title: Exposure to welding fumes activates DNA damage response and redox-sensitive transcription factor signalling in Sprague-Dawley rats.
abstract: BACKGROUND
  Occupational exposure to welding fumes containing a complex mixture of genotoxic heavy metals, radiation, gases and nanoparticles poses a serious health hazard to welders. Since their categorization as possible carcinogens, welding fumes have gained increasing attention as high priority agents for risk assessment.
  
  
  OBJECTIVE
  The present study was undertaken to investigate the effects of welding fume inhalation on oxidative stress, DNA damage response (DDR), and nuclear factor erythroid 2-related factor-2 (Nrf2) and nuclear factor kappa B (NFκB) signalling in the lung tissues of male Sprague-Dawley rats.METHODS: Animals were divided into five groups. Group 1 animals served as control. Rats in groups 2-5 were exposed to 50mg/m3stainless steel (SS) welding fumes for 1h for 1day, 1 week, 2 weeks, and 4 weeks respectively. Reactive oxygen species (ROS) generation, 8-oxo-2'-deoxyguanosine (8-oxodG), xenobiotic-metabolizing enzymes (XMEs) and antioxidants were analysed. DNA damage sensors, DNA repair enzymes, inflammatory mediators, cell cycle progression, apoptosis and key players in Nrf2 and NFκB signalling were assessed by flow cytometry, quantitative real-time reverse transcriptase PCR, immunoblotting, immunohistochemistry and immunofluorescence.
  
  
  RESULTS
  Rats exposed to welding fumes showed increased levels of chromium and ROS in lung tissues associated with accumulation of 8-oxodG and enhanced expression of XMEs and antioxidants. This was accompanied by upregulation of DNA damage sensors, cell cycle arrest in G1/S phase, overexpression of a multitude of DNA repair enzymes and caspase-mediated apoptosis. In addition, exposure to welding fumes induced activation of Nrf2 and NFκB signalling with enhanced expression of inflammatory mediators.
  
  
  CONCLUSIONS
  The results of the present study unequivocally demonstrate that exposure of rats to SS welding fumes alters the expression of 37 genes involved in oxidative stress, detoxification, inflammation, DNA repair, cell cycle progression, and apoptosis. Activation of DDR and the ROS-sensitive Nrf2 and NFκB signalling pathways may be key molecular events that mediate adaptive cellular response to welding fume exposure.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Krishnaraj
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: Jaganathan
authors.initials: J
authors.lastname: Kowshik
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.
authors.forename: Robin
authors.initials: R
authors.lastname: Sebastian
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India.
authors.forename: Sathees C
authors.initials: SC
authors.lastname: Raghavan
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India. Electronic address: snlabau@gmail.com.
authors.forename: Siddavaram
authors.initials: S
authors.lastname: Nagini
mesh_terms: D000393:Air Pollutants; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008670:Metals / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014896:Welding
chemical_list: D000393:Air Pollutants; D000975:Antioxidants; D008670:Metals; D017382:Reactive Oxygen Species; D014157:Transcription Factors
keywords: ATM chromium; DNA damage response; NF kappaB; Nrf2/Keap-1; Welding fumes