My research interests center around metal toxicology and physiology-based pharmacokinetic-pharmacodynamic (PBPK) modeling. My goals are to further investigate the relationship between pharmacokinetics of metal absorption and metal-induced toxicity in the context of environmental exposure and genetic susceptibility (gene-environment interactions). The major underlying hypothesis of this research proposal is that absorption of ingested and inhaled metals is up-regulated upon HFE-deficiency such that patients with mutations in HFE (C282Y;H62D) are more vulnerable to neurotoxicity induced by environmental metal exposure. Mentored phase: During the mentored phase of this grant at the Harvard School of Public Health, I will gain knowledge and expertise in new areas of research that complement my past training and that are essential for my future studies as an independent investigator. The research areas are: i) biochemical assays for expression of DMT1 and its regulation by iron status and ii) pharmacokinetics of metal absorption from various routes of exposure, and inhalation in particular.
The specific aims are: 1) To determine protein levels of DMT1 in duodenal, respiratory and olfactory epithelium from 3, 6, and 10 wk-old Hfe-/- and Hfe+/+ mice fed iron-deficient, basal and iron-loaded diets. 2) To determine and compare the pharmacokinetics and tissue distribution of 59Fe and 54Mn administered to Hfe-/- and Hfe+/+ """"""""wild-type"""""""" control mice by intravenous injection and by intragastric gavage. 3) To determine and compare the pharmacokinetics and tissue distribution of 54Mn administered to Hfe-/- and Hfe+/+ mice by intranasal and intratracheal instillation. Independent phase: My long-term career goal is to obtain a tenure-track faculty position at an academic institution where I will be able to expand my area of research, train and instruct graduate and undergraduate students, and collaborate with and learn from my academic peers. Utilizing the training and results obtained during the mentored phase, the hypothesis that HFE-deficiency enhances manganese neurotoxicity will be tested. 4) To test motor coordination and learning/memory capacity of Hfe-/- and Hfe+/+ mice after Mn exposure. 5) To examine CNS damage in Hfe-/- and Hfe+/+ mice due to Mn intoxication. 6) To develop a physiology-based pharmacokinetic/pharmacodynamic model to describe the role of Hfe on metal pharmacokinetics and toxicity. By directly examining the influence of HFE on the uptake and disposition of metals and their associated neurotoxicity, this investigation will provide the groundwork to assess the future risk of health effects due to metal absorption from environmental sources and genetic vulnerability. The research has broad relevance to the management of HFE-associated hemochromatosis and iron-overload.

Public Health Relevance

This investigation will provide the groundwork to assess the future risk of health effects due to metal absorption from environmental sources and genetic vulnerability. The research has broad relevance to the management of HFE-associated hemochromatosis and iron-overload.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Transition Award (R00)
Project #
5R00ES017781-04
Application #
8536288
Study Section
Special Emphasis Panel (NSS)
Program Officer
Kirshner, Annette G
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$242,597
Indirect Cost
$86,586
Name
Northeastern University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Ye, Qi; Park, Jo Eun; Gugnani, Kuljeet et al. (2017) Influence of iron metabolism on manganese transport and toxicity. Metallomics 9:1028-1046
Sukumaran, Abitha; Chang, JuOae; Han, Murui et al. (2017) Iron overload exacerbates age-associated cardiac hypertrophy in a mouse model of hemochromatosis. Sci Rep 7:5756
Han, Murui; Chang, JuOae; Kim, Jonghan (2016) Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity. J Neurochem 138:918-28
Menon, Archita Venugopal; Chang, JuOae; Kim, Jonghan (2016) Mechanisms of divalent metal toxicity in affective disorders. Toxicology 339:58-72
Ye, Qi; Kim, Jonghan (2016) Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure. Metallomics 8:618-27
Kang, Homan; Mintri, Shrutika; Menon, Archita Venugopal et al. (2015) Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles. Nanoscale 7:18848-62
Ye, Qi; Kim, Jonghan (2015) Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis. Environ Toxicol Pharmacol 40:333-41
Han, Murui; Kim, Jonghan (2015) Effect of dietary iron loading on recognition memory in growing rats. PLoS One 10:e0120609
Kim, Jonghan; Wessling-Resnick, Marianne (2014) Iron and mechanisms of emotional behavior. J Nutr Biochem 25:1101-1107
Kim, Jonghan; Buckett, Peter D; Wessling-Resnick, Marianne (2013) Absorption of manganese and iron in a mouse model of hemochromatosis. PLoS One 8:e64944