Background

Exposure to consumer product chemicals during pregnancy may increase susceptibility to pregnancy disorders by influencing maternal inflammation. However, effects on specific inflammatory pathways have not been well characterized. Oxylipins are a diverse class of lipids that act as important mediators and biomarkers of several biological pathways that regulate inflammation. Adverse pregnancy outcomes have been associated with circulating oxylipin levels in pregnancy. In this study, we aimed to determine the longitudinal associations between plasma oxylipins and urinary biomarkers of three classes of consumer product chemicals among pregnant women.

Methods

Data come from a study of 90 pregnant women nested within the LIFECODES cohort. Maternal plasma and urine were collected at three prenatal visits. Plasma was analyzed for 61 oxylipins, which were grouped according to biosynthetic pathways that we defined by upstream: 1) fatty acid precursor, including linoleic, arachidonic, docosahexaenoic, or eicosapentaenoic acid; and 2) enzyme pathway, including cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 (CYP). Urine was analyzed for 12 phenol, 12 phthalate, and 9 organophosphate ester (OPE) biomarkers. Linear mixed effect models were used for single-pollutant analyses. We implemented a novel extension of quantile g-computation for longitudinal data to examine the joint effect of class-specific chemical mixtures on individual plasma oxylipin concentrations.

Results

We found that urinary biomarkers of consumer product chemicals were positively associated with pro-inflammatory oxylipins from several biosynthetic pathways. Importantly, these associations depended upon the chemical class of exposure biomarker. We estimated positive associations between urinary phenol biomarkers and oxylipins produced from arachidonic acid by LOX enzymes, including several important pro-inflammatory hydroxyeicosatetraenoic acids (HETEs). On average, mean concentrations of oxylipin produced from the arachidonic acid/LOX pathway were 48%–71% higher per quartile increase in the phenol biomarker mixture. For example, a simultaneous quartile increase in all urinary phenols was associated with 53% higher (95% confidence interval [CI]: 11%, 111%) concentrations of 12-HETE. The positive associations among phenols were primarily driven by methyl paraben, 2,5-dichlorophenol, and triclosan. Additionally, we observed that phthalate and OPE metabolites were associated with higher concentrations of oxylipins produced from linoleic acid by CYP enzymes, including the pro-inflammatory dihydroxy-octadecenoic acids (DiHOMEs). Associations among DiHOME oxylipins were driven by metabolites of benzylbutyl and di-isodecyl phthalate, and by the metabolite of tris(1,3-dichloro-2-propyl) phosphate among OPEs. We also observed inverse associations between phthalate and OPE metabolites and oxylipins produced from other pathways; however, adjusting for a plasma indicator of dietary fatty acid intake attenuated those results.

Conclusions

Our findings support the hypothesis that consumer product chemicals may have diverse impacts on inflammation processes in pregnancy. Certain pro-inflammatory oxylipins were generally higher among participants with higher urinary chemical biomarker concentrations. Associations varied by class of chemical and by the biosynthetic pathway of oxylipin production, indicating potential specificity in the inflammatory effects of these environmental chemicals during pregnancy that warrant investigation in larger studies.

中文翻译：

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纵向暴露于消费品化学品和孕妇血浆氧磷脂的变化

背景

怀孕期间接触消费品化学品可能会影响母体炎症，从而增加对妊娠疾病的易感性。然而，对特定炎症通路的影响尚未得到很好的表征。Oxylipins 是一类不同的脂质，可作为调节炎症的几种生物途径的重要介质和生物标志物。不良妊娠结局与妊娠期循环氧磷脂水平有关。在这项研究中，我们旨在确定孕妇血浆氧化脂蛋白与三类消费品化学品的尿液生物标志物之间的纵向关联。

方法

数据来自对 LIFECODES 队列中嵌套的 90 名孕妇的研究。在三次产前检查时收集母体血浆和尿液。分析了血浆中的 61 种氧化脂质，这些氧化脂质根据我们定义的上游生物合成途径进行分组：1) 脂肪酸前体，包括亚油酸、花生四烯酸、二十二碳六烯酸或二十碳五烯酸；2) 酶途径，包括环氧合酶 (COX)、脂氧合酶 (LOX) 或细胞色素 P450 (CYP)。分析了尿液中的 12 种苯酚、12 种邻苯二甲酸酯和 9 种有机磷酸酯 (OPE) 生物标志物。线性混合效应模型用于单一污染物分析。我们对纵向数据实施了分位数 g 计算的新扩展，以检查特定类别的化学混合物对个体血浆氧磷脂浓度的联合影响。

