Mathematics PhD Candidate Duke University, United States
Disclosure(s):
Allison Cruikshank: No financial relationships to disclose
Objectives: Reactive oxygen species (ROS) are produced naturally in the body as byproducts of cellular metabolism. Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, leading to the accumulation of ROS. Excessive ROS can damage lipids, proteins, and DNA, contributing to cellular dysfunction and disease. Interestingly, premenopausal women tend to have lower levels of oxidative stress and higher concentrations of certain antioxidants, such as glutathione (GSH), compared to men. These differences point to the important role of sex hormones in regulating oxidative stress and its effects on the body. In this work, we aim to uncover the mechanisms behind various experimental and clinical results regarding the effects of estradiol on oxidative stress in healthy individuals and patients with Cystathionine -Synthase Deficiency (CBS-def).
Methods: We developed a dynamic, mechanistic model of Hydrogen Peroxide (H2O2), a key ROS, using physiological parameters taken from the experimental literature. The model includes the production and removal of H2O2 in both the cytosol and mitochondria of liver cells. Removal of H2O2 is mediated by the three major scavenging pathways, the GSH and thioredoxin systems, and catalase. We calibrated and validated these scavenging pathways using in vitro experiments measuring the relative contributions of the glutathione, thioredoxin, and catalase systems in liver mitochondria. To simulate CBS-def, we reduced the maximum velocity of Cystathionine -Synthase (CBS), resulting in an end flux through CBS consistent with clinical studies. We validated this CBS simulation by comparing predicted levels of key metabolites, including homocysteine and cysteine, with clinical data.
Results: We show that estradiol’s regulation of key enzymes in the GSH pathway results in lower oxidative stress levels in premenopausal women compared to men. Our mathematical model also highlights the complex role of estradiol in oxidative stress, since cytosolic H2O2 levels exhibit nonmonotonic behavior as estradiol changes. Additionally, we demonstrate how variations in mitochondrial H2O2 production and estradiol levels lead to distinct effects on cytosolic H2O2, helping to clarify contradictory results in the literature. Lastly, our mathematical model explains the attenuation of sex differences in CBS-def. While control simulations show sex differences in oxidative stress, CBS-def disrupts this pattern.
Conclusions: Our work provides insights into the underlying mechanisms that cause sex differences and the complex role of estradiol in oxidative stress. The results have implications for estradiol supplementation in premenopausal and postmenopausal women and therefore for women’s health in general.
Citations: [1] Cruikshank, A., Reed, M.C., & Nijhout, H.F. (2024). Sex differences in glutathione metabolism and acetaminophen toxicity. Metabolism and Target Organ Damage, 4(17). https://dx.doi.org/10.20517/mtod.2023.44 [2] Kim, R., Nijhout, H.F., & Reed, M.C. (2021). One-carbon metabolism during the menstrual cycle and pregnancy. PLoS Computational Biology, 17(12). https://doi.org/10.1371/journal.pcbi.1009708 [3] Sadre-Marandi, F., Dahdoul, T., Reed, M. & Nijhout, H.F. (2018). Sex differences in hepatic one-carbon metabolism. BMC Systems Biology, 12(89). https://doi.org/10.1186/s12918-018-0621-7
Keywords: Oxidative Stress, Sex Differences, Estradiol Supplementation
