Contribution of poly(ADP-ribose)polymerase-1 activation and apoptosis in trichloroethene-mediated autoimmunity

Toxicol Appl Pharmacol. 2019 Jan 1;362:28-34. doi: 10.1016/j.taap.2018.10.012. Epub 2018 Oct 10.

Abstract

Trichloroethene (TCE), a common environmental toxicant and widely used industrial solvent, has been implicated in the development of various autoimmune diseases (ADs). Although oxidative stress has been involved in TCE-mediated autoimmunity, the molecular mechanisms remain to be fully elucidated. These studies were, therefore, aimed to further explore the contribution of oxidative stress to TCE-mediated autoimmune response by specifically assessing the role of oxidative DNA damage, its repair enzyme poly(ADP-ribose)polymerase-1 (PARP-1) and apoptosis. To achieve this, groups of female MRL +/+ mice were treated with TCE, TCE plus N-acetylcysteine (NAC) or NAC alone (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day in drinking water) for 6 weeks. TCE treatment led to significantly higher levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the livers compared to controls, suggesting increased oxidative DNA damage. TCE-induced DNA damage was associated with significant activation of PARP-1 and increases in caspase-3, cleaved caspase-8 and -9, and alterations in Bcl-2 and Bax in the livers. Moreover, the TCE-mediated alterations corresponded with remarkable increases in the serum anti-ssDNA antibodies. Interestingly, NAC supplementation not only attenuated elevated 8-OHdG, PARP-1, caspase-3, cleaved caspase-9, and Bax, but also the TCE-mediated autoimmune response supported by significantly reduced serum anti-ssDNA antibodies. These results suggest that TCE-induced activation of PARP-1 followed by increased apoptosis presents a novel mechanism in TCE-associated autoimmune response and could potentially lead to development of targeted preventive and/or therapeutic strategies.

Keywords: Apoptosis; Autoimmune disease; N-acetylcysteine; Oxidative stress; Poly(ADP-ribose)polymerase-1; Trichloroethene.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Acetylcysteine / pharmacology
  • Animals
  • Antibodies, Antinuclear / blood
  • Apoptosis / drug effects
  • Autoimmunity / drug effects*
  • DNA Damage
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Female
  • Liver / drug effects
  • Liver / metabolism
  • Mice, Knockout
  • Poly (ADP-Ribose) Polymerase-1 / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Solvents / toxicity*
  • Trichloroethylene / toxicity*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antibodies, Antinuclear
  • Bax protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Solvents
  • bcl-2-Associated X Protein
  • Trichloroethylene
  • 8-Hydroxy-2'-Deoxyguanosine
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Deoxyguanosine
  • Acetylcysteine