antioxidants Article Lasting Effects of Low to Non-Lethal Radiation Exposure during Late Gestation on Offspring’s Cardiac Metabolism and Oxidative Stress Ashley S. Nemec-Bakk 1 , Sarah Niccoli 2 , Caitlund Davidson 2 , Danika Roy 3 , Lisa Stoa 4 , Shayenthiran Sreetharan 4 , Alain Simard 3 , Douglas R. Boreham 3,5,6 , Joanna Y. Wilson 4 , T.C. Tai 3,5,6 , Simon J. Lees 2,3,5 and Neelam Khaper 2,3,5,6, *   Citation: Nemec-Bakk, A.S.; Niccoli, S.; Davidson, C.; Roy, D.; Stoa, L.; Sreetharan, S.; Simard, A.; Boreham, D.R.; Wilson, J.Y.; Tai,T.C.; et al. Lasting Effects of Low to Non-Lethal Radiation Exposure during Late Gestation on Offspring’s Cardiac Metabolism and Oxidative Stress. Antioxidants 2021, 10, 816. https:// doi.org/10.3390/antiox10050816 Academic Editor: Ashley J. Smuder Received: 18 March 2021 Accepted: 15 May 2021 Published: 20 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Science and Environmental Studies, Lakehead University, Thunder Bay, ON P7B 5E1, Canada; asnemec@lakeheadu.ca 2 Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada; saniccol@lakeheadu.ca (S.N.); cqdavids@lakeheadu.ca (C.D.); simon.lees@nosm.ca (S.J.L.) 3 Northern Ontario School of Medicine, Laurentian University, Sudbury, ON P3E 2C6, Canada; droy5@laurentian.ca (D.R.); asimard@nosm.ca (A.S.); dboreham@nosm.ca (D.R.B.); tc.tai@nosm.ca (T.C.T.) 4 Department of Biology, McMaster University, Hamilton, ON L8S 4L8, Canada; lisastoa@mcmaster.ca (L.S.); sreeths@mcmaster.ca (S.S.); joanna.wilson@mcmaster.ca (J.Y.W.) 5 Northern Ontario School of Medicine, Lakehead University, Thunder Bay, ON P7B 5E1, Canada 6 Biomolecular Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada * Correspondence: nkhaper@nosm.ca Abstract: Ionizing radiation (IR) is known to cause fetal programming, but the physiological effects of low-dose IR are not fully understood. This study examined the effect of low (50 mGy) to non-lethal (300 and 1000 mGy) radiation exposure during late gestation on cardiac metabolism and oxidative stress in adult offspring. Pregnant C57BL/6J mice were exposed to 50, 300, or 1000 mGy of gamma ra- diation or Sham irradiation on gestational day 15. Sixteen weeks after birth, 18 F-Fluorodeoxyglucose (FDG) uptake was examined in the offspring using Positron Emission Tomography imaging. Western blot was used to determine changes in oxidative stress, antioxidants, and insulin signaling related proteins. Male and female offspring from irradiated dams had lower body weights when compared to the Sham. 1000 mGy female offspring demonstrated a significant increase in 18 F-FDG uptake, glycogen content, and oxidative stress. 300 and 1000 mGy female mice exhibited increased superox- ide dismutase activity, decreased glutathione peroxidase activity, and decreased reduced/oxidized glutathione ratio. We conclude that non-lethal radiation during late gestation can alter glucose uptake and increase oxidative stress in female offspring. These data provide evidence that low doses of IR during the third trimester are not harmful but higher, non-lethal doses can alter cardiac metabolism later in life and sex may have a role in fetal programming. Keywords: low-dose radiation; cardiac; antioxidants; oxidative stress 1. Introduction An unfavorable fetal environment can affect growth and development of the fetus, and these changes can persist throughout life, which is commonly referred to as fetal programming. Adverse fetal environment can also result in changed placental morphology, low birth weight, and accelerated growth, which have been linked to many diseases later, including cardiovascular disease, cancer, diabetes mellitus, coronary heart disease, and hypertension [1–5]. Exposure to a variety of stressors during pregnancy can lead to low birth weight [6]. Stressors have the ability to activate the hypothalamic-pituitary- adrenal (HPA) axis [2,7]. Activation of the HPA axis can result in increased glucocorticoid production [2,7], which is known to cause insulin resistance and could result in altered cardiac glucose metabolism [8,9]. Antioxidants 2021, 10, 816. https://doi.org/10.3390/antiox10050816 https://www.mdpi.com/journal/antioxidants