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Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice
Helal Hussain Alsulimani1, Qi Ye1, Jonghan Kim1
1Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
Abstract:
Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders.
Insights
Manganese (Mn) neurotoxicity is worsened by hereditary hemochromatosis (HH) gene deficiency, impairing spatial memory after ingestion. This suggests HH patients may be more vulnerable to environmental manganese exposure.
Area of Science:
- Neuroscience
- Toxicology
- Genetics
Background:
- Excess manganese (Mn) is neurotoxic, causing behavioral issues.
- Hereditary hemochromatosis (HH) affects iron metabolism and may influence Mn neurotoxicity.
- Previous studies showed altered Mn transport and toxicity in Hfe-deficient mice via intranasal instillation.
Purpose of the Study:
- To investigate the role of Hfe gene function in manganese neurotoxicity following oral exposure.
- To determine if Hfe deficiency modifies behavioral and cognitive deficits induced by ingested manganese.
Main Methods:
- Hfe-knockout (Hfe (-/-)) and wild-type (Hfe (+/+)) mice were exposed to manganese chloride (MnCl2) in drinking water for 5 weeks.
- Motor coordination was assessed using the rotarod test, and spatial memory using the Barnes maze test.
- Brain and liver metal concentrations (Mn, Fe, Cu, Zn) were quantified using inductively coupled plasma mass spectrometry.
Main Results:
- Mn exposure increased Mn levels in the liver and brain of both Hfe (-/-) and Hfe (+/+) mice.
- Mn exposure decreased liver iron but did not affect brain iron, copper, or zinc levels.
- Hfe (+/+) mice showed impaired motor skills, while Hfe (-/-) mice did not. Hfe (-/-) mice exhibited impaired spatial memory compared to Hfe (+/+) mice.
Conclusions:
- Loss of Hfe function exacerbates spatial memory deficits in mice exposed to manganese via drinking water.
- Individuals with hereditary hemochromatosis may be more susceptible to memory impairments from environmental manganese ingestion.
- Further investigation into the pathophysiological role of HFE in manganese neurotoxicity is warranted for patients with HH and other iron overload disorders.
