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DOI | 10.1289/EHP9262 |
Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice | |
Yipeng Sui; Zhaojie Meng; Jianzhong Chen; Jingwei Liu; Rebecca Hernandez; Miko B. Gonzales; Taesik Gwag; Andrew J. Morris; Changcheng Zhou | |
2021-12-01 | |
发表期刊 | Environmental Health Perspectives
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出版年 | 2021 |
英文摘要 | AbstractBackground: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 |
领域 | 资源环境 |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/343000 |
专题 | 资源环境科学 |
推荐引用方式 GB/T 7714 | Yipeng Sui,Zhaojie Meng,Jianzhong Chen,et al. Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice[J]. Environmental Health Perspectives,2021. |
APA | Yipeng Sui.,Zhaojie Meng.,Jianzhong Chen.,Jingwei Liu.,Rebecca Hernandez.,...&Changcheng Zhou.(2021).Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice.Environmental Health Perspectives. |
MLA | Yipeng Sui,et al."Effects of Dicyclohexyl Phthalate Exposure on PXR Activation and Lipid Homeostasis in Mice".Environmental Health Perspectives (2021). |
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