The Use of Topical Estrogen Supplementation to Combat Arsenic‐Induced Redox Stress in Ovariectomized Murine Models

Abstract

Background Chronic environmental arsenic exposure is a health hazard that can lead to cancer, cardiovascular disease and diabetes. Arsenic exposure stimulates the production of reactive oxygen species (ROS) increasing systemic oxidative stress. Estrogen contains antioxidant properties that assist in the upregulation of various antioxidant enzymes, including glutathione. The present study investigated the effects of estrogen as a therapeutic agent to combat oxidative stress caused by arsenic exposure in ovariectomized murine models. Methods Ovariectomized mice (10 weeks old) (n=24) were randomized to four treatment groups (CON= control, CE=control + estrogen, ARS=arsenic, AE= arsenic + estrogen). Arsenic treated groups (ARS & AE) were exposed to controlled arsenic levels (10µM) via drinking water for 3-wks. Following the arsenic exposure, estrogen supplementation (0.75 µg/g of 0.06% Estradiol Benzoate) was applied topically to respective treatment groups (CE & AE). One week following the first estrogen dosage (3 total doses), mice were euthanized, and skeletal muscle and cardiac tissue were collected. Oxidized and reduced glutathione and catalase (CAT) activity were measured in skeletal muscle. Superoxide dismutase (SOD) and thioredoxin reductase (TrxR) were measured in cardiac tissue. A One-way ANOVA was performed with post-hoc comparisons using Least Significant Differences (LSD) for pairwise comparisons. Results For reduced glutathione levels, CE was significantly higher than CON (p = 0.004) and ARS (p = 0.001). CE was also significantly higher than all other groups for GSSG (p < 0.05) for all pairwise comparisons). Catalase activity was significantly higher in AE compared to CON (p = 0.032), and CE (p = 0.001), and ARS (p = 0.009). Superoxide dismutase (SOD) and thioredoxin reductase (TrxR) levels did not differ across treatment groups. Conclusion Estrogen treatment increased total glutathione content in the CE group indicated by the high levels of GSH as well as GSSG. Estrogen treatment combined with the arsenic exposure also increased catalase activity levels pointing to higher levels of hydrogen peroxide in the AE group, although this was not measured directly. Taken together, these data suggest estrogen may increase antioxidant capacity by elevating total glutathione and catalase content within skeletal muscle. These data indicate that estrogen alone and estrogen in the presence arsenic may play a role in modulating antioxidant activity in arsenic-induced oxidative damage and may be a potential treatment option for individuals suffering from environmental arsenic exposure.