This topic comes from the NIEHS-sponsored Superfund Research Program. Certainly, it qualifies for the GEITP pages because it is a great example of gene-environment interactions (GxE): the non-essential metal cadmium (Cd) is the environmental signal; specific genes and genetic networks in the genome (especially those in neurons of the mouse hippocampus in brain) respond to this toxic metal as best it can — with the result being “unwanted effects on normal learning and memory processes.” 😊
Criticism of this work by these GEITP pages is that “10 ppb” = “10 µg of Cd per kg of solid (µg/kg) = 10 µg/L = 0.09 µM = 90 nanoMolar (which is what was used in cell culture) — is probably NOT what one would consider “environmentally relevant concentrations” of this non-essential metal. Authors were even more vague with their intact-animal studies, saying only that the exposure consisted of “low levels of Cd in their drinking water for 13 weeks.” Conclusions are therefore that Cd levels used to elicit “defects in learning and memory” and “diminished numbers of neurons in the hippocampus” in the intact animal — as well as levels of Cd used to evoke “oxidative stress pathways in cell culture” — may or may not be clinically relevant to humans exposed to naturally-occuring Cd levels in the environment. ☹
Cadmium Exposure Impairs Production of Neurons
Responsible for Learning and Memory
A new study funded by the Superfund Research Program (SRP) shows cadmium exposure can impair new neurons from forming and maturing in the hippocampus region of the brain. Led by Zhengui Xia, Ph.D., the researchers at the University of Washington (UW) SRP Center also found that cadmium can lead to the death of stem cells that produce these neurons. In humans, learning and memory formation depends on the production of new neurons in this region of the brain.
Because alterations to adult hippocampal neuron development has been reported to be associated with cognitive behavior deficits, cognitive decline, and Alzheimer disease, these findings may have implications for “the role of environmentally relevant cadmium exposure” in neurodegenerative diseases.
Previous research has linked cadmium exposure to impaired learning and memory formation in behavioral studies in adult mice, but the mechanism by which cadmium created this effect remained unclear. In the new study, a combination of stem cells and mice were used to identify whether neuron formation in the hippocampus was affected, leading to learning and memory impairment.Lower stem cell counts are observed in images from cells exposed to cadmium.
Identifying Changes in Cells
The researchers applied cadmium directly to the cells (in culture) and found that it reduced the total number of cells, led to cell death, and interfered with the production and maturation of new neurons derived from the stem cells. These effects were seen at concentrations as low as 10 parts per billion.
They also discovered cadmium exposure increases the activation of Jun NH2-terminal kinase (JNK) and p38 kinase, two proteins that play a role in key stages of neuron development in adults. By inhibiting these pathways, they observed diminished stem cell death with exposure to cadmium, suggesting that these proteins are involved in a cadmium-induced oxidative stress form of cell toxicity.
Assessing Alterations in Mice
The team also exposed adult male mice to low levels of cadmium in their drinking water for 13 weeks. The treated mice had blood levels of cadmium that resemble those found in human cigarette smokers. The blood levels in treated mice were also lower than the Occupational Safety and Health Administration (OSHA) standard for cadmium that triggers medical surveillance. They found that this level of cadmium exposure decreased the number of new neurons in the hippocampus and impaired their maturation, compared to mice that were not exposed. Cadmium also appeared to significantly decrease the complexity of dendrites, the segments of the neuron that receive stimulation for the cell to become active, in a region of the hippocampus.
According to the authors, because learning and memory formation depends on production of new neurons in the hippocampus, these results provide the first strong evidence of a mechanism by which cadmium might impair cognitive functioning in adults.
For more information, contact:
Zhengui Xia, Ph.D.
University of Washington
Department of Environmental and Occupational Health Sciences
Health Sciences Building, F-561C
Seattle, Washington 98195
To learn more about this research, please refer to the following source:
Wang H, Abel GM, Storm DR, Xia Z. Cadmium exposure impairs adult hippocampal neurogenesis. Toxicol Sci July 2019; 171: 501-514. doi: 10.1093/toxsci/kfz152 PMID: 31271426