Influence of Lead on Repetitive Behavior and Dopamine Metabolism in a Mouse Model of Iron Overload

Abstract

Exposures to lead (Pb) are associated with neurological problems including psychiatric disorders and impaired learning and memory. Pb can be absorbed by iron transporters, which are up-regulated in hereditary hemochromatosis, an iron overload disorder in which increased iron deposition in various parenchymal organs promote metal-induced oxidative damage. While dysfunction in HFE (High Fe) gene is the major cause of hemochromatosis, the transport and toxicity of Pb in Hfe-related hemochromatosis are largely unknown. To elucidate the relationship between HFE gene dysfunction and Pb absorption, H67D knock-in Hfe-mutant and wild-type mice were given drinking water containing Pb 1.6 mg/ml ad libitum for 6 weeks and examined for behavioral phenotypes using the nestlet-shredding and marble-burying tests. Latency to nestlet-shredding in Pb-treated wild-type mice was prolonged compared with non-exposed wild-types (p < 0.001), whereas Pb exposure did not alter shredding latency in Hfe-mutant mice. In the marble-burying test, Hfe-mutant mice showed an increased number of marbles buried compared with wild-type mice (p = 0.002), indicating more repetitive behavior upon Hfe mutation. Importantly, Pb-exposed wild-type mice buried more marbles than non-exposed wild-types, whereas the number of marbles buried by Hfe-mutant mice did not change whether or not exposed to Pb. These results suggest that Hfe mutation could normalize Pb-induced behavioral alteration. To explore the mechanism of repetitive behavior caused by Pb, western blot analysis was conducted for proteins involved in brain dopamine metabolism. The levels of tyrosine hydroxylase and dopamine transporter increased upon Pb exposure in both genotypes, whereas Hfe-mutant mice displayed down-regulation of the dopamine transporter and dopamine D1 receptor with D2 receptor elevated. Taken together, our data support the idea that both Pb exposure and Hfe mutation increase repetitive behavior in mice and further suggest that these behavioral changes could be associated with altered dopaminergic neurotransmission, providing a therapeutic basis for psychiatric disorders caused by Pb toxicity.

Combined exposure of low dose lead, cadmium, arsenic, and mercury in mice

“…In the experiments where mice were exposed to Pb for 30 days, for example, the average value in the control is 0.81 mg/g (810 ng/g). This is much higher than most researches concerning Pb-exposed mice, where brain Pb concentration in the control is either below 0.1 mg/g or undetectable Ferlemi et al, 2014;Chang et al, 2014;Ivanova et al, 2016;Li et al, 2016). The value 810 ng/g of control in this study is even higher than that of a high level Pb-exposed group in other studies (Ferlemi et al, 2014;Li et al, , 2016Ivanova et al, 2016).…”

Role of fatty acid composites in the toxicity of titanium dioxide nanoparticles used in cosmetic products

“…Furthermore, the cytotoxicity of soluble metals resulting from intracellular dissolution of metal NPs should be rigorously examined. Numerous studies have demonstrated biochemical alterations and behavioural dysfunction in animals and humans caused by exposure to various metals (Chang et al, 2014;Kim, 2015a, 2015b;Menon et al, 2016). Measuring the soluble metal concentrations of NP-exposed cells and cell culture media would provide important information about the potential effect of NP dissolution on metal toxicity.…”

Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats

“…Immunoreactivity was detected using ECL Amersham (GE Healthcare, Little Chalfont, Buckinghamshire, UK). The resulting protein bands were visualized by ChemiDoc XRS (Bio-Rad, Hercules, CA, USA) and their intensities were quantitated using Quantity One software (version 4.6.6; Bio-Rad) (Chang et al, 2014).…”