2007 Progress Report: Manganese, Iron, Cadmium, and Lead Transport from the Environment to Critical Organs During Gestation and Early Development in a Rat Model

EPA Grant Number: R831725C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R831725
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Harvard Center for Children’s Environmental Health and Disease Prevention Research
Center Director: Hu, Howard
Title: Manganese, Iron, Cadmium, and Lead Transport from the Environment to Critical Organs During Gestation and Early Development in a Rat Model
Investigators: Brain, Joseph D. , Molina, Ramon , Wessling-Resnick, Marianne
Institution: Harvard T.H. Chan School of Public Health
EPA Project Officer: Callan, Richard
Project Period: June 1, 2004 through May 31, 2009 (Extended to May 31, 2011)
Project Period Covered by this Report: June 1, 2007 through May 31,2008
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text |  Recipients Lists
Research Category: Health , Children's Health , Health Effects

Objective:

The Center for Children’s Environmental Health and Disease Prevention at the Harvard School of Public Health is now in its fourth year. Our fifth year of funding begins on April 1, 2008. More and more, this Center is emerging as a model of effective translational research. Our Center uses animal models to address fundamental mechanisms of metal pharmacokinetics and mechanisms of injury. It utilizes exposure measurements in humans, and is also measuring health outcomes in humans. Most importantly, we involve the community. Especially we have established communications with individuals in that community, as well as with government stake-holders. This year continued to see functioning partnerships with our community-based colleagues and with other collaborating institutions.

Year 04 was marked by substantial progress in all Projects and Cores.

Progress Summary:

Project 3 is utilizing a pregnant rat model to better understand metal exposures of children and their mothers in contaminated settings like Tar Creek by:  (1) utilizing exposures during and after pregnancy, (2) using metal ions as well as complex environmental samples from Tar Creek, and (3) comparing different routes of entry from the environment into the body. Rats are being exposed during gestation, lactation, an after weaning by intratracheal instillation, by gavage, via intranasal administration, or by intravenous injection. We have now completed studies on how routes of administration of 5 soluble metals at different stages in rat development influence the absorbed dose in rats. During this past year, we completed our studies on iron and arsenic. Comparable doses of 59FeCl3 (2.5 μCi/kg) or 73As (H3AsO4) (4 μCi/kg) were administered to pregnant rats (E2) or their litters by intratracheal instillation, by gavage, via intranasal route or by intravenous injection every 3.5 days.

Our results show that the absorbed dose of different metals depends on:  a) metal, b) route of entry and c) rat developmental stage. The results show that for all metals studied, there are significant differences among the various metals, and routes of metal administration. In general, metal deposition in the nose and the lungs results in higher levels in most tissues of offsprings than deposition in the gastrointestinal tract. Most metals are bioavailable throughout early life with significant deposition in young pups obtained in utero from the maternal circulation. The greater susceptibility during gestation (e.g., brain) may increase the significance of maternal exposure. These data are useful in assessing the relative risks for metal toxicity of various exposures to metals in the environment. In addition, we neutron-activated chat particles, and have determined their elemental composition and the bioavailability of metals when these particles are given to rats. Our data clearly show that the absorbed dose of metals in critical organs such as the brain depends on route of entry and duration of exposure. They also indicate that uptake from the nose and the lungs may