Decreased Trf1-Trf2 Negatively Regulates Telomere Length and DNA Damage Foci in Rat Liver Tissue After a High-Fat Diet and Welding Fume Exposure

Details

• Personal Author:
  Shoeb M
• Description:
  Telomeric DNA and shelterin proteins prevent loss of essential genetic information during cell division. Telomere attrition resulting in DNA damage contributes to liver pathology. The telomeric repeat-binding factor 1 (Trf1) and 2 (Trf2), and the protection of telomere 1 (Pot1) are involved in telomere maintenance by preventing telomere end-to-end fusion through proper folding of the telomere. The goal of this study was to describe the regulation of expression of these genes and proteins along with their relationship to telomere length in an animal model comparing different diets and a simulated occupational exposure. Male Sprague-Dawley rats were maintained on a regular (REG) or high fat (HF) diet for 24 wk. At wk 7 during diet maintenance, groups of rats from each strain were exposed by inhalation of stainless-steel welding fume (WF; 20 mg/m3 x 3 hr/d x 4 d/wk x 5 wk) or filtered air until wk12, at which time some animals were euthanized. A separate set of rats were allowed to recover from WF exposure until the end of the 24 wk period. At 12 and 24 wk, the effect on shelterin proteins and telomere length was examined in peripheral blood mononuclear cells (PBMCs) and homogenized liver tissue. Double- and single-stranded telomere DNA-binding proteins Trf1/Trf2 and Pot1, as well as telomeric DNA damage foci LambdaH2AX and 53BP1, were influenced at 12 wk and 24 wk by both diet and exposure. A significant reduction in telomere length in PBMCs was observed in the WF+REG and Air+HF groups, which was further shortened in WF+HF group. However, an opposite telomere length trend was observed in livers obtained from the same groups at both 12 and 24 wk. ATM kinase phosphorylation and DNA damage activation was observed in the liver at 12 wk of WF exposure. Single-stranded binding protein Pot1, initially up-regulated at 12 wk in the WF+REG group, was later down-regulated in liver tissue at 24 wk along with the WF+HF group. In conclusion, our data suggest that disruption/down-regulation of single-stranded Pot1 and double-stranded Trf1/Trf2 expression in liver might act as an anti-apoptotic mechanism in the DNA-damage response leading to multistep liver injury by involvement in the telomere response to diet changes and WF exposure. [Description provided by NIOSH]
• Subjects:
  Air Pollutants, Occupational Animals Blood Cell Division Diet Environmental Exposure Hazardous Substances Laboratories Occupational Health Respiratory System Safety Toxicology Welding

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• Keywords:
  Animal Studies Biological Effects Blood Cells Cell Alteration Cell Division Cell Function Deoxyribonucleic Acids DNA DNA Damage Exposure Assessment Exposure Levels Fats Gene Expression Gene Regulation Genotoxicity Inhalation Laboratory Animals Laboratory Testing Liver Liver Damage Models Proteins Stainless Steel Tissue Culture Toxic Effects Toxic Fumes Welding Fumes

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  60
• Volume:
  174
• Issue:
  1
• NIOSHTIC Number:
  nn:20058870
• Citation:
  Toxicologist 2020 Mar; 174(1):60
• CAS Registry Number:
  Stainless Steel (CAS RN 12597-68-1)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Construction
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 59th Annual Meeting and ToxExpo, March 15-19, 2020, Anaheim, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:4d1da7a0dff0880a6e59cc3217a56f2e1000628bd6ba0b12a6ea3b7027161eb29035b616f3ec5f3e7c72cd2b20a8d5d5fcd776792088597abdf0834fb4dfec89
• Download URL:
  https://stacks.cdc.gov/view/cdc/223245/cdc_223245_DS1.pdf
• File Type:
  [PDF - 523.39 KB ]