Alterations in the Expression of Shelterin Complex Genes in Crystalline Silica Exposed Rat Lungs

Details

• Personal Author:
  Antonini JM ; Erdely A ; Joseph P ; Kodali V ; Mustafa GM ; Roberts, Jennifer R. ; Shoeb M ; Umbright C ; Antonini JM ; Erdely A ; Joseph P ; Kodali V ; Mustafa GM ; Roberts, Jennifer R. ; Shoeb M ; Umbright C
• Description:
  Occupational exposure to silica can result in advanced pulmonary fibrosis and lung carcinoma through several complex mechanisms. Therefore, it is imperative to identify the key biomarkers of silica-induced pulmonary toxicity for the intervention of lung pathologies. Telomeres (the nucleoprotein structures with repetitive (TTAGGG) sequences at the end of chromosomes) are a molecular "clock of life" and alterations are associated with several chronic diseases. Shelterin complex: protection of telomerase1 (POT1), telomeric repeat-binding factor1 (TRF1), telomeric repeat-binding factor2 (TRF2), TRF1-interacting nuclear factor2 (Tin2), TRF2-interacting telomeric protein (Rap1), and POT1 and Tin2- organizing protein (TPP1) play an important role in maintaining telomere length and integrity and any alteration in telomeres activate DNA damage machinery resulting in telomere attrition. The goal of this study was to assess the effect of crystalline silica exposure on the regulation of shelterin complex genes in an animal model. Male Fisher 344 rats were exposed by inhalation to Min-U-Sil 5 silica for 3, 6, and 12 weeks at a concentration of 15 mg/m3 for 6 hours/day for 5 consecutive days/week. After the final day of exposure the right lung was homogenized, total RNA was isolated and reverse transcribed to obtain cDNA, and expression of shelterin complex genes was assessed. At all-time points after exposure, mRNA expression of POT1, TRF1, TRF2, Tin2, Rap1, and TPP1 were significantly decreased (p<0.05) in the silica-exposed animals compared to air controls, and the decrease observed were exposure time dependent. POT1 and TPP1 which mediates telomerase-dependent telomere extension were significantly decreased in exposed animals. In conclusion, our results suggested that silica inhalation promoted shelterin complex instability. This study indicated that measurement of expressions of shelterin genes involved in telomere regulation may serve as a potential biomarker for silica-induced pathology including carcinogenesis. In addition, changes in shelterin complex could potentially promote telomere end-to-end fusions and cancer formation. [Description provided by NIOSH]
• Subjects:
  Animals Biomarkers Carcinogens Environmental Exposure Genetics Laboratories Lung Lung Diseases Neoplasms Occupational Health Pathology Respiratory System Respiratory Tract Diseases Safety Silicon Dioxide Toxicology

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• Keywords:
  Analytical Models Cancer Carcinogenesis Crystalline Silica Deoxyribonucleic Acids DNA Exposure Assessment Exposure Levels Gene Expression Gene Regulation Genes Laboratory Animals Laboratory Testing Lung Cells Lung Disorders Proteins Pulmonary Disorders Ribonucleic Acids RNA

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary ; Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; OSHA Region 6 ; Texas ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Pages in Document:
  61
• Volume:
  162
• Issue:
  1
• NIOSHTIC Number:
  nn:20051172
• Citation:
  Toxicologist 2018 Mar; 162(1):61
• CAS Registry Number:
  Quartz (SiO2) (CAS RN 14808-60-7) ; Quartz (SiO2) (CAS RN 14808-60-7)
• Federal Fiscal Year:
  2018
• NORA Priority Area:
  Construction ; Manufacturing ; Construction ; Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 57th Annual Meeting and ToxExpo, March 11-15, 2018, San Antonio, Texas
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:cbe6712ee359e1405eddbe498a34704901fbd32ac252a3e0ffa45085586d18489296b49e48056143f4dacffd13d1a9f4bbf3511a02695bcb231b6bfb5d692fd0
• Download URL:
  https://stacks.cdc.gov/view/cdc/211264/cdc_211264_DS1.pdf
• File Type:
  [PDF - 832.22 KB ]