Cadmium impairs the survival and proliferation of cultured adult subventricular neural stem cells through activation of the JNK and p38 MAP kinases.
Cadmium (Cd) is a heavy metal with a long biological half-life in humans and is recognized as a toxic pollutant. Cd is also a potential neurotoxicant and its exposure is associated with olfactory impairment in humans. However, the molecular and cellular mechanisms of Cd neurotoxicity are not well defined. Adult neurogenesis is a process that generates functional neurons from adult neural stem/progenitor cells (aNPCs). It occurs in specific regions of the adult brain including the subventricular zone (SVZ) along the lateral ventricles in mammals, a process that is critical for olfaction. Various external stimuli can modulate adult neurogenesis and the effect of neurotoxicants on adult neurogenesis is just beginning to be elucidated. Since Cd exposure can impair olfaction in humans, the goal of this study is to investigate the effects of Cd on SVZ adult neurogenesis and underlying mechanisms using primary cultured SVZ-aNPCs. In this study, we report that low-level Cd exposure decreases cell number, induces apoptosis, and inhibits cell proliferation in SVZ-aNPCs. Furthermore, Cd exposure significantly increases phosphorylation of c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase in these cells, indicative of JNK and p38 activation. Pharmacological inhibition of JNK or p38 MAPK kinases attenuated Cd-induced cell loss and apoptosis. Cd treatment did not cause cell loss or apoptosis in SVZ-aNPCs prepared from transgenic mice null for the neural-specific JNK3 isoform. These data suggest a critical role for p38 and JNK3 MAP kinases in Cd neurotoxicity. These results are, to our knowledge, the first demonstration that Cd impairs SVZ adult neurogenesis in vitro, which may contribute to its neurotoxicity in olfaction.
Toxicology Program in the Department of Environmental and Occupational Health Science, University of Washington, United States.
Hao
H
Wang
Toxicology Program in the Department of Environmental and Occupational Health Science, University of Washington, United States.
Anna K
AK
Engstrom
Toxicology Program in the Department of Environmental and Occupational Health Science, University of Washington, United States. Electronic address: zxia@uw.edu.
Zhengui
Z
Xia
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002104:Cadmium / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D020547:Lateral Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000473:pathology; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D002104:Cadmium; D048057:Mitogen-Activated Protein Kinase 10; D048051:p38 Mitogen-Activated Protein Kinases
Adult neurogenesis; Apoptosis; Cadmium; MAPK signaling pathway; Neurotoxicity; Proliferation