Melnyk Stepan, Korourian Soheila, Levy Joseph W, Pavliv Oleksandra, Evans Teresa, Hakkak Reza
Department of Pediatrics, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205, USA.
Arkansas Children's Research Institute, 13 Children's Way, Little Rock, AR 72202, USA.
Metabolites. 2017 Jun 8;7(2):26. doi: 10.3390/metabo7020026.
The prevalence of the overweight and obesity is on the rise worldwide. Obesity can increase the risk of certain cancers and liver steatosis development. Previously, we reported that obesity increased liver steatosis in a mammary tumor model, but little is known about the effects of obesity in the liver in regard to global DNA methylation, DNA damage, and oxidative/nitrosative stress. Using a mammary tumor model, we investigated the effects of obesity on oxidative stress and DNA reaction. Five-week-old lean and obese female rats were used. At 50 days of age, all rats received 7,12-dimethylbenz()anthracene (DMBA) and were sacrificed 155 days later. HPLC with electrochemical and ultraviolet detection and LC-MS were used. Obesity caused higher ( < 0.0004) methionine levels, had no effect ( < 0.055) on SAM levels, caused lower ( < 0.0005) SAH levels, caused higher ( < 0.0005) SAM/SAH ratios, and increased ( < 0.02) global DNA methylation. Levels of free reduced GSH were not significantly lower ( < 0.08), but free oxidized GSSG was higher ( < 0.002) in obese rats. The GSH/GSSG ratio was lower ( < 0.0001), and oxidized guanosine was higher ( < 0.002) in DNA of obese rats compared to lean rats. Obesity caused significant oxidative/nitrosative stress, oxidative DNA damage, and change of DNA methylation pattern in the liver, and these changes may contribute to the development of liver steatosis in breast cancer models.
超重和肥胖在全球范围内的患病率正在上升。肥胖会增加某些癌症和肝脂肪变性发展的风险。此前，我们报道过在乳腺肿瘤模型中肥胖会增加肝脂肪变性，但关于肥胖对肝脏中整体DNA甲基化、DNA损伤以及氧化/亚硝化应激的影响，我们知之甚少。利用乳腺肿瘤模型，我们研究了肥胖对氧化应激和DNA反应的影响。使用了5周龄的瘦型和肥胖型雌性大鼠。在50日龄时，所有大鼠均接受7,12-二甲基苯并(a)蒽（DMBA）处理，并在155天后处死。采用了带电化学和紫外检测的高效液相色谱法以及液相色谱-质谱联用技术。肥胖导致蛋氨酸水平升高（P<0.0004），对SAM水平无影响（P<0.055），导致SAH水平降低（P<0.0005），导致SAM/SAH比值升高（P<0.0005），并增加了整体DNA甲基化（P<0.02）。肥胖大鼠体内游离还原型谷胱甘肽（GSH）水平并无显著降低（P<0.08），但游离氧化型谷胱甘肽（GSSG）水平较高（P<0.002）。与瘦型大鼠相比，肥胖大鼠体内GSH/GSSG比值较低（P<0.0001），且DNA中氧化鸟苷水平较高（P<0.002）。肥胖在肝脏中引发了显著的氧化/亚硝化应激、氧化性DNA损伤以及DNA甲基化模式的改变，而这些变化可能有助于乳腺癌模型中肝脂肪变性的发展。
