Background and aim

Our objective was to use metabolomics in a toxicological-relevant target tissue to gain insight into the biological processes that may underlie the negative association between air pollution exposure and oocyte quality.

Methods

Our study included 125 women undergoing in vitro fertilization at an academic fertility center in Massachusetts, US (2005–2015). A follicular fluid sample was collected during oocyte retrieval and untargeted metabolic profiling was conducted using liquid chromatography with ultra-high-resolution mass spectrometry and two chromatography columns (C18 and HILIC). Daily exposure to nitrogen dioxide (NO₂), ozone, fine particulate matter, and black carbon was estimated at the women’s residence using spatiotemporal models and averaged over the period of ovarian stimulation (2-weeks). Multivariable linear regression models were used to evaluate the associations between the air pollutants, number of mature oocytes, and metabolic feature intensities. A meet-in-the-middle approach was used to identify overlapping features and metabolic pathways.

Results

Of the air pollutants, NO₂ exposure had the largest number of overlapping metabolites (C18: 105; HILIC: 91) and biological pathways (C18: 3; HILIC: 6) with number of mature oocytes. Key pathways of overlap included vitamin D3 metabolism (both columns), bile acid biosynthesis (both columns), C21-steroid hormone metabolism (HILIC), androgen and estrogen metabolism (HILIC), vitamin A metabolism (HILIC), carnitine shuttle (HILIC), and prostaglandin formation (C18). Three overlapping metabolites were confirmed with level-1 or level-2 evidence. For example, hypoxanthine, a metabolite that protects against oxidant-induced cell injury, was positively associated with NO₂ exposure and negatively associated with number of mature oocytes. Minimal overlap was observed between the other pollutants and the number of mature oocytes.

Conclusions

Higher exposure to NO₂ during ovarian stimulation was associated with many metabolites and biologic pathways involved in endogenous vitamin metabolism, hormone synthesis, and oxidative stress that may mediate the observed associations with lower oocyte quality.

中文翻译：

---

使用卵泡液代谢组学研究空气污染与卵母细胞质量之间的关系

背景和目标

我们的目标是在毒理学相关的靶组织中使用代谢组学来深入了解可能构成空气污染暴露与卵母细胞质量之间负相关的生物学过程。

方法

我们的研究包括 125 名在美国马萨诸塞州学术生育中心接受体外受精的女性 (2005–2015)。在取卵过程中收集了卵泡液样本，并使用液相色谱、超高分辨率质谱和两个色谱柱（C18 和 HILIC）进行了非靶向代谢分析。每天接触二氧化氮 (NO ₂)、臭氧、细颗粒物和黑碳是在女性住所使用时空模型估算的，并在卵巢刺激期间（2 周）取平均值。多变量线性回归模型用于评估空气污染物、成熟卵母细胞数量和代谢特征强度之间的关联。使用中间相遇的方法来识别重叠特征和代谢途径。

结果

在空气污染物中，NO ₂暴露具有最多数量的重叠代谢物（C18：105；HILIC：91）和生物途径（C18：3；HILIC：6）以及成熟卵母细胞的数量。重叠的关键途径包括维生素 D3 代谢（双列）、胆汁酸生物合成（双列）、C21 类固醇激素代谢 (HILIC)、雄激素和雌激素代谢 (HILIC)、维生素 A 代谢 (HILIC)、肉碱穿梭 (HILIC)和前列腺素形成 (C18)。三个重叠的代谢物被 1 级或 2 级证据证实。例如，次黄嘌呤是一种可防止由氧化剂引起的细胞损伤的代谢物，与 NO _{2呈正相关}暴露并与成熟卵母细胞数量呈负相关。在其他污染物和成熟卵母细胞的数量之间观察到最小的重叠。

结论

促排卵期间较高的 NO _{2暴露与许多代谢物和涉及内源性维生素代谢、激素合成和氧化应激的生物途径有关，这些代谢物和生物途径可能介导观察到的与较低卵母细胞质量的关联。}