Effects of Obesity on Pro-Oxidative Conditions and DNA Damage in Liver of DMBA-Induced Mammary Carcinogenesis Models

Abstract

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(α)anthracene (DMBA) and were sacrificed 155 days later. HPLC with electrochemical and ultraviolet detection and LC-MS were used. Obesity caused higher (p < 0.0004) methionine levels, had no effect (p < 0.055) on SAM levels, caused lower (p < 0.0005) SAH levels, caused higher (p < 0.0005) SAM/SAH ratios, and increased (p < 0.02) global DNA methylation. Levels of free reduced GSH were not significantly lower (p < 0.08), but free oxidized GSSG was higher (p < 0.002) in obese rats. The GSH/GSSG ratio was lower (p < 0.0001), and oxidized guanosine was higher (p < 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.

Chemically induced carcinogenesis in rodent models of aging: assessing organismal resilience to genotoxic stressors in geroscience research

“…Epigenetic silencing of DNA repair genes via promoter methylation during carcinogenesis has been reported for several DNA repair pathways including base excision repair, nucleotide excision repair, DNA mismatch repair, and several other DNA damage processing mechanisms (Dobrovic and Simpfendorfer 1997;Esteller et al 2001;Guan et al 2008;Howard et al 2009;Kane et al 1997;Lahtz and Pfeifer 2011;Lawes et al 2005;Lee et al 2007;Narayan et al 2004;Peng et al 2005;Peng et al 2006;Vo et al 2004). Further, several risk factors that promote breast cancer and/or shorten lifespan, including obesity, were shown to alter DNA methylation patterns (Melnyk et al 2017). The current view is that promoter methylation and silencing of DNA repair genes are early events in tumorigenesis that contribute to both cancer initiation and progression by increasing genomic instability.…”

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

“…DNA replication of guanine oxidation products may result in somatic mutations that can cause proliferation of smooth muscle cells contributing to the etiology of atherosclerosis plaque formation, a risk factor of obesity . Obesity is also associated with NAFLD, and ROS‐induced oxidative DNA damage that may contribute to chronic conditions, such as liver fibrosis and HCC in NAFLD patients . The molecular mechanisms connecting obesity, ROS, and cancer are unclear; however, obesity‐stimulated oxidative stress, contributing to DNA damage and consequently to genetic instability, appears to play an important role.…”

“…100,101 Obesity is also associated with NAFLD, and ROS-induced oxidative DNA damage that may contribute to chronic conditions, such as liver fibrosis and HCC in NAFLD patients. [102][103][104] The molecular mechanisms connecting obesity, ROS, and cancer are unclear; however, obesity-stimulated oxidative stress, contributing to DNA damage and consequently to genetic instability, appears to play an important role.…”

Metabolic Status of Lean and Obese Zucker Rats Based on Untargeted and Targeted Metabolomics Analysis of Serum

“…For the past several years, our laboratory has used the Zucker rat model to investigate the effects of obesity and different diets on the development of breast cancer and non-alcoholic fatty liver disease [ 15 ].…”