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Influence of Lead on Repetitive Behavior and Dopamine Metabolism in a Mouse Model of Iron Overload
Open accessAbstract
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.
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Animal models of developmental lead exposure indicate changes in behavioral and neurochemical endpoints similar to those seen in children with ASD.
“Animal models of developmental lead exposure also indicate changes in behavioral and neurochemical endpoints similar to those seen in children with ASD [ 119 , 120 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [120]
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Metadata
- Authors
- Chang, J., Kueon, C., & Kim, J.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Chang, JuOae
- ORCID
- Kim, Jonghan
- Venue
- Toxicological Research
- Published
- 2014-12-31
- Volume
- 30
- Issue
- 4
- Pages
- 267-276
- ISSN
- 1976-8257 (ISSN-L)
- PMC
- PMC4289927
- OpenAlex
- W2072605705
- Cited by
- 47
- References
- 32
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 9 · 2015: 5
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Research (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Heavy Metal Exposure and Toxicity
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- lead exposure, repetitive behavior, dopamine metabolism, hereditary hemochromatosis, HFE gene mutations, iron overload, dopamine transporter, tyrosine hydroxylase, dopamine D1 receptor, dopamine D2 receptor, marble burying test, dopamine signaling, lead neurotoxicity, mental illness
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