An environmentally relevant mixture of organophosphate esters induces cholesterol biosynthesis in THP-1 macrophages

ABSTRACT: Organophosphate esters (OPEs), widely used as flame retardants and plasticizers, are environmental toxicants known to disrupt lipid metabolism. Although most studies have focused on individual OPEs, environmental exposures typically involve complex mixtures. Our previous studies demonstrated that a representative OPE mixture from Canadian household dust promotes cholesterol and lipid droplet accumulation in THP-1 macrophages. However, the molecular mechanisms underlying this lipid dysregulation remain unclear. Here, we employed tandem mass tag (TMT)-based quantitative proteomics to investigate how OPE mixtures alter protein expression and lipid regulation in macrophages. THP-1 macrophages were exposed to vehicle or environmentally relevant dilutions (1:100,000 and 1:20,000) of the OPE mixture for 48 hours. Lysates were subjected to TMT labeling and mass spectrometry. Bioinformatic analyses using STRING and Ingenuity Pathway Analysis identified 162 differentially expressed proteins, with unsupervised clustering highlighting cholesterol biosynthesis as a key pathway. Further validation via qPCR and upstream analysis implicated the sterol regulatory element-binding protein 2 (SREBP2) signaling axis in OPE-induced cholesterol biosynthesis. Functional assays revealed that co-treatment with atorvastatin, an HMG-CoA reductase inhibitor, prevented cholesterol accumulation and mitigated lipid droplet formation. These findings provide the first evidence that an environmentally relevant OPE mixture can induce cholesterol biosynthesis in human macrophages.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Macrophage

SUBMITTER: Koren Mann  

LAB HEAD: Koren Mann

PROVIDER: PXD067007 | Pride | 2026-05-25

REPOSITORIES: Pride