Abstract
Occupational exposure to silica has been observed to cause pulmonary fibrosis and lung cancer through complex mechanisms. Telomeres, the nucleoprotein structures with repetitive (TTAGGG) sequences at the end of chromosomes, are a molecular “clock of life”, and alterations are associated with chronic disease. The shelterin complex (POT1, TRF1, TRF2, Tin2, Rap1, and POT1 and TPP1) plays an important role in maintaining telomere length and integrity, and any alteration in telomeres may activate DNA damage response (DDR) machinery resulting in telomere attrition. The goal of this study was to assess the effect of silica exposure on the regulation of the shelterin complex in an animal model. Male Fisher 344 rats were exposed by inhalation to Min-U-Sil 5 silica for 3, 6, or 12 wk at a concentration of 15 mg/m3 for 6 hr/d for 5 consecutive d/wk. Expression of shelterin complex genes was assessed in the lungs at 16 hr after the end of each exposure. Also, the relationship between increased DNA damage protein (γH2AX) and expression of silica-induced fibrotic marker, αSMA, was evaluated. Our findings reveal new information about the dysregulation of shelterin complex after silica inhalation in rats, and how this pathway may lead to the initiation of silica-induced pulmonary fibrosis.
Highlights
2.3 million U.S workers are exposed to respirable crystalline silica, including 100,000 who are considered at high risk[1]
Both TRF1 and TRF2 are homodimers binding to the telomeric dsDNA, whereas POT1 interacts with tripeptidyl peptidase 1 (TPP1) and binds to the telomeric ssDNA22–24
We provide the first experimental evidence that DNA damage-induced shelterin dysfunction after silica exposure could allow for the development of pulmonary fibrosis
Summary
2.3 million U.S workers are exposed to respirable crystalline silica, including 100,000 who are considered at high risk[1]. Pulmonary fibrosis is a life-threatening lung disease characterized by difficulty breathing, frequent infections, and severe lung dysfunction with approximately 2 to 3 years survival time after diagnosis[2,3]. Occurance of this disease has been reported to be due to the repetitive epithelial cell injury and poor tissue regeneration processes, but a complete understanding of the mechanisms remains unclear[4]. The TRF proteins serve as the foundation for the shelterin complex at telomeres Both TRF1 and TRF2 are homodimers binding to the telomeric dsDNA, whereas POT1 interacts with TPP1 and binds to the telomeric ssDNA22–24. Mutations in Tin[2], telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and RTEL1 genes have been reported in pulmonary fibrosis[40,41,42]
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