2‑Ethylhexyl\nDiphenyl Phosphate Induces Autism\nSpectrum Disorder-Like Behaviors in Offspring Mice by Disrupting Postsynaptic\nDevelopment

As organophosphorus flame retardants (OPFRs) are constantly\ndetected\nin human samples, the neurotoxicity of OPFRs is of concern. In this\nstudy, pregnant ICR mice were exposed to 2-ethylhexyl diphenyl phosphate\n(EHDPP) in drinking water from gestation to lactation to investigate\nits effects on autism spectrum disorder-like (ASD-like) behaviors\nin offspring. Serum EHDPP concentrations in dams in the 0.4, 2, and\n10 mg/kg groups were 0.282 ± 0.051, 0.713 ± 0.115, and 0.974\n± 0.048 ng/mL, respectively, within the concentration range in\nhumans. At the highest dose, EHDPP exposure induced ASD-like behaviors\nin both female and male offspring. Significant reductions in mature\ndendritic spines and structural damage to the postsynaptic density\nzone were noted in all but the lowest exposure groups, indicating\npostsynaptic membrane impairment. Mechanistically, EHDPP significantly\ndownregulated disc large MAGUK scaffold protein 4 expression by inhibiting\nprotein kinase B and type 1 insulin-like growth factor receptor phosphorylation.\nIn the heterologous synapse formation assay <i>in vivo</i>, EHDPP significantly reduced the levels of postsynaptic density\nprotein 95 expression in neurons at 1 μM. Overall, the study\nutilized <i>in vitro</i> and <i>in vivo</i> experiments\nto confirm that EHDPP damaged postsynaptic membrane formation and\nmight increase the incidence of ASD in offspring.