Simulated Galactic Cosmic Radiation Exposure-Induced Mammary Tumorigenesis in Mice Coincides with Activation of ERα-ERRα-SPP1 Signaling Axis.

Background: Exposure to galactic cosmic radiation (GCR) is a breast cancer risk factor for female astronauts on deep-space missions. However, the specific signaling mechanisms driving GCR-induced breast cancer have not yet been determined.

Methods: This study aimed to investigate the role of the estrogen-induced ERα-ERRα-SPP1 signaling axis in relation to mammary tumorigenesis in female mice exposed to simulated GCR (GCRsim) at 100-110 days post-exposure.

Long-term Radiation Signal Persistence in Urine and Blood: A Two-year Analysis in Non-human Primates Exposed to a 4 Gy Total-Body Gamma-Radiation Dose.

National security concerns regarding radiological incidents, accidental or intentional in nature, have increased substantially over the past few years. A primary area of intense planning is the assessment of exposed individuals and timely medical management. However, exposed individuals who receive survivable radiation doses may develop delayed effects of acute radiation exposure many months or years later.

Effects of High-Linear-Energy-Transfer Heavy Ion Radiation on Intestinal Stem Cells: Implications for Gut Health and Tumorigenesis.

Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses a risk to intestinal stem cells (ISCs), which are vital for maintaining intestinal homeostasis. Earlier studies have shown that heavy-ion radiation can cause chronic oxidative stress, persistent DNA damage, cellular senescence, and the development of a senescence-associated secretory phenotype (SASP) in mouse intestinal mucosa. However, the specific impact on different cell types, particularly Lgr5 intestinal stem cells (ISCs), which are crucial for maintaining cellular homeostasis, GI function, and tumor initiation under genomic stress, remains understudied.

8-OxodG: A Potential Biomarker for Chronic Oxidative Stress Induced by High-LET Radiation.

Oxidative stress-mediated biomolecular damage is a characteristic feature of ionizing radiation (IR) injury, leading to genomic instability and chronic health implications. Specifically, a dose- and linear energy transfer (LET)-dependent persistent increase in oxidative DNA damage has been reported in many tissues and biofluids months after IR exposure. Contrary to low-LET photon radiation, high-LET IR exposure is known to cause significantly higher accumulations of DNA damage, even at sublethal doses, compared to low-LET IR.

Impact of Partial Body Shielding from Very High Dose Rates on Untargeted Metabolomics in Biodosimetry.

A realistic exposure to ionizing radiation (IR) from an improvised nuclear device will likely include individuals who are partially shielded from the initial blast delivered at a very high dose rate (VHDR). As different tissues have varying levels of radiosensitivity, e.g.

p16 immune cell - controlled disease tolerance as a broad defense and healthspan extending strategy.

The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16 immune cells play a key role in establishing disease tolerance.

Host microbiome depletion attenuates biofluid metabolite responses following radiation exposure.

Development of novel biodosimetry assays and medical countermeasures is needed to obtain a level of radiation preparedness in the event of malicious or accidental mass exposures to ionizing radiation (IR). For biodosimetry, metabolic profiling with mass spectrometry (MS) platforms has identified several small molecules in easily accessible biofluids that are promising for dose reconstruction. As our microbiome has profound effects on biofluid metabolite composition, it is of interest how variation in the host microbiome may affect metabolomics based biodosimetry.

FAILLA MEMORIAL LECTURE How We Got Here: One Laboratory's Odyssey in the Field of Radiation-Inducible Genes.

This review focuses on early discoveries that contributed to our understanding and the scope of transcriptional responses after radiation damage. Before the development of modern approaches to assess overall global transcriptomic responses, the idea that mammalian cells could respond to DNA-damaging agents in a manner analogous to bacteria was not generally accepted. To investigate this possibility, the development of technology to identify differentially expressed low-abundance transcripts substantially facilitated our appreciation that DNA damaging agents like UV radiation and subsequently ionizing radiation did in fact produce robust transcriptional responses.

Expression of Stem Cell Markers in High-LET Space Radiation-Induced Intestinal Tumors in Mouse Intestine.

