Exposure to welding fumes activates DNA damage response and redoxsensitive transcription factor signalling in Sprague-Dawley rats

Krishnaraj, Jayaraman and Kowshik, Jaganathan and Sebastian, Robin and Raghavan, Sathees C and Nagini, Siddavaram (2017) Exposure to welding fumes activates DNA damage response and redoxsensitive transcription factor signalling in Sprague-Dawley rats. In: TOXICOLOGY LETTERS, 274 . pp. 8-19.

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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 (NF kappa B) 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 50 mg/m(3) stainless steel (SS) welding fumes for 1 h for 1 day, 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 NF kappa B 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 NF kappa B signalling with enhanced expression of inflammatory mediators. Conclusion: 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 NF kappa B signalling pathways may be key molecular events that mediate adaptive cellular response to welding fume exposure.

Item Type:	Journal Article
Publication:	TOXICOLOGY LETTERS
Additional Information:	Copy right for this article belongs to the ELSEVIER IRELAND LTD, ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	10 Jun 2017 04:38
Last Modified:	10 Jun 2017 04:38
URI:	http://eprints.iisc.ac.in/id/eprint/57156

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