A priming dose of protons alters the early cardiac cellular and molecular response to 56 Fe irradiation

Abstract

Purpose Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a “priming” dose of protons on the cardiac cellular and molecular response to a “challenge” dose of 56Fe in a mouse model. Methods Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

Densely ionizing radiation affects DNA methylation of selective LINE-1 elements

“…The acute dose of 56 Fe was selected to reflect the estimated cumulative dose to which astronauts could be potentially exposed during deep space exploration due to the galactic cosmic rays and is the lowest dose previously shown to cause cell loss in in vivo settings during deep space exploration due to the galactic cosmic rays (Rola et al, 2008). Sequential irradiation with protons before iron ions reflects the likely exposure of cells in the space environment where daily traversals by protons are accompanied by infrequent traversals by heavy ions (Ramadan et al, 2016). At the selected energy of 600 MeV/n, thorough penetration of the animals with a relatively flat Bragg peak entrance region is expected.…”

Effects of ionizing radiation on the heart

“…However, when administered 24 hours before a subsequent exposure to iron ions (0.5 Gy, 600 MeV/n), proton exposure prevented iron ion-induced markers of inflammatory infiltration, cardiac remodeling, and formation of cleaved caspase 3 [108]. These results suggest that proton exposure induced an as of yet unknown response in the heart that provided protection against further charged particle exposure.…”

In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells

“…More recent murine studies have shown similar effects of sequential irradiation with protons followed by HZE ions in the lung, heart and hippocampus. 27‐29 Collectively, these studies suggest that exposure of human cells, notably hematopoietic stem cells (HSC), to SEP and GCR radiation may significantly increase risk of carcinogenesis, and highlights the need for additional research on human cells using combinations of radiation species (ions) and exposure schemes that best approximate the space radiation environment.…”