Time‐Dependent Measurement of Nrf2‐Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury

Abstract

Purpose Potential acute exposure to ionizing radiation in nuclear or radiological accidents presents complex mass casualty scenarios that demand prompt triage and treatment decisions. Due to delayed symptoms and varied response of radiation victims, there is an urgent need to develop robust biomarkers to assess the extent of injuries in individuals. Experimental design The transcription factor Nrf2 is the master of redox homeostasis and there is transcriptional evidence of Nrf2‐dependent antioxidant response activation upon radiation. The biomarker potential of Nrf2‐dependent downstream target enzymes is investigated by measuring their response in bone marrow extracted from C57Bl/6 and C3H mice of both genders for up to 4 days following 6 Gy total body irradiation using targeted MS. Results Overall, C57Bl/6 mice have a stronger proteomic response than C3H mice. In both strains, male mice have more occurrences of upregulation in antioxidant enzymes than female mice. For C57Bl/6 male mice, three proteins show elevated abundances after radiation exposure: catalase, superoxide dismutase 1, and heme oxygenase 1. Across both strains and genders, glutathione S‐transferase Mu 1 is consistently decreased. Conclusions and clinical relevance This study provides the basis for future development of organ‐specific protein biomarkers used in diagnostic blood test for radiation injury.

Identification of miRNA signatures associated with radiation-induced late lung injury in mice

“…Equal numbers of female and male mice were used to study gender differences. Prior to irradiation, mice (8)(9)(10) week-old males, [10][11][12] week-old females) were randomized into groups for an average body weight of 29 ± 1 g. Mice were anesthetized using an intraperitoneal injection a mixture of ketamine and xylazine (80 mg/kg ketamine and 4 mg/kg xylazine) and an ophthalmic ointment was applied to prevent corneal drying (Puralube 1 vet ointment, Dechra Veterinary Products, Northwich, UK). Anesthetized mice were placed in a jig (S1 Fig) with the thorax positioned so that a 2.75 cm wide strip was exposed to X-rays administered vertically with a focus-to-surface distance of 32 cm with the rest of the body shielded with 3 mm lead that gives 99.5% attenuation.…”

“…Biomarkers to predict both acute and late adverse outcomes of radiation exposure are critically needed to identify individuals at risk after a radiological incident, especially since early therapeutic intervention can dramatically improve survival rates in the context of ARS [1][2][3][4][5][6], and perhaps late disease [2]. Efforts into monitoring changes in blood or plasma have yielded encouraging data and identified potential biomarkers of radiation exposure, including proteins [7][8][9][10], mRNA [11][12][13][14][15][16], non-coding RNA [17], and microRNA (miRNA) [18][19][20][21][22][23][24]. Because circulating miRNA are protected from degradation in extracellular vesicles or protein complexes, and are stable at room temperature for hours to days, they are exceptionally well suited for triage in the field [25].…”

Effects of neutron radiation on Nrf2‑regulated antioxidant defense systems in rat lens

“…4C and D ). The protein levels of HO-1 and GCLC, downstream antioxidant enzymes of Nrf2( 4 ), exhibited similar trends (P<0.05 in the 1.2 Sv group vs. control group for HO-1; P<0.05 in the 0.4 Sv and 1.2 Sv groups vs. control group for GCLC; Fig. 4E and F ).…”

“…Nrf2 is normally sequestered in the cytoplasm, which can be activated by signals, such as ROS, which subsequently translocates into the nucleus to regulate expression of downstream antioxidant and detoxificationgenes that counteract ROS ( 31 ). These target genes include glutathione peroxidase, SOD, HO-1, quinone oxidoreductase (NQO1) and GCLC ( 4 , 32 ). Activation of the Nrf2 signaling pathway is one of the critical defensive mechanisms against oxidative stress in a number of tissues, including heart, retina, liver and kidney ( 23 ).…”

“…This ultimately leads to the modification and degradation of proteins, damage to the mitochondria and cell death ( 1 , 2 ). Ionizing radiation (IR) causes damage to biological tissues by inducing ROS production and can cause oxidative injury to cellular macromolecules like DNA, lipids and proteins, resulting in the impairment of organs and systems and even mortality ( 3 , 4 ). IR can arise from occupational exposure, medical procedures or exposure to nuclear explosion ( 5-7 ).…”