Abstract
Exposure to ionizing radiation contributing to negative health outcomes is a widespread concern. However, the impact of low dose and sub-lethal dose radiation (SLDR) exposures remain contentious, particularly in pregnant women who represent a vulnerable group. The fetal programming hypothesis states that an adverse in utero environment or stress during development of an embryo or fetus can result in permanent physiologic changes often resulting in progressive metabolic dysfunction with age. To assess changes in gene expression profiles of glucose/insulin signaling and lipid metabolism caused by radiation exposure in utero, pregnant C57Bl/6J mice were irradiated using a dose response ranging from low dose to SLDR and compared to a Sham-irradiated group. mRNA expression analysis in 16 week old offspring (n = 84) revealed that genes involved in metabolic function including glucose metabolism, insulin signaling and lipid metabolism were unaffected by prenatal radiation exposures up to 300 mGy. However, female offspring of dams exposed to 1000 mGy had upregulated expression of genes contributing to insulin resistance and gluconeogenesis. In a second cohort of mice, the effects of SLDR on fetal programming of hepatic SOCS3 and PEPCK protein expression were assessed. 4 month old female offspring of dams irradiated at 1000 mGy had: 1) increased liver weights, 2) increased hepatic expression of proteins involved in glucose metabolism and 3) increased 18F-fluorodeoxyglucose (FDG) uptake in interscapular brown adipose tissue (IBAT) measured by positron emission tomography (PET) (n = 25). The results of this study indicate that prenatal radiation exposure does not affect metabolic function up to 300 mGy and 1000 mGy may be a threshold dose for sex-specific alterations in glucose uptake and hepatic gene and protein expression of SOCS3, PEPCK, PPARGC1A and PPARGC1B. These findings suggest that SLDR doses alter glucose uptake in IBAT and hepatic gene and protein expression of offspring and these changes may progress with age.
Highlights
Exposure to ionizing radiation and the possibility of radiation contributing to negative health outcomes is a widespread concern among the public, scientific community, and workers in the nuclear energy industry and diagnostic imaging
Doses 5, 10 and 50 mGy resemble radiation doses achieved during diagnostic imaging and are considered low dose radiation (LDR), while 300 and 1000 mGy are considered sub-lethal dose radiation (SLDR) and may represent relevant doses for the translation of mouse model data to the potential effects in humans
In order to identify the metabolic systems altered due to in utero radiation exposure, the liver from 4-month old offspring were analyzed using a panel of genes targeting the following systems: glucose metabolism/ insulin signaling and lipid metabolism
Summary
Exposure to ionizing radiation and the possibility of radiation contributing to negative health outcomes is a widespread concern among the public, scientific community, and workers in the nuclear energy industry and diagnostic imaging. There are several established models of fetal programming that induce in utero stress including maternal undernutrition, protein-restricted diets, maternal obesity, prenatal hypoxia, and exposure to stress hormones [7,8,9,10,11,12,13,14,15]. These models all result in similar outcomes with the offspring demonstrating alterations in birth weight followed by weight normalization within the first few months. A poor maternal state leads to placental insufficiency and negative health outcomes of the offspring
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