Developmental neurotoxicity of short-chain phthalates in human neurospheres

Short-chain phthalates (SCPs) are widely used as solvents in personal care products, resulting in prevalent exposure among women and pregnant women, but their effects remain poorly understood. Given the possibility of fetal exposure to SCPs during pregnancy, this study aimed to investigate the developmental neurotoxicity (DNT) of single and mixed SCPs using human neurospheres. Five SCPs - dimethyl-, diethyl-, dipropyl-, dibutyl-, and dipentyl phthalate - were screened, of which three - diethyl-, dipropyl-, and dipentyl phthalate - significantly reduced neurite outgrowth. The mixture of these three SCPs (DEPPP) also showed similar effects. RNA-seq analysis identified oxidative phosphorylation as the most enriched pathway. Individual SCPs and DEPPP bound to respiratory complexes reducing mitochondrial ATP production. Exogenous ATP and vitamin B complex restored neurite outgrowth inhibition. SCPs induce DNT through mitochondrial energy metabolism disruption, with similar effects observed in DEPPP. These results identify the DNT potential of SCPs, raising public health concerns during critical neurodevelopmental periods.