Estimation of cancer risk among astronauts planning to undertake future deep-space missions requires understanding the quantitative and qualitative differences in radiogenic cancers after low- and high-LET radiation exposures. Previously, we reported a multifold higher RBE for high-LET radiation-induced gastrointestinal (GI) tumorigenesis in mice. Using the same model system, i.

High-LET-Radiation-Induced Persistent DNA Damage Response Signaling and Gastrointestinal Cancer Development.

Ionizing radiation (IR) dose, dose rate, and linear energy transfer (LET) determine cellular DNA damage quality and quantity. High-LET heavy ions are prevalent in the deep space environment and can deposit a much greater fraction of total energy in a shorter distance within a cell, causing extensive DNA damage relative to the same dose of low-LET photon radiation. Based on the DNA damage tolerance of a cell, cellular responses are initiated for recovery, cell death, senescence, or proliferation, which are determined through a concerted action of signaling networks classified as DNA damage response (DDR) signaling.

Galactic cosmic ray simulation at the NASA space radiation laboratory - Progress, challenges and recommendations on mixed-field effects.

For missions beyond low Earth orbit to the moon or Mars, space explorers will encounter a complex radiation field composed of various ion species with a broad range of energies. Such missions pose significant radiation protection challenges that need to be solved in order to minimize exposures and associated health risks. An innovative galactic cosmic ray simulator (GCRsim) was recently developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL).

Simulated galactic cosmic radiation (GCR)-induced expression of Spp1 coincide with mammary ductal cell proliferation and preneoplastic changes in Apc mouse.

Female astronauts inevitably exposed to galactic cosmic radiation (GCR) are considered at a greater risk for mammary cancer development. The purpose of this study is to assess the status of mammary cancer-associated preneoplasia markers after GCR and γ-ray irradiation using a mouse model of human mammary cancer. Female Apc mice were irradiated to 50 cGy of either γ-ray (Cs) or full-spectrum simulated galactic cosmic radiation (GCR) (33-beam), and at 110 - 120 days post-irradiation mice were euthanized, and normal-appearing mammary tissues were analyzed for histological and molecular markers of preneoplasia.

Heavy-ion radiation-induced colitis and colorectal carcinogenesis in Il10-/- mice display co-activation of β-catenin and NF-κB signaling.

Space radiation-induced gastrointestinal (GI) cancer risk models for future interplanetary astronauts are being developed that primarily rely on quantitative animal model studies to assess radiation-quality effects of heavy-ion space radiation exposure in relation to γ-rays. While current GI-cancer risk estimation efforts are focused on sporadic GI-cancer mouse models, emerging in-vivo data on heavy-ion radiation-induced long-term GI-inflammation are indicative of a higher but undetermined risk of GI-inflammation associated cancers, such as colitis-associated cancer (CAC). Therefore, we aimed to assess radiation quality effects on colonic inflammation, colon cancer incidence, and associated signaling events using an in-vivo CAC model i.

Low dose radiation upregulates Ras/p38 and NADPH oxidase in mouse colon two months after exposure.

Background: Exposure to ionizing is known to cause persistent cellular oxidative stress and NADPH oxidase (Nox) is a major source of cellular oxidant production. Chronic oxidative stress is associated with a myriad of human diseases including gastrointestinal cancer. However, the roles of NADPH oxidase in relation of long-term oxidative stress in colonic epithelial cells after radiation exposure are yet to be clearly established.

White-Nose Syndrome Disrupts the Splenic Lipidome of Little Brown Bats () at Early Disease Stages.

White-nose syndrome (WNS)-positive little brown bats () may exhibit immune responses including increased cytokine and pro-inflammatory mediator gene levels. Bioactive lipid mediators (oxylipins) formed by enzymatic oxidation of polyunsaturated fatty acids can contribute to these immune responses, but have not been investigated in WNS pathophysiology. Nonenzymatic conversion of polyunsaturated fatty acids can also occur due to reactive oxygen species, however, these enantiomeric isomers will lack the same signaling properties.

Countermeasure development against space radiation-induced gastrointestinal carcinogenesis: Current and future perspectives.

