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Subcytotoxic mercury chloride inhibits gap junction intercellular communication by a redox- and

Claudia Piccoli1, Annamaria D'Aprile, Rosella Scrima

  • 1Department of Biomedical Sciences, University of Foggia, Foggia, Italy.

Free Radical Biology & Medicine
|January 14, 2012
PubMed

Insights

Mercury (Hg(II)) inhibits gap junction communication in human keratinocytes at low concentrations, despite increased connexin expression. This disruption involves altered redox balance and signaling pathways, potentially priming cells for cancer.

Area of Science:

  • Cell Biology
  • Toxicology
  • Cancer Research

Background:

  • Gap junctions are crucial for tissue homeostasis and their communication (GJIC) is often disrupted in cancer.
  • Environmental pollutants, such as heavy metals, can act as tumor promoters by modulating GJIC through unknown mechanisms.
  • Understanding how specific carcinogens impact GJIC is vital for cancer prevention and risk assessment.

Purpose of the Study:

  • To investigate the effects of mercury(II) chloride (HgCl2) on gap junctional intercellular communication (GJIC) in cultured human keratinocytes.
  • To elucidate the underlying molecular mechanisms, including redox balance and signaling pathways, involved in HgCl2-induced GJIC inhibition.
  • To explore potential therapeutic interventions to restore GJIC function in HgCl2-exposed cells.

Main Methods:

  • Cultured human keratinocytes were treated with subcytotoxic concentrations of HgCl2.
  • GJIC was assessed using a dye transfer assay.
  • Changes in connexin expression, free thiols, and mitochondrial reactive oxygen species (ROS) were measured.
  • The effects of protein kinase C (PKC) inhibitor (calphostin C), all-trans retinoic acid, and protein kinase A (PKA) activator (db-cAMP) were evaluated.

Main Results:

  • Subcytotoxic HgCl2 concentrations (as low as 10 nM) significantly inhibited GJIC, despite enhanced connexin expression.
  • HgCl2 treatment led to decreased free thiols and increased mitochondrial ROS production, without affecting respiratory chain activity.
  • Inhibition of PKC and modulation of PKA activity, along with all-trans retinoic acid, rescued ROS overproduction and restored GJIC.
  • A cross-talk between intracellular redox tone and PKA/PKC signaling was identified in HgCl2-exposed keratinocytes.

Conclusions:

  • HgCl2 disrupts GJIC in human keratinocytes at non-cytotoxic levels by altering intracellular redox state and activating PKA/PKC signaling pathways.
  • These alterations, while not directly cytotoxic, may contribute to carcinogenic priming by inhibiting essential cell communication.
  • Targeting redox balance and specific signaling pathways presents a potential strategy to counteract the adverse effects of HgCl2 on GJIC.

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