Maternal Exposure to Di-(2-ethylhexyl) Phthalate Impairs Hippocampal Synaptic Plasticity in Male Offspring: Involvement of Damage to Dendritic Spine Development

Abstract

Exposure to di-(2-ethylhexyl) phthalate (DEHP), a widely used kind of plasticizer, can result in neurodevelopment impairments and learning and memory disorders. We studied the effects and possible mechanisms of maternal DEHP treatment on hippocampal synaptic plasticity in offspring. Pregnant Wistar rats were randomly divided into four groups and received 0, 30, 300, 750 (mg/kg)/d DEHP by gavage from gestational day (GD) 0 to postnatal day (PN) 21. Our data showed that DEHP exposure impaired hippocampal synaptic plasticity, damaged synaptic ultrastructure, and decreased synaptic protein levels in male pups. Furthermore, DEHP decreased the density of dendritic spines, affected F-actin polymerization, and downregulated the Rac1/PAK/LIMK1/cofilin signaling pathway in male offspring. However, the alterations in the hippocampi of female offspring were not observed. These results illustrate that maternal DEHP exposure could impair hippocampal synaptic plasticity by affecting synaptic structure and dendritic spine development in male offspring, which may be attributed to altered cytoskeleton construction induced by downregulation of the Rac1/PAK/LIMK1/cofilin signaling pathway.

Whole-Transcriptome Analysis of Repeated Low-Level Sarin-Exposed Rat Hippocampus and Identification of Cerna Networks to Investigate the Mechanism of Sarin-Induced Cognitive Impairment

“…Synaptic plasticity in the hippocampus is well recognized as being directly tied to learning and memory, and dendritic spines have been considered as the morphological foundation of synaptic plasticity. Studies have shown that a reduction in the dendritic spine density leads to the weakening of synaptic plasticity, which in turn affects learning and memory function [ 43 , 44 ]. According to research, the damage to synaptic plasticity caused by OPs is not only impacted by ACh and other neurotransmitters, but is also linked to the activation of the learning and memory-related signaling systems, the degradation of neuronal cytoskeleton, and neurogenesis [ 45 ].…”

Prenatal Di‐methoxyethyl phthalate exposure impairs cortical neurogenesis and synaptic activity in the mice

“…Similarly, DEHP exposure modulates minisynaptic transmission of projection neurons by inhibiting the calcium channel in the Drosophila [ 45 ]. In addition, prenatal DEHP exposure impairs hippocampal synaptic activity by inhibiting dendritic spine formation and synaptic structure in male offspring [ 46 ]. We found that prenatal DMEP exposure changed postsynaptic neurotransmitter receptor activity in the parietal cortex and that prenatal DMEP exposure resulted in abnormal behaviors such as hyperactivity and reduced anxiety in the offspring.…”

Behavioral Effects of Exposure to Phthalates in Female Rodents: Evidence for Endocrine Disruption?

“…Table S2 summarizes the data from other studies assessing the effects of developmental exposure to phthalates on brain morphology and key signaling pathways that underlie hippocampal and cortical functions. Three studies assessing the effects of gestational and lactational exposure to DEHP at high doses ranging from 30 to 750 mg/kg/d did not report any effect on hippocampal structural neuroplasticity and protein markers of functional plasticity, or cortical signaling pathways in the hippocampus on PND7, PND14, PND21 [ 86 , 87 , 88 ], or LTP in adult female rats [ 86 ]. Postnatal exposure of rats to 10 mg/kg/d of DEHP affected neither hippocampal neurogenesis nor plasticity in PND26 animals [ 89 , 90 ].…”