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TDCPP mimics thyroid hormones associated with the activation of integrin αvβ3 and ERK1/2

Jian Li1, Hedan Liu1, Na Li2

  • 1Engineering Research Center of Groundwater Pollution Control and Remediation, Ministry of Education, College of Water Sciences, Beijing Normal University, Beijing, 100875, China.

Chemosphere
|May 21, 2020
PubMed

Insights

Tri(1,3-dichloropropyl) phosphate (TDCPP) and its metabolite BDCPP mimic thyroid hormones, affecting cell growth and gene expression. They interact with integrin αvβ3, activating the ERK1/2 pathway, revealing new toxic mechanisms.

Area of Science:

  • Endocrinology
  • Toxicology
  • Cell Biology

Background:

  • Tri(1,3-dichloropropyl) phosphate (TDCPP) is a flame retardant with suspected thyroid-disrupting properties.
  • Limited knowledge exists regarding the specific toxic effects and mechanisms of TDCPP and its metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP).

Purpose of the Study:

  • To investigate the thyroid hormone-disrupting effects of TDCPP and BDCPP.
  • To elucidate the underlying molecular mechanisms of TDCPP and BDCPP toxicity in rat pituitary GH3 cells.

Main Methods:

  • Utilized rat pituitary GH3 cell lines.
  • Assessed cell proliferation and cell cycle progression.
  • Measured gene expression of c-fos and Tshβ via real-time PCR.
  • Investigated binding interactions with membrane thyroid hormone receptor (integrin αvβ3) using competition assays.
  • Performed molecular docking analysis.
  • Analyzed extracellular signal-regulated protein kinase (ERK1/2) pathway activation.

Main Results:

  • TDCPP and BDCPP promoted GH3 cell proliferation and modulated cell cycle progression.
  • Both compounds upregulated c-fos and downregulated Tshβ gene expression, mimicking thyroid hormone (TH) effects.
  • Significant competition for binding to integrin αvβ3 was observed, indicating strong binding.
  • Molecular docking confirmed high binding affinities for TDCPP and BDCPP to integrin αvβ3 at the RGD-binding site.
  • Evidence suggests TDCPP and BDCPP activate the ERK1/2 signaling pathway after binding to integrin αvβ3.

Conclusions:

  • TDCPP and BDCPP exhibit thyroid hormone-mimicking properties.
  • Their mechanism of action involves interaction with integrin αvβ3 and subsequent activation of the ERK1/2 pathway.
  • These findings provide novel insights into the cytotoxicity of TDCPP and BDCPP.
Keywords:
BDCPPERK1/2Integrin α(v)β(3)TDCPPThyroid disruption

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