Abstract

Background:

Aryl phosphate esters (APEs) are widely used and commonly present in the environment. Health hazards associated with these compounds remain largely unknown and the effects of diphenyl phosphate (DPhP), one of their most frequent derivatives, are poorly characterized.

Objective:

Our aim was to investigate whether DPhP per se may represent a more relevant marker of exposure to APEs than direct assessment of their concentration and determine its potential deleterious biological effects in chronically exposed mice.

Methods:

Conventional animals (FVB mice) were acutely or chronically exposed to relevant doses of DPhP or to triphenyl phosphate (TPhP), one of its main precursors. Both molecules were measured in blood and other tissues by liquid chromatography–mass spectrometry (LC-MS). Effects of chronic DPhP exposure were addressed through liver multi-omics analysis to determine the corresponding metabolic profile. Deep statistical exploration was performed to extract correlated information, guiding further physiological analyses.

Results:

Multi-omics analysis confirmed the existence of biological effects of DPhP, even at a very low dose of $0.1\mathrm{mg}/\mathrm{mL}$ in drinking water. Chemical structural homology and pathway mapping demonstrated a clear reduction of the fatty acid catabolic processes centered on acylcarnitine and mitochondrial $\mathrm{\beta }\text{-oxidation}$ in mice exposed to DPhP in comparison with those treated with vehicle. An interesting finding was that in mice exposed to DPhP, mRNA, expression of genes involved in lipid catabolic processes and regulated by peroxisome proliferator–activated receptor alpha ($\text{PPAR}\mathrm{\alpha }$) was lower than that in vehicle-treated mice. Immunohistochemistry analysis showed a specific down-regulation of HMGCS2, a kernel target gene of $\text{PPAR}\mathrm{\alpha }$. Overall, DPhP absorption disrupted body weight–gain processes.

Conclusions:

Our results suggest that in mice, the effects of chronic exposure to DPhP, even at a low dose, are not negligible. Fatty acid metabolism in the liver is essential for controlling fast and feast periods, with adverse consequences on the overall physiology. Therefore, the impact of DPhP on circulating fat, cardiovascular pathologies and metabolic disease incidence deserves, in light of our results, further investigations. https://doi.org/10.1289/EHP6826

中文翻译：

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体内表征DPhP的毒性，DPhP是芳基磷酸酯的主要降解产物之一

摘要

背景：

芳基磷酸酯（APE）已被广泛使用并普遍存在于环境中。与这些化合物有关的健康危害仍是未知之数，磷酸二苯酯（DPhP）（其最常见的衍生物之一）的作用尚不明确。

目的：

我们的目的是研究与直接评估其浓度相比，DPhP本身是否可以代表与APE接触更为相关的标志物，并确定其在慢性接触小鼠中的潜在有害生物效应。

方法：

常规动物（FVB小鼠）急性或慢性暴露于相关剂量的DPhP或磷酸三苯酯（TPhP）（其主要前体之一）。液相色谱-质谱法（LC-MS）测定了血液和其他组织中的两种分子。慢性DPhP暴露的影响通过肝脏多组学分析来确定相应的代谢谱。进行了深度统计探索，以提取相关信息，指导进一步的生理分析。

结果：

多组学分析证实，即使在很低剂量的DPhP下，DPhP仍具有生物学作用。 $0.1\mathrm{毫克}/\mathrm{毫升}$在饮用水中。化学结构同源性和途径作图表明，以酰基肉碱和线粒体为中心的脂肪酸分解代谢过程明显减少$\mathrm{\beta }\text{-氧化}$与用赋形剂处理的小鼠相比，暴露于DPhP的小鼠体内的抗氧化活性更高。一个有趣的发现是，在暴露于DPhP，mRNA的小鼠中，参与脂质分解代谢过程的基因的表达受过氧化物酶体增殖物激活的受体α（$\text{PPAR}\mathrm{\alpha }$）低于载体治疗的小鼠。免疫组织化学分析显示HMGCS2是HCC的核心靶基因$\text{PPAR}\mathrm{\alpha }$。总体而言，DPhP的吸收破坏了体重增加过程。

结论：

我们的结果表明，即使在低剂量下，长期暴露于DPhP的小鼠的影响也不容忽视。肝脏中的脂肪酸代谢对于控制快速和丰盛的时期至关重要，会对整体生理产生不利影响。因此，根据我们的结果，DPhP对循环脂肪，心血管疾病和代谢疾病发生率的影响值得进一步研究。https://doi.org/10.1289/EHP6826