# Prenatal exposure to di(2-ethylhexyl) phthalate alters the association of glutamatergic proteins with PTEN in the hippocampus of male rat offspring

## TL;DR

Prenatal exposure to a common chemical called DEHP disrupts brain development in rat offspring by altering protein interactions in the hippocampus, potentially affecting learning and memory.

## Contribution

This study reveals how prenatal DEHP exposure alters PTEN protein interactions in the hippocampus, providing new insights into molecular mechanisms of phthalate-induced neurotoxicity.

## Key findings

- Prenatal DEHP exposure reduces the association of glutamatergic proteins with PTEN in rat offspring hippocampus.
- DEHP exposure leads to decreased calcineurin activity and reduced autophosphorylation of calcium/calmodulin-dependent protein kinase II.
- Akt kinase activity is upregulated in the hippocampus of offspring following prenatal DEHP exposure.

## Abstract

Phthalates are extensively used chemicals known to have adverse effects on human health. Prenatal exposure to phthalates has been associated with potential disruptions in brain development and an elevated susceptibility to cognitive and behavioral disorders. The effects of phthalates on learning, memory, and related hippocampal processes have been widely studied; however, the molecular pathways through which phthalates modulate synaptic processes are not fully understood. Previous studies have shown that the molecular mechanism of DEHP-induced hippocampal neurotoxicity in the maturing male brain involves changes in phosphatase and tensin homolog (PTEN) subcellular location, which suppresses Akt/mTOR signaling and enhances GluN2B NMDA-mediated synapse depression. Immunoprecipitation experiments revealed that the prenatal administration of DEHP to rats led to a reduction in the association of the scaffold protein NHERF1, NMDA receptor subunits, AMPA receptor subunits, metabotropic glutamate receptor 5, and excitatory amino acid transporter-2 with PTEN in the hippocampus of offspring, while the overall quantity of these proteins remained unchanged. Furthermore, our results demonstrated that prenatal exposure of rats to phthalates resulted in downregulation of calcineurin phosphatase activity, decreased autophosphorylation of calcium/calmodulin-dependent protein kinase II, reduced protein kinase A activity, and upregulation of Akt kinase in the hippocampus of young rats. These findings suggest that the susceptibility of the PTEN protein interactome to phthalates in the glutamatergic postsynaptic density may influence synaptic plasticity at excitatory neurons in the hippocampus of offspring after exposure of parent rats to DEHP during gestation.