Superfund Research Program
Cellular and Molecular Mechanisms of Cadmium Neurotoxicity
Project Leader: Zhengui Xia
Co-Investigators: Daniel Storm, Evan P. Gallagher
Grant Number: P42ES004696
Funding Period: 2015-2022
Final Progress Reports
Cadmium (Cd) is a heavy metal of high interest to the Superfund Initiative, ranking #7 on the Superfund hazardous waste priority list. It has no known physiological function but is a potential neurotoxicant. Several epidemiology studies reported an association between Cd exposure and olfactory impairment in humans. However, data from epidemiological studies cannot exclude other uncontrolled compounding factors and little is known concerning the underlying mechanisms.
Adult neurogenesis is a process that generates functional neurons from adult neural stem/progenitor cells. It occurs in specific regions of the adult brain including the subventricular zone along the lateral ventricles in mammals, and these adult born neurons are critical for olfaction. Various external stimuli can modulate adult neurogenesis. Since Cd exposure may impair olfaction in humans, the researchers investigated the effects of Cd on adult neurogenesis and the underlying mechanisms using adult neural stem/progenitor cells that they cultured from the subventricular zone of adult mouse brain. They found that low-level Cd exposure (as low as 10 ppb) induces programmed cell death and inhibits cell proliferation, resulting in reduced cell numbers. Through biochemical, pharmacological and genetic studies, the research team also identified two specific enzymes, the p38 and JNK3 MAP kinases that play a critical role in this process. These results are, to the researchers’ knowledge, the first demonstration that Cd impairs adult neurogenesis. This mechanism may contribute to Cd neurotoxicity in impairing olfaction (Wang et al, Toxicology. Accepted pending minor revision).