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.
Inorganic arsenic is highly toxic metalloid considered a water contaminant that is naturally occurring through geological formations where it leaches into ground water sources and is anthropogenically sourced through pollution and found in surface water as a contaminant. Acute and chronic arsenic exposure can stimulate the production of reactive oxygen species and increase systemic oxidative stress. The aim of the present study was to investigate sex differences in the redox response induced by chronic arsenic exposure in a murine model. Twenty‐four (12 female & 12 male) 10‐wk old mice were randomized to arsenic treatment or control. Arsenic groups were exposed to controlled arsenic levels (10µM = ppb = ug/L) via drinking water for 8‐wks. Following the treatment, mice were euthanized, and skeletal muscle was collected. The tissue was homogenized and processed for measures of gene expression for seven antioxidant genes (Sod2, Cas1, Gpx, Gst, Gsr, Gclc, Nrf2). One‐way ANOVA was performed with post‐hoc comparisons depending on normality of data. Interactions between sex and arsenic were determined using univariate testing. There was a significant sex‐by‐treatment interaction for Cas1, Gpx1, Gsr, Gclc, and Nrf2 where the female mice treated with arsenic responded by upregulating these genes in comparison to controls (p<0.05), whereas the males did not. Only Sod2 was lower in the arsenic treated female mice versus controls and there were no effects on Gst across the 4 groups. These data demonstrate that sex differences only emerged under stimulated conditions (arsenic exposure) and support the protective role of estrogen in antioxidant defenses.
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