DEHP exposure induces cholesterol dysregulation and inflammatory signaling in human colonic epithelial cells: Implications for early colorectal carcinogenesis.

Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer and a classified Group 2B carcinogen, is associated with increased colorectal cancer (CRC) incidence, but its causal role and mechanisms are unclear. We investigated DEHP toxicity in human colonic epithelial cells (NCM460) using an integrated multi-omics approach. Phenotypic assays showed that low-dose (200 μM) exposure markedly inhibited cell migration by 32% independent of cytotoxicity within 48 h. Transcriptomics revealed a biphasic stress response: an early disruption of cholesterol metabolism and ABC transporters, followed by activation of pro-oncogenic pathways. Metabolomics confirmed concurrent redox imbalance and lipid/steroid dysregulation. Integrated analysis identified ABCA1, ABCG1, and SREBF1 as central regulatory nodes linking metabolic dysfunction to inflammatory and oncogenic pathways. The downregulation of ABCA1 and ABCG1 was validated at the mRNA level, a finding corroborated by their significant underexpression in clinical CRC tumors (TCGA database). Tumor tissues exhibited a 0.54-fold decrease in ABCA1 and a 0.47-fold decrease in ABCG1 compared to normal controls (p < 0.0001, n = 286). Moreover, ABCA1 knockdown phenocopied the inhibitory effect of DEHP on cell migration. In conclusion, these findings suggest that short-term DEHP exposure may disrupt intestinal epithelial homeostasis through a mechanism involving cholesterol transport impairment (SREBF1/ABCA1/ABCG1 axis), representing an early event in DEHP-associated colorectal pathogenesis.