Assessment of lipid metabolism-disrupting effects of non-phthalate plasticizer diisobutyl adipate through in silico and in vitro approaches

Diisobutyl adipate (DIBA), as a novel non-phthalate plasticizer, is widely used in various products. However, little effort has been made to investigate whether DIBA might have adverse effects on human health. In this study, we integrated an in silico and in vitro strategy to assess the impact of DIBA on cellular homeostasis. Since numerous plasticizers could activate peroxisome proliferator-activated receptor gamma (PPAR gamma) pathway to interrupt metabolism systems, we first utilized molecular docking to analyze interaction between DIBA and PPAR gamma. Results indicated that DIBA had strong affinity with the ligand-binding domain of PPAR gamma (PPAR gamma-LBD) at Histidine 499. Afterwards, we used cellular models to investigate in vitro effects of DIBA. Results demonstrated that DIBA exposure increased intracellular lipid content in murine and human hepatocytes, and altered transcriptional expression of genes related to PPAR gamma signaling and lipid metabolism pathways. At last, target genes regulated by DIBA were predicted and enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Protein-protein interaction (PPI) network and transcriptional factors (TFs)-genes network were established accordingly. Target genes were enriched in Phospholipase D signaling pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and Epidermal growth factor receptor (EGFR) signaling pathway which were related to lipid metabolism. These findings suggested that DIBA exposure might disturb intracellular lipid metabolism homeostasis via targeting PPAR gamma. This study also demonstrated that this integrated in silico and in vitro methodology could be utilized as a high throughput, cost-saving and effective tool to assess the potential risk of various environmental chemicals on human health.

Automated summary

In this study, the potential adverse effects of DIBA on cellular homeostasis were evaluated using an integrated in silico and in vitro approach. The results showed that DIBA could disrupt lipid metabolism pathways by binding to PPAR gamma, leading to an increase in intracellular lipid content. This study demonstrates the utility of the integrated in silico and in vitro methodology for assessing the potential risk of environmental chemicals on human health.