结果

我们发现，消费品化学品的尿液生物标志物与来自多种生物合成途径的促炎性氧化磷脂呈正相关。重要的是，这些关联取决于暴露生物标志物的化学类别。我们评估了尿酚生物标志物与 LOX 酶从花生四烯酸产生的氧磷脂之间的正相关性，包括几种重要的促炎性羟基二十碳四烯酸 (HETE)。平均而言，从花生四烯酸/LOX 途径产生的氧化磷脂的平均浓度在苯酚生物标志物混合物中每四分位数增加 48%–71%。例如，所有尿酚的四分位数同时增加与 12-HETE 浓度升高 53%（95% 置信区间 [CI]：11%，111%）相关。酚类之间的正相关主要是由对羟基苯甲酸甲酯、2,5-二氯苯酚和三氯生驱动的。此外，我们观察到邻苯二甲酸酯和 OPE 代谢物与 CYP 酶从亚油酸产生的较高浓度的 oxylipins 有关，包括促炎性二羟基十八碳烯酸 (DiHOMEs)。DiHOME oxylipins 之间的关联是由苄基丁基和邻苯二甲酸二异癸酯的代谢物以及 OPE 中的磷酸三（1,3-二氯-2-丙基）代谢物驱动的。我们还观察到邻苯二甲酸酯和 OPE 代谢物与其他途径产生的 oxylipins 之间的负相关；然而，调整膳食脂肪酸摄入量的血浆指标会减弱这些结果。我们观察到邻苯二甲酸酯和 OPE 代谢物与 CYP 酶从亚油酸产生的较高浓度的 oxylipins 有关，包括促炎性二羟基十八碳烯酸 (DiHOMEs)。DiHOME oxylipins 之间的关联是由苄基丁基和邻苯二甲酸二异癸酯的代谢物以及 OPE 中的三（1,3-二氯-2-丙基）磷酸盐的代谢物驱动的。我们还观察到邻苯二甲酸酯和 OPE 代谢物与其他途径产生的 oxylipins 之间的负相关；然而，调整膳食脂肪酸摄入量的血浆指标会减弱这些结果。我们观察到邻苯二甲酸酯和 OPE 代谢物与 CYP 酶从亚油酸产生的较高浓度的 oxylipins 有关，包括促炎性二羟基十八碳烯酸 (DiHOMEs)。DiHOME oxylipins 之间的关联是由苄基丁基和邻苯二甲酸二异癸酯的代谢物以及 OPE 中的三（1,3-二氯-2-丙基）磷酸盐的代谢物驱动的。我们还观察到邻苯二甲酸酯和 OPE 代谢物与其他途径产生的 oxylipins 之间的负相关；然而，调整膳食脂肪酸摄入量的血浆指标会减弱这些结果。DiHOME oxylipins 之间的关联是由苄基丁基和邻苯二甲酸二异癸酯的代谢物以及 OPE 中的三（1,3-二氯-2-丙基）磷酸盐的代谢物驱动的。我们还观察到邻苯二甲酸酯和 OPE 代谢物与其他途径产生的 oxylipins 之间的负相关；然而，调整膳食脂肪酸摄入量的血浆指标会减弱这些结果。DiHOME oxylipins 之间的关联是由苄基丁基和邻苯二甲酸二异癸酯的代谢物以及 OPE 中的磷酸三（1,3-二氯-2-丙基）代谢物驱动的。我们还观察到邻苯二甲酸酯和 OPE 代谢物与其他途径产生的 oxylipins 之间的负相关；然而，调整膳食脂肪酸摄入量的血浆指标会减弱这些结果。

结论

我们的研究结果支持消费品化学品可能对妊娠期炎症过程产生不同影响的假设。在具有较高尿化学生物标志物浓度的参与者中，某些促炎性氧化磷脂通常较高。相关性因化学物质类别和 oxylipin 产生的生物合成途径而异，表明这些环境化学物质在怀孕期间的炎症作用具有潜在的特异性，值得在更大规模的研究中进行调查。