title: Effects of airborne toxicants on pulmonary function and mitochondrial DNA damage in rodent lungs.
abstract: Inhalation of airborne toxicants such as cigarette smoke and ozone is a shared health risk among the world's populations. The use of toxic herbicides like paraquat (PQ) is restricted by many countries, yet in the developing world PQ has demonstrable ill effects. The present study examined changes in pulmonary function, mitochondrial DNA (mtDNA) integrity and markers of DNA repair induced by acute or repeated exposure of PQ to rats. Similar to cigarette smoke and ozone, PQ promotes oxidative stress, and the impact of PQ on mtDNA was compared with that obtained with these agents. Tracheal instillation (i.t.) of PQ (0.01-0.075 mg/kg) dose dependently increased Penh (dyspnoea) by 48 h while body weight and temperature declined. Lung wet weight and the wet/dry weight ratio rose; for the latter, by as much as 52%. At low doses (0.02 and 0.03 mg/kg), PQ increased Penh by about 7.5-fold at 72 h. It quickly waned to near baseline levels. The lung wet/dry weight ratio remained elevated 7 days after administration coincident with marked inflammatory cell infiltrate. Repeated administration of PQ (1 per week for 8 weeks) resulted in a similar rise in Penh on the first instillation, but the magnitude of this response was markedly attenuated upon subsequent exposures. Pulmonary [lactate] and catalase activity, [8-oxodG] and histone fragmentation (cell death) were significantly increased. Repeated PQ instillation downregulated the expression of the mitochondrial-encoded genes, mtATP8, mtNd2 and mtcyB and nuclear ones for the DNA glycosylases, Ogg1, Neil1, Neil2 and Neil3. Ogg1 protein content decreased after acute and repeated PQ administration. mtDNA damage or changes in mtDNA copy number were evident in lungs of PQ-, cigarette smoke- and ozone-exposed animals. Taken together, these data indicate that loss of pulmonary function and inflammation are coupled to the loss of mtDNA integrity and DNA repair capability following exposure to airborne toxicants.
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Rumsey
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bolognese
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Alicia B
authors.initials: AB
authors.lastname: Davis
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Pearl L
authors.initials: PL
authors.lastname: Flamberg
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Foley
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Katchur
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Kotzer
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Osborn
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Podolin
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000187:drug effects* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D015536:Down-Regulation; D005260:Female; D006540:Herbicides / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D007322:Instillation, Drug; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010269:Paraquat / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D014132:Trachea
chemical_list: D004272:DNA, Mitochondrial; D006540:Herbicides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; D003849:Deoxyguanosine; D010269:Paraquat