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ToxSci Advance Access originally published online on May 5, 2007
Toxicological Sciences 2007 98(2):488-494; doi:10.1093/toxsci/kfm106
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Published by Oxford University Press 2007.

Cadmium-Induced Toxicity in Rat Primary Mid-brain Neuroglia Cultures: Role of Oxidative Stress from Microglia

Zhengqin Yang*,{dagger}, Sufen Yang{ddagger}, Steven Y. Qian{ddagger},§, Jau-Shyong Hong{ddagger}, Maria B. Kadiiska{ddagger}, Raymond W. Tennant*, Michael P. Waalkes and Jie Liu,1

* Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 {dagger} Pharmacy College of Zhengzhou University, Zhengzhou 450001, China {ddagger} Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carloina 27709 § Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105 Inorganic Carcinogenesis, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Research Triangle Park, North Carolina 27709

1 To whom correspondence should be addressed at Inorganic Carcinogenesis Section, LCC, NCI at NIEHS, Research Triangle Park, NC 27709. E-mail: liu6{at}niehs.nih.gov.

Received March 5, 2007; accepted April 7, 2007


  Abstract

This study examined the role of oxidative stress in neurotoxic effects of cadmium chloride (Cd) in rat primary mid-brain neuron-glia cultures. Cd accumulated in neuron-glia cultures and produced cytotoxicity in a dose-dependent manner, with IC50 of 2.5µM 24 h after exposure. 3H-dopamine uptake into neuron-glia cultures was decreased 7 days after Cd exposure, with IC50 of 0.9µM, indicative of the sensitivity of dopaminergic neurons to Cd toxicity. To investigate the role of microglia in Cd-induced toxicity to neurons, microglia-enriched cultures were prepared. Cd significantly increased intracellular reactive oxygen species production in microglia-enriched cultures, as evidenced by threefold increases in 2',7'-dichlorofluorescein signals. Using 5,5-dimethyl-1-pyrroline N-oxide as a spin-trapping agent, Cd increased electron spin resonance signals by 3.5-fold in microglia-enriched cultures. Cd-induced oxidative stress to microglia-enriched cultures was further evidenced by activation of redox-sensitive transcription factor nuclear factor kappa B and activator protein-1 (AP-1), and the increased expression of oxidative stress-related genes, such as metallothionein, heme oxygenase-1, glutathione S-transferase pi, and metal transport protein-1, as determined by gel-shift assays and real-time reverse transcription–PCR, respectively, in microglia-enriched cultures. In conclusion, Cd is toxic to neuron-glia cultures, and the oxidative stress from microglia may play important roles in Cd-induced damage to dopaminergic neurons.

Key Words: cadmium; neurotoxicity; neuron-glia cultures; oxidative stress; NF-{kappa}B and AP-1; gene expression.


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