Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in lung tissue of rats

Abstract

Exposure to silica can cause lung fibrosis and cancer. Identification of molecular targets is important for the intervention and/or prevention of silica-induced lung diseases. Telomeres consist of tandem repeats of DNA sequences at the end of chromosomes, preventing chromosomal fusion and degradation. Regulator of telomere length-1 (RTEL1) and telomerase reverse transcriptase (TERT), genes involved in telomere regulation and function, play important roles in maintaining telomere integrity and length. The goal of this study was to assess the effect of silica inhalation on telomere length and the regulation of RTEL1 and TERT. Lung tissues and blood samples were collected from rats at 4, 32, and 44 wk after exposure to 15 mg/m3 of silica × 6 h/d × 5 d. Controls were exposed to air. At all-time points, RTEL1 expression was significantly decreased in lung tissue of the silica-exposed animals compared to controls. Also, significant increases in telomere length and TERT were observed in the silica group at 4 and 32 wk. Telomere length, RTEL1 and TERT expression may serve as potential biomarkers related to silica exposure and may offer insight into the molecular mechanism of silica-induced lung disease and tumorigeneses.

Initiation of Pulmonary Fibrosis after Silica Inhalation in Rats is linked with Dysfunctional Shelterin Complex and DNA Damage Response

“…The current study further corroborates the findings of our previous study in which we identified telomere instability as observed by significant increases in telomere length and TERT expression at 4 and 32 wk after 15 mg/m 3 of silica × 6 h/d × 5 d exposure 55 . Here, we provide the first experimental evidence that DNA damage-induced shelterin dysfunction after silica exposure could allow for the development of pulmonary fibrosis.…”

“…RTEL1 is transiently associated with telomeres and is involved in the maintenance of T-Loop structure of telomeres by unwinding telomeric G4 DNA and allowing efficient telomere replication and stability. Its deletion or reduction could result in the loss of T-Loop structure 55,57 . Similar to our previous findings using an acute 5-d silica exposure regimen 55 , we observed significant decreases in RTEL1 expression in lung tissue of rats at 16 hr after 3, 6, and 12 wk of silica exposure compared to air control (Fig.…”

“…Its deletion or reduction could result in the loss of T-Loop structure 55,57 . Similar to our previous findings using an acute 5-d silica exposure regimen 55 , we observed significant decreases in RTEL1 expression in lung tissue of rats at 16 hr after 3, 6, and 12 wk of silica exposure compared to air control (Fig. 1D–F).…”

“…The National Institute for Occupational Safety and Health has recommended development of a more sensitive and practical approach for the analysis of silicosis 54 . Previously, we have shown telomere alteration in rat peripheral blood mononuclear cells after stainless steel welding fume exposure and in rat lung tissue after inhalation exposure to silica 12,55 . Increased expression of TERT also was observed in the lung tissue of silica-exposed rats 55 .…”

“…Previously, we have shown telomere alteration in rat peripheral blood mononuclear cells after stainless steel welding fume exposure and in rat lung tissue after inhalation exposure to silica 12,55 . Increased expression of TERT also was observed in the lung tissue of silica-exposed rats 55 . Previously, similar silica exposure led to significantly higher pulmonary toxicity in rats at 3, 6 and 12 wk of silica inhalation compared to their respective controls.…”