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.