Abstract 3459: Effects of Dehydroepiandrosterone (DHEA) treatment on serum methylation, oxidative and nitrosative stress biomarkers in an obesity model of mammary carcinogenesis

Abstract

Abstract Free oxygen and free nitrogen radicals, commonly named as reactive oxygen species (ROS) and reactive nitrogen species (RNS) play an important role in cancer promotion. The cumulative effect of ROS/RNS termed oxidative and nitrosative stress is commonly seen in the development of several cancers. Obesity has been also linked with the risk of development of various cancers, including breast cancer. DHEA is a dietary supplement used as an anti-cancer agent and anti-obesity supplement. Previously, we reported that obese rats fed DHEA had lower body weight gain and developed no mammary tumor in DMBA model. The effect of DHEA on development of oxidative/nitrosative stress is not known. The objectives of this study were to investigate the possible mechanism of DHEA tumor protection by determining the DHEA effects on serum concentration of methylation cycle metabolites, oxidative and nitrosative stress biomarkers. Twenty (20) six-week-old obese female Zucker rats were randomly assigned ad libitum to water and a diet of either chow as a control diet or chow with the addition of DHEA at a concentration of 6 g/kg of chow as a DHEA diet. All rats were orally gavaged at age 50 days with 65 mg DMBA/kg body weight and were sacrificed 155 days later. Serum concentration of Methionine, S-sdenosylmethionine (SAM), S-adenosylhomocysteine (SAH), homocysteine, free reduced glutathione (fGSH), oxidized glutathione (GSSG), nitroglutathione (GSNO), free Cysteine, Cystine and 3-nitroTyrosine (3NT) were measured by HPLC method with electrochemical detection or LC-MS method. There were no significant differences in serum concentration of fGSH between control and DHEA fed-rats. However, DHEA-fed rats had lower (P<0.03) serum concentration of GSSG which led to higher (P<0.02) glutathione “intracellular oxidative ratio” (fGSH/GSSG) compared to control rats. Despite higher (P<0.004) serum concentration of free Cysteine in control rats, DHEA-fed rats had lower (P<0.04) serum concentration of Cystine (P<0.003) compared to control rats which led to a lower (P<0.04) Cystine/fCysteine “extacellular oxidative ratio”. Concentration of biomarkers for “nitrosative stress” were lower for 3NT (P<0.04) and GSNO (P<0.02) in serum of DHEA-fed rats compared to control rats. Also, DHEA-fed rats had a lower (P<0.02) Methionine concentration which was accompanied with increased serum SAM concentration (P<0.005) and lower (P<0.02) concentration of SAH and homocysteine (P<0.03) compared to control rats. These changes lead to an increase (P<0.0001) in SAM/SAH “methylation ratio” in DHEA-fed rats compared to control rats. In summary, our results suggest that DHEA fed-rats are capable of reducing body weight gain and protecting mammary tumors formation by improving “methylation environment conditions” and decreasing damaging effect oxidative and nitrosative stress. Supported by ABI and ACHRI to RH and SM. Citation Format: Reza Hakkak, Soheila Korourian, Teresa Evans, Oleksandra Pavliv, Stepan Melnyk. Effects of Dehydroepiandrosterone (DHEA) treatment on serum methylation, oxidative and nitrosative stress biomarkers in an obesity model of mammary carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3459.