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

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

  • Sci Total Environ. 2023 Nov 30:168949. doi: 10.1016/j.scitotenv.2023.168949.
Yiyun Liu 1,  Naima Hamid 2,  Rakia Manzoor 3,  Bao-Fu Zhang 1,  Yan-Ling Liao 1,  Jin-Xia Wang 1,  De-Sheng Pei 4
Affiliations

Affiliations

  • 1 School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • 2 Faculty of Science and Marine Environment, Ocean Pollution and Ecotoxicology (OPEC) Research Group, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia.
  • 3 College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China.
  • 4 School of Public Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: peids@cqmu.edu.cn.
PMID: 38042186 DOI: 10.1016/j.scitotenv.2023.168949
Abstract

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) β/δ 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 PPARβ/δ protein and initiate the expression of the downstream gene angiopoietin-like 4 (ANGPTL4), the PPARβ/δ-specific agonist GW501516 and antagonist GSK3787, the recombinant human ANGPTL4 protein, and the knockdown of gene expression confirmed the regulation of the PPARβ/δ-ANGPTL4 axis on the malignant phenotype of neuroblastoma. Based on the critical role of PPARβ/δ 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 PPARβ/δ and affect the progression of neuroblastoma by activating the PPARβ/δ-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.

Keywords

Lipid metabolism; MEHP; Migration; Neuroblastoma; Plasticizer; Proliferation.

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