Abstract

Background:

Exposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo.

Objective:

We sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors.

Methods:

Cell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD.

Results:

DCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild-type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings.

Discussion:

Although the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs. https://doi.org/10.1289/EHP9262

中文翻译：

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邻苯二甲酸二环己酯暴露对小鼠 PXR 活化和脂质稳态的影响

摘要

背景：

接触塑料相关内分泌干扰物 (EDC) 与人类心血管疾病 (CVD) 风险增加有关。然而，这种关联的潜在机制尚不清楚。许多 EDC 已被证明可作为核受体孕烷 X 受体 (PXR) 的配体发挥作用，PXR 可作为外源性传感器发挥作用，但在体内也具有促动脉粥样硬化作用。

客观的：

我们试图研究 PXR 对邻苯二甲酸二环己酯 (DCHP)（一种广泛使用的邻苯二甲酸酯增塑剂）对脂质稳态和 CVD 危险因素的不利影响的贡献。

方法：

基于细胞的测定、原代类器官培养、PXR 条件性敲除和 PXR 人源化小鼠模型用于研究 DCHP 暴露对体外和体内PXR 活化和脂质稳态的影响。进行靶向脂质组学以测量循环神经酰胺，这是 CVD 的新预测因子。

结果：

DCHP 被确定为一种有效的 PXR 选择性激动剂，可导致野生型小鼠血浆胆固醇水平升高。然后通过使用组织特异性 PXR 缺陷小鼠证明 DCHP 可以激活肠道 PXR 以引发高脂血症。有趣的是，DCHP 暴露也以 PXR 依赖的方式导致更高的循环神经酰胺。DCHP 介导的 PXR 激活刺激了介导脂肪生成和神经酰胺合成的肠道基因的表达。鉴于 PXR 在受体药理学上表现出相当大的物种特异性差异，PXR 人源化小鼠也被用来复制这些发现。

讨论：

尽管几种众所周知的邻苯二甲酸酯对健康的不利影响引起了相当大的关注，但人们对 DCHP 对人类健康的潜在影响知之甚少。我们的研究表明，DCHP 激活 PXR 以在小鼠中诱导高胆固醇血症和神经酰胺产生。这些结果表明 PXR 在促进塑料相关 EDC 对人类心血管健康的有害影响方面可能发挥重要作用。对于邻苯二甲酸盐和其他 EDC 的风险评估，应考虑测试 PXR 活化。https://doi.org/10.1289/EHP9262