Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model

Abstract

The development of the Artemis programme with the goal of returning to the moon is spurring technology advances that will eventually take humans to Mars and herald a new era of interplanetary space travel. However, long-term space travel poses unique challenges including exposure to ionising radiation from galactic cosmic rays and potential solar particle events, exposure to microgravity and specific nutritional challenges arising from earth independent exploration. Ionising radiation is one of the major obstacles facing future space travel as it can generate oxidative stress and directly damage cellular structures such as DNA, in turn causing genomic instability, telomere shortening, extracellular-matrix remodelling and persistent inflammation. In the gastrointestinal tract (GIT) this can lead to leaky gut syndrome, perforations and motility issues, which impact GIT functionality and affect nutritional status. While current countermeasures such as shielding from the spacecraft can attenuate harmful biological effects, they produce harmful secondary particles that contribute to radiation exposure. We hypothesised that induction of a torpor-like state would confer a radioprotective effect given the evidence that hibernation extends survival times in irradiated squirrels compared to active controls. To test this hypothesis, a torpor-like state was induced in zebrafish using melatonin treatment and reduced temperature, and radiation exposure was administered twice over the course of 10 days. The protective effects of induced-torpor were assessed via RNA sequencing and qPCR of mRNA extracted from the GIT. Pathway and network analysis were performed on the transcriptomic data to characterise the genomic signatures in radiation, torpor and torpor + radiation groups. Phenotypic analyses revealed that melatonin and reduced temperature successfully induced a torpor-like state in zebrafish as shown by decreased metabolism and activity levels. Genomic analyses indicated that low dose radiation caused DNA damage and oxidative stress triggering a stress response, including steroidal signalling and changes to metabolism, and cell cycle arrest. Torpor attenuated the stress response through an increase in pro-survival signals, reduced oxidative stress via the oxygen effect and detection and removal of misfolded proteins. This proof-of-concept model provides compelling initial evidence for utilizing an induced torpor-like state as a potential countermeasure for radiation exposure.

Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5

“…FDR is the expected fraction of false positive tests among significant tests and was calculated using the Benjamini-Hochberg multiple testing adjustment procedure. Differentially expressed genes (DEGs) were defined by q-value < 0.05 and log2FC > 0.6 for upregulated DEGs, and log2FC < −0.6 for downregulated DEGs [96,97].…”

Investigating the effects of chronic low-dose radiation exposure in the liver of a hypothermic zebrafish model

“…On the other hand, our results showed that exposure to low-dose radiation caused DNA damage, oxidative stress, glucocorticoid signalling, and cell cycle arrest. When irradiated under induced/synthetic torpor, radiation-induced stress signals were observed, however, the increase in anti-apoptotic, mitogenic, and pro-survival signals were all maintained, suggesting radio-protective effects 37 . Here we report our findings in the context of hepatic health.…”

Synthetic torpor protects rats from exposure to accelerated heavy ions

“…Moreover, we used investigated in vitro to clarify the mechanism of radioresistance. It has been argued that the lower concentration of oxygen in the tissues of an animal in synthetic torpor could be a relevant factor in preventing cell damage by radiation-induced ROS 24 . Furthermore, changes in the metabolism at low temperature may also have an impact on DNA repair 25 .…”