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Di-n-butyl phthalate exposure negatively influences structural and functional neuroplasticity via Rho-GTPase

Yuemin Ding1, Lingchao Lu1, Chengkai Xuan1

  • 1Department of Clinical Medicine, School of Medicine, Zhejiang University City College, 50 Huzhou Street, Hangzhou 310015, China.

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
|April 2, 2017
PubMed

Insights

Di-n-butyl phthalate (DBP) impairs spatial learning and neuroplasticity in male mice by disrupting Rho-GTPase signaling pathways in the hippocampus. This phthalate alters cofilin activity and neurite outgrowth, impacting brain function.

Area of Science:

  • Neuroscience
  • Toxicology
  • Cell Biology

Background:

  • Di-n-butyl phthalate (DBP) is known to disrupt hippocampal plasticity.
  • The precise molecular mechanisms underlying DBP's neurotoxic effects remain unclear.

Purpose of the Study:

  • To investigate the specific mechanisms by which DBP affects neuroplasticity.
  • To elucidate the role of Rho-GTPase signaling pathways in DBP-induced neurotoxicity.

Main Methods:

  • Chronic DBP exposure in a mouse model (intragastric administration).
  • Spatial learning assessment using the Morris water maze.
  • Analysis of Rho-GTPase signaling pathway activity in hippocampal tissues.
  • Acute DBP exposure in cultured neuronal cells to assess cell morphology and neurite outgrowth.

Main Results:

  • Chronic high-dose DBP exposure caused spatial learning deficits in male mice.
  • DBP differentially regulated Rho-GTPase pathways, inhibiting Rac1/PAK1/LIMK1 while activating RhoA/ROCK/LIMK2.
  • DBP suppressed cofilin activity via phosphorylation and inhibited neurite outgrowth in neuronal cells.
  • ROCK inhibition, but not Rac1 or PAK1 inhibition, reversed DBP's effects on cofilin and neurite outgrowth.

Conclusions:

  • DBP exposure impairs neuroplasticity through the differential regulation of Rho-GTPase signaling pathways.
  • The findings highlight a novel mechanism of DBP neurotoxicity involving the RhoA/ROCK/cofilin pathway.
  • DBP's disruption of these pathways may contribute to cognitive deficits observed in exposed individuals.
Keywords:
Di-n-butyl phthalate (DBP)NeuroplasticityRho-GTPase

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