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.