Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary

R. K. Gupta, R. A. Schuh, G. Fiskum, J. A. Flaws

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)436-445
Number of pages10
JournalToxicology and Applied Pharmacology
Volume216
Issue number3
DOIs
StatePublished - Nov 1 2006
Externally publishedYes

Fingerprint

Methoxychlor
Ovary
Reactive Oxygen Species
Respiration
Mitochondria
Cell death
Glutathione Peroxidase
Dimethyl Sulfoxide
Catalase
Cell Death
Antioxidants
Sesame Oil
Oxidative stress
Ovarian Follicle
Experiments
Periodicity
Pesticides
Atrophy
Fertility
Rodentia

Keywords

  • Methoxychlor
  • Mouse model
  • Ovary
  • Oxidative damage

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary. / Gupta, R. K.; Schuh, R. A.; Fiskum, G.; Flaws, J. A.

In: Toxicology and Applied Pharmacology, Vol. 216, No. 3, 01.11.2006, p. 436-445.

Research output: Contribution to journalArticle

Gupta, R. K. ; Schuh, R. A. ; Fiskum, G. ; Flaws, J. A. / Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary. In: Toxicology and Applied Pharmacology. 2006 ; Vol. 216, No. 3. pp. 436-445.
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