PPARβ/δ-ANGPTL4 axis mediates the promotion of mono-2-ethylhexyl phthalic acid on MYCN-amplified neuroblastoma development

作者全名："Liu, Yiyun; Hamid, Naima; Manzoor, Rakia; Zhang, Bao-Fu; Liao, Yan-Ling; Pei, De-Sheng"

作者地址："[Liu, Yiyun; Zhang, Bao-Fu; Liao, Yan-Ling; Pei, De-Sheng] Chongqing Med Univ, Sch Publ Hlth, Chongqing 400016, Peoples R China; [Hamid, Naima] Univ Malaysia Terengganu, Fac Sci & Marine Environm, Ocean Pollut & Ecotoxicol OPEC Res Grp, Kuala Nerus 21030, Terengganu, Malaysia; [Manzoor, Rakia] Southwest Univ, Coll Pharmaceut Sci, Chongqing 400715, Peoples R China"

通信作者："Pei, DS (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Chongqing 400016, Peoples R China."

来源：SCIENCE OF THE TOTAL ENVIRONMENT

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001138889800001

JCR分区：Q1

影响因子：9.8

年份：2024

卷号：912

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Plasticizer; MEHP; Neuroblastoma; Proliferation; Migration; Lipid metabolism

摘要："Di-2-ethylhexyl phthalic acid (DEHP) is one of the most widely used plasticizers in the industry, which can improve the flexibility and durability of plastics. It is prone to migrate from various daily plastic products through wear and leaching into the surrounding environment and decompose into the more toxic metabolite mono-2-ethylhexyl phthalic acid (MEHP) after entering the human body. However, the impacts and mechanisms of MEHP on neuroblastoma are unclear. We exposed MYCN-amplified neuroblastoma SK-N-BE(2)C cells to an environmentally related concentration of MEHP and found that MEHP increased the proliferation and migration ability of tumor cells. The peroxisome proliferator-activated receptor (PPAR) beta/delta pathway was identified as a pivotal signaling pathway in neuroblastoma, mediating the effects of MEHP through transcriptional sequencing analysis. Because MEHP can bind to the PPAR beta/delta protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPAR beta/delta-specific agonist GW501516 and antagonist GSK3787, the recom-binant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPAR beta/ delta-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPAR beta/delta and ANGPTL4 in the metabolic process, a non-targeted metabolomics analysis revealed that MEHP altered multiple metabolic pathways, particularly lipid metabolites involving fatty acyls, glycerophospholipids, and sterol lipids, which may also be potential factors promoting tumor progression. We have demonstrated for the first time that MEHP can target binding to PPAR beta/delta and affect the progression of neuroblastoma by activating the PPAR beta/ delta-ANGPTL4 axis. This mechanism confirms the health risks of plasticizers as tumor promoters and provides new data support for targeted prevention and treatment of neuroblastoma."

基金机构："Scientific Research Foundation of Chongqing Medical University, China [R4014, R4021]; Chongqing Postdoctoral Science Foundation [2022TQ0394, CSTB2022NSCQ-BHX0641]; Chongqing Special Funding for Post-doctoral Research Projects [2022CQBSHTB1006]; Chongqing Postdoctoral Innovation Mentor Studio [X7928]"

基金资助正文："This work was supported by the Scientific Research Foundation of Chongqing Medical University (R4014 and R4021) , China and Chongqing Postdoctoral Science Foundation (2022TQ0394, CSTB2022NSCQ-BHX0641) , Chongqing Special Funding for Post-doctoral Research Projects (2022CQBSHTB1006) , and Chongqing Postdoctoral Innovation Mentor Studio (X7928 D.S.P.) ."