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ToxSci Advance Access published online on May 5, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm106
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Published by Oxford University Press 2007.

Cadmium-induced toxicity in rat primary mid-brain neuro-glia cultures: role of oxidative stress from microglia

Zhengqin Yang1,2, Sufen Yang3, Steven Y. Qian3,4, Jau-Shyong Hong3, Maria B. Kadiiska3, Raymond W. Tennant1, Michael P. Waalkes5 and Jie Liu5

1 National Center for Toxicogenomics, NIEHS, National Institutes of Health, USA 2 Pharmacy College of Zhengzhou University, Zhengzhou, 450001, China 3 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA 4 Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, USA 5 Inorganic Carcinogenesis, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Research Triangle Park, North Carolina 27709, USA

Correspondence to: Jie Liu, Ph.D., Inorganic Carcinogenesis Section, LCC, NCI at NIEHS, Research Triangle Park, NC 27709, USA. E-mail: liu6{at}niehs.nih.gov

Received March 5, 2007; revision received April 6, 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 2.5 µM 24 hours after exposure. 3H-dopamine uptake into neuron-glia cultures was decreased 7 days after Cd exposure, with IC50 of 0.9 µM, 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 3-fold increases in 2', 7'-dichlorofluorescein signals. Using 5, 5-dimethyl-1-pyrroline N-oxide (DMPO) 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 NF-{kappa}B and 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 RT-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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