Elucidating the toxicity of the plasticizer DPhP: Evidence of neurotoxicity and developmental impairment from in vitro to in vivo models

As an emerging substitute for conventional phthalates, diphenyl phthalate (DPhP) raises growing environmental health concerns, yet its systemic toxicity profile remains poorly characterized. We used human umbilical vein endothelial cell (HUVEC) and Caenorhabditis elegans models to study the toxic effects and the underlying mechanisms of DPhP exposure. The results demonstrate that DPhP significantly suppresses cell viability and proliferation. Mechanistically, DPhP induces G1/S phase cell cycle alterations by upregulating cyclin-dependent kinase inhibitors (p21 and p27) and downregulating CDK-cyclin complexes, consistent with a stress-induced delay in cell cycle progression. In C. elegans , DPhP exposure impairs growth and locomotor behavior. Molecular analyses reveal that these adverse outcomes are associated with the dysregulation of key signaling pathways, including IIS, PI3K/AKT, and MAPK. Notably, DPhP disrupts the expression of neurodevelopmental genes, particularly those governing dopaminergic and cholinergic neurotransmission. Consistent with this finding, DPhP-exposed nematodes exhibit deficits in chemotaxis and learning, accompanied by reduced dopamine and GABA levels, and a loss of dopaminergic neurons, indicating substantial neurotoxicity. Collectively, this study provides comprehensive evidence that DPhP disrupts cellular growth, development, and neural function across models, highlighting its underappreciated health risks and offering crucial insights for environmental safety assessment