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ToxSci Advance Access originally published online on September 21, 2005
Toxicological Sciences 2005 88(2):495-504; doi:10.1093/toxsci/kfi334
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Methoxychlor Inhibits Brain Mitochondrial Respiration and Increases Hydrogen Peroxide Production and CREB Phosphorylation

Rosemary A. Schuh*,{dagger},{ddagger}, Tibor Kristián*, Rupesh K. Gupta{dagger},{ddagger}, Jodi A. Flaws{dagger},{ddagger} and Gary Fiskum*,{ddagger},1

* Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland 21201; {dagger} Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201; {ddagger} Program in Toxicology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Received July 28, 2005; accepted September 14, 2005

The organochlorine insecticide methoxychlor (mxc) is an established reproductive toxicant that affects other systems including the central nervous system (CNS), possibly by mechanisms involving oxidative stress. This study tested the hypothesis that mxc inhibits brain mitochondrial respiration, resulting in increased production of reactive oxygen species (ROS). Oxygen electrode measurements of mitochondrial respiration and Amplex Red measurements of H2O2 production were performed with rat brain mitochondria exposed in vitro to mxc (0–10 µg/ml) and with brain mitochondria from mice chronically exposed in vivo to mxc (0–64 mg/kg/day) for 20 days by intraperitoneal injection. In vitro mxc exposure inhibited ADP-dependent respiration (state 3) using both complex I- and II-supported substrates. Similarly, state 3 respiration was inhibited following in vivo mxc exposure using complex I substrates. H2O2 production was stimulated after in vitro mxc treatment in the presence of complex I substrates, but not in mitochondria isolated from in vivo mxc-treated mice. Because previous studies demonstrated a relationship between oxidative stress and CREB phosphorylation, we also tested the hypothesis that mxc elevates phosphorylated CREB (pCREB) in mitochondria. Enzyme-linked immunosorbent assay (ELISA) measurements demonstrated that pCREB immunoreactivity was elevated by in vitro mxc exposure in the presence or absence of respiratory substrates, indicating that stimulation of H2O2 production is not necessary for this effect. These multiple effects of mxc on mitochondria may play an important role in its toxicity, particularly in the CNS.

Key Words: methoxychlor; mitochondria; CREB; oxidative stress.


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