Title: Contribution of poly(ADP-ribose)polymerase-1 activation and apoptosis in trichloroethene-mediated autoimmunity.
Authors: Wang, Gangduo; Ma, Huaxian; Wang, Jianling; Khan, M Firoze
Published In Toxicol Appl Pharmacol, (2019 01 01)
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.
PubMed ID: 30315841
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