2）的个体及联合影响仍未得到探索。本研究调查了邻苯二甲酸酯代谢物与过敏症状（喘息、过敏性鼻结膜炎和湿疹）、T2生物标志物（呼出一氧化氮分数（FeNO）、血液嗜酸性粒细胞计数和总免疫球蛋白E（IgE））以及非T2生物标志物（绝对中性粒细胞计数（ANC））的关联，还研究了它们与氧化应激生物标志物（如4-羟基壬烯醛、己酰赖氨酸和8-羟基-2-脱氧鸟苷）的关联。使用超高效液相色谱-串联质谱法（UPLC-MS/MS）测量了日本北海道队列中421名9至12岁儿童的十种尿邻苯二甲酸酯代谢物。症状通过儿童哮喘和过敏国际研究问卷进行定义，生物标志物在血液中进行测量。逻辑回归评估个体代谢物，而分位数g计算和贝叶斯核机器回归分析混合物对二元结局的影响。个体分析表明，单丁基邻苯二甲酸酯（MnBP）与过敏性鼻结膜炎和嗜酸性粒细胞≥300个/μL呈正相关，而邻苯二甲酸二丁酯（∑DBP）和单羟基异壬基邻苯二甲酸酯（OH-MiNP）与FeNO≥35 ppb有关。邻苯二甲酸二（2-乙基己基）酯（DEHP）代谢物与血液嗜酸性粒细胞≥300个/μL的高患病率相关。我们发现邻苯二甲酸盐与氧化应激标志物之间存在正相关，但未观察到氧化应激与炎症标志物之间的联系。混合物分析确定MnBP是FeNO水平升高的主要贡献者，邻苯二甲酸二正丁酯（DnBP）和DEHP代谢物导致嗜酸性粒细胞计数≥300个/μL和ANC≥4400个/μL。这些发现表明，DnBP和DEHP的邻苯二甲酸盐暴露通过引发T2和非T2炎症反应与免疫失调有关。