A significantly higher probability of space radiation-induced gastrointestinal (GI) cancer incidence and mortality after a Mars mission has been projected using biophysical and statistical modeling approaches, and may exceed the current NASA mandated limit of less than 3% REID (risk of exposure-induced death). Since spacecraft shielding is not fully effective against heavy-ion space radiation, there is an unmet need to develop an effective medical countermeasure (MCM) strategy against heavy-ion space radiation-induced GI carcinogenesis to safeguard astronauts. In the past, we have successfully applied a GI cancer mouse model approach to understand space radiation-induced GI cancer risk and associated molecular signaling events.

Integrated Genotoxicity Testing of three anti-infective drugs using the TGx-DDI transcriptomic biomarker and high-throughput CometChip assay in TK6 cells.

Genotoxicity testing relies on the detection of gene mutations and chromosome damage and has been used in the genetic safety assessment of drugs and chemicals for decades. However, the results of standard genotoxicity tests are often difficult to interpret due to lack of mode of action information. The TGx-DDI transcriptomic biomarker provides mechanistic information on the DNA damage-inducing (DDI) capability of chemicals to aid in the interpretation of positive genotoxicity data.

Predominant contribution of the dose received from constituent heavy-ions in the induction of gastrointestinal tumorigenesis after simulated space radiation exposure.

Gastrointestinal (GI) cancer risk among astronauts after encountering galactic cosmic radiation (GCR) is predicted to exceed safe permissible limits in long duration deep-space missions. Current predictions are based on relative biological effectiveness (RBE) values derived from in-vivo studies using single-ion beams, while GCR is essentially a mixed radiation field composed of protons (H), helium (He), and heavy ions. Therefore, a sequentially delivered proton (H) → Helium (He) → Oxygen (O) → Silicon (Si) beam was designed to simulate simplified-mixed-field GCR (Smf-GCR), and Apc mice were total-body irradiated to sham or γ (Cs) or Smf-GCR followed by assessment of GI-tumorigenesis at 150 days post-exposure.

Crohn's disease in endoscopic remission, obesity, and cases of high genetic risk demonstrates overlapping shifts in the colonic mucosal-luminal interface microbiome.

Background: Crohn's disease (CD) patients demonstrate distinct intestinal microbial compositions and metabolic characteristics compared to unaffected controls. However, the impact of inflammation and underlying genetic risk on these microbial profiles and their relationship to disease phenotype are unclear. We used lavage sampling to characterize the colonic mucosal-luminal interface (MLI) microbiome of CD patients in endoscopic remission and unaffected controls relative to obesity, disease genetics, and phenotype.

Biofluid Metabolomics and Lipidomics of Mice Exposed to External Very High-Dose Rate Radiation.

High-throughput biodosimetry methods to determine exposure to ionizing radiation (IR) that can also be easily scaled to multiple testing sites in emergency situations are needed in the event of malicious attacks or nuclear accidents that may involve a substantial number of civilians. In the event of an improvised nuclear device (IND), a complex IR exposure will have a very high-dose rate (VHDR) component from an initial blast. We have previously addressed low-dose rate (LDR, ≤1 Gy/day) exposures from internal emitters on biofluid small molecule signatures, but further research on the VHDR component of the initial blast is required.

GADD45 in Stress Signaling, Cell Cycle Control, and Apoptosis.

GADD45 is a gene family consisting of GADD45A, GADD45B, and GADD45G that is often induced by DNA damage and other stress signals associated with growth arrest and apoptosis. Many of these roles are carried out via signaling mediated by p38 mitogen-activated protein kinases (MAPKs). The GADD45 proteins can contribute to p38 activation either by activation of upstream kinase(s) or by direct interaction, as well as suppression of p38 activity in certain cases.

Effect of the p38 Mitogen-Activated Protein Kinase Signaling Cascade on Radiation Biodosimetry.

Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including chronic inflammation or immune suppression, can potentially obscure the predictive power of the method. Members of the p38 mitogen-activated protein kinase (MAPK) family respond to pro-inflammatory signals and environmental stresses, whereas genetic ablation of the p38 signaling pathway in mice leads to reduced susceptibility to collagen-induced arthritis and experimental autoimmune encephalomyelitis that model human rheumatoid arthritis and multiple sclerosis, respectively.