Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

Abstract

Both exposure to ionizing radiation and obesity have been associated with various pathologies including cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and other risk factors, such as obesity. In order to evaluate radiation responses in obese animals, C3H and C57BL/6J mice fed a control normal fat or a high fat (HF) diet were exposed to fractionated doses of X-rays (0.75 Gy ×4). Bone marrow micronucleus assays did not suggest a modulation of radiation-induced genotoxicity by HF diet. Using MSP, we observed that the promoters of p16 and Dapk genes were methylated in the livers of C57BL/6J mice fed a HF diet (irradiated and non-irradiated); Mgmt promoter was methylated in irradiated and/or HF diet-fed mice. In addition, methylation PCR arrays identified Ep300 and Socs1 (whose promoters exhibited higher methylation levels in non-irradiated HF diet-fed mice) as potential targets for further studies. We then compared microRNA regulations after radiation exposure in the livers of C57BL/6J mice fed a normal or an HF diet, using microRNA arrays. Interestingly, radiation-triggered microRNA regulations observed in normal mice were not observed in obese mice. miR-466e was upregulated in non-irradiated obese mice. In vitro free fatty acid (palmitic acid, oleic acid) administration sensitized AML12 mouse liver cells to ionizing radiation, but the inhibition of miR-466e counteracted this radio-sensitization, suggesting that the modulation of radiation responses by diet-induced obesity might involve miR-466e expression. All together, our results suggested the existence of dietary effects on radiation responses (especially epigenetic regulations) in mice, possibly in relationship with obesity-induced chronic oxidative stress.

Influence of maternal obesity, diet and exercise on epigenetic regulation of adipocytes

“…Epigenetic modification of genes acquired early in life by exposure to environmental factors, may contribute to the later development of obesity in offspring (Vogt et al, 2014), correlate with offspring adiposity (Dick et al, 2014), and is important for transgenerational propagation of changes in energy metabolism that promotes weight gain and obesity (Desai et al, 2015). Unlike alterations in genetic codes, epigenetic changes are modifiable by dietary energy and factors (Dong et al, 2014; Myzak et al, 2006, 2007; Rajendran et al, 2011; Vares et al, 2014). This review focuses on the current understanding of the role of epigenetic mechanisms and alterations that regulate metabolic processes in beige and brown adipocytes, and how these epigenetic alterations might be transmitted to subsequent generations.…”

Dietary Modification of Mouse Response to Total-Body-Irradiation

“…Epigenetic mechanisms may play a key role in the response of our body to IR. For examples, in the experimental animal models, diet-induced obesity modulated epigenetic responses (DNA methylation and microRNA regulation) to IR in mice [3]; antioxidant diets containing blueberry or strawberry extract were capable of mitigating the effects from exposure to heavy particles on behavioral alterations in rats [4,5]. Multiple dietary, lifestyle and environmental factors, in addition to genetic factors, have a big impact on the health of our body [6].…”

Metabolic Profile as a Potential Modifier of Long-Term Radiation Effects on Peripheral Lymphocyte Subsets in Atomic Bomb Survivors

“…It should be noted here that metabolic abnormalities, including serum levels of high triglyceride, low HDL cholesterol and fatty liver development, have been reported in association with radiation dose among A-bomb survivors (13)(14)(15). Moreover, emerging evidence from mouse studies suggests direct interactions between diet-induced obesity and biological responses to radiation, e.g., DNA double-strand breaks, microRNA expression and cell survival (16,17). Therefore, lymphocyte subsets in A-bomb survivors may be influenced by their metabolic profiles especially after radiation exposure.…”

“…Metabolic profile indicators associated with lymphocyte subset percentages (Table 1) might be potential modifiers of the radiation effects on lymphocyte subsets, because biological interactions between radiation responses and metabolic conditions were demonstrated in mouse studies (16,17). To test this hypothesis, we investigated the association of the interaction term between radiation dose and each of the metabolic indicators whose associations with lymphocyte subsets were significant (see Table 1).…”