Prenatal exposure to di (2-ethylhexyl) phthalate causes autism-like behavior through inducing Nischarin expression in the mouse offspring

Abstract

Epidemiologic evidence has suggested a relationship between di (2-ethylhexyl) phthalate (DEHP) prenatal exposure and autism spectrum disorders (ASD), but the underlying mechanisms are still at large unknown. In this study, pregnant mice were intragastrically administered with DEHP once a day from GD 3 to GD 17 and the neurobehavioral changes of offspring were evaluated. In addition to the repetitive stereotyped behaviors, DEHP at the concentration of 50 mg/kg/day and above significantly impaired the sociability of the offspring (P < 0.05) and decreased the density of dendritic spines of pyramidal neurons in the prefrontal cortex (P < 0.05). At the same time, the expression of Nischarin protein in prefrontal lobe increased (P < 0.05). Similarly, after 12-h incubation of DEHP at the concentration of 100 nM, the total spine density, especially the mushroom and stubby spine populations, significantly decreased in the primary cultured prefrontal cortical neurons (P < 0.05). However, the inhibitory effect of DEHP were reversed by knockdown of Nischarin expression. Collectively, these results suggest that prenatal DEHP exposure induces Nischarin expression, causes dendritic spine loss, and finally leads to autism-like behavior in mouse offspring.