Estrogen as a therapeutic agent to protect against oxidative stress in aging and endocrine disruptors in humans and murine models

Berry, Savannah Rose (2022) Estrogen as a therapeutic agent to protect against oxidative stress in aging and endocrine disruptors in humans and murine models. Doctoral thesis, Northern Arizona University.

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Abstract

Redox dysfunction and oxidative stress are common etiology of some of the world’s most prominent and deadly diseases such are cardiovascular disease, cancer, diabetes, pulmonary diseases, and neurodegenerative diseases. In many of these diseases, apparent sex differences have emerged. While some studies related to redox biology have included both sexes, the emphasis on comparing the differences across sex is lacking. Sources of reactive oxygen species can be both endogenous like mitochondria, peroxisomes, and lipids, and others are exogenous like foods, drugs, physical stressors (ischemia/reperfusion) or environmental (environmental toxins, pollutants, and contaminants). The goal of this dissertation was to investigate the effects of oxidative stressors on redox function across sex. Aerobic fitness has been shown to increase redox capacity in order adults, but whether adaptation differ between sexes remains unknown. Healthy men and women were evaluated for fitness levels and then underwent an ischemia-reperfusion (oxidative stress) trial. In response to the I/R trial, women had significantly higher lipid peroxidation levels at baseline compared to men, yet women recovered to baseline levels, where men continued to increase. While these data support that menopause may cause increases in oxidative stress due to a loss in estrogen, women are more responsive to the effects of physical fitness on attenuating oxidative stress, possibly mediated by body composition. Arsenic exposure is an exogenous environmental toxin and source of reactive oxygen species. It has been previously determined that the loss of estrogen associated with menopause can lead to an accumulation of oxidative stress and thus an unbalanced redox state. Therefore, the effects of estrogen as a therapeutic agent to combat oxidative stress caused by arsenic exposure was tested in murine models ovariectomized murine models. Ovariectomized 8-week old mice were split into four groups (controls, control + estrogen, arsenic, and arsenic + estrogen) and antioxidant capacity was assessed in enzymatic activity and gene expression. These data suggested that arsenic may play a role in inducing oxidative stress by interfering with antioxidant activity and that estrogen may play a role in increasing antioxidant capacity in acute arsenic exposure. Due to the effects of both arsenic and estrogen shown in our previous study, we decided to investigate sex differences in 8-week old intact females and age- matched male mice. Mice were either exposed to arsenic or a control. Mice were treated for 8 weeks via drinking water. These data demonstrate that sex differences only emerged under stimulated conditions (arsenic exposure) and support the protective role of estrogen in antioxidant defenses. In conclusion, this dissertation determined that there are sex-specific differences that only emerge in response to oxidative stressors and that estrogen may play a role in maintaining redox function.

Item Type:	Thesis (Doctoral)
Publisher’s Statement:	© Copyright is held by the author. Digital access to this material is made possible by the Cline Library, Northern Arizona University. Further transmission, reproduction or presentation of protected items is prohibited except with permission of the author.
Keywords:	aging; antioxidants; endocrine disruptors; exercise; redox balance; sex differences; estrogen therapy
Subjects:	R Medicine > RG Gynecology and obstetrics
MeSH Subjects:	E Analytical,Diagnostic and Therapeutic Techniques and Equipment > E02 Therapeutics
NAU Depositing Author Academic Status:	Student
Department/Unit:	Graduate College > Theses and Dissertations College of the Environment, Forestry, and Natural Sciences > Biological Sciences
Date Deposited:	14 Jul 2022 17:10
Last Modified:	14 Jul 2022 17:10
URI:	https://openknowledge.nau.edu/id/eprint/5846

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