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A Method to Study the Impact of Chemically-induced Ovarian Failure on Exercise Capacity and Cardiac Adaptation in Mice
Published on: April 7, 2014
Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary
R K Gupta1, R A Schuh, G Fiskum
1Program in Toxicology, Department of Epidemiology and Preventive Medicine, University of Maryland, 660 W. Redwood Street, Howard Hall 133B, Baltimore, MD, USA.
Abstract:
Methoxychlor (MXC) is an organochlorine pesticide that reduces fertility in female rodents by causing ovarian atrophy, persistent estrous cyclicity, and antral follicle atresia (apoptotic cell death). Oxidative damage resulting from reactive oxygen species (ROS) generation has been demonstrated to lead to toxicant-induced cell death. Thus, this work tested the hypothesis that MXC causes oxidative damage to the mouse ovary and affects mitochondrial respiration in a manner that stimulates ROS production. For the in vitro experiments, mitochondria were collected from adult cycling mouse ovaries, treated with vehicle (dimethyl sulfoxide; DMSO) or MXC, and subjected to polarographic measurements of respiration. For the in vivo experiments, adult cycling CD-1 mice were dosed with either vehicle (sesame oil) or MXC for 20 days. After treatment, ovarian mitochondria were isolated and subjected to measurements of respiration and fluorimetric measurements of H2O2 production. Some ovaries were also fixed and processed for immunohistochemistry using antibodies for ROS production markers: nitrotyrosine and 8-hydroxy-2'-deoxyguanosine (8-OHG). Ovaries from in vivo experiments were also used to measure the mRNA expression and activity of antioxidants such as Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX), and catalase (CAT). The results indicate that MXC significantly impairs mitochondrial respiration, increases production of H2O2, causes more staining for nitrotyrosine and 8-OHG in antral follicles, and decreases the expression and activity of SOD1, GPX, and CAT as compared to controls. Collectively, these data indicate that MXC inhibits mitochondrial respiration, causes ROS production, and decreases antioxidant expression and activity in the ovary, specifically in the antral follicles. Therefore, it is possible that MXC causes atresia of ovarian antral follicles by inducing oxidative stress through mitochondrial production of ROS.
Insights
Methoxychlor (MXC) pesticide exposure impairs ovarian mitochondrial respiration, increasing reactive oxygen species (ROS) and decreasing antioxidant defenses. This oxidative stress in ovarian antral follicles may lead to reproductive toxicity.
Area of Science:
- Reproductive Toxicology
- Mitochondrial Biology
- Environmental Health
Background:
- Methoxychlor (MXC) is an organochlorine pesticide linked to reduced female fertility.
- Oxidative damage from reactive oxygen species (ROS) contributes to toxicant-induced cell death.
- The mechanism by which MXC affects ovarian function, particularly oxidative stress, requires further investigation.
Purpose of the Study:
- To test the hypothesis that MXC causes oxidative damage to the mouse ovary.
- To investigate MXC's effect on mitochondrial respiration and ROS production in ovarian tissue.
- To assess MXC's impact on antioxidant levels and markers of oxidative damage in vivo.
Main Methods:
- In vitro and in vivo experiments using adult cycling mouse ovaries.
- Mitochondrial respiration measurements using polarography.
- Measurement of hydrogen peroxide (H2O2) production, nitrotyrosine, and 8-hydroxy-2'-deoxyguanosine (8-OHG) as markers of ROS.
- Analysis of antioxidant enzyme (SOD1, GPX, CAT) mRNA expression and activity.
Main Results:
- MXC significantly impaired mitochondrial respiration and increased H2O2 production in ovarian mitochondria.
- In vivo MXC treatment led to increased nitrotyrosine and 8-OHG staining in ovarian antral follicles.
- MXC decreased the expression and activity of key antioxidant enzymes (SOD1, GPX, CAT) in the ovary.
Conclusions:
- MXC inhibits mitochondrial respiration, leading to increased ROS production in the mouse ovary.
- MXC exposure decreases ovarian antioxidant capacity and increases oxidative damage markers.
- These findings suggest MXC induces ovarian antral follicle atresia via oxidative stress mediated by mitochondrial ROS production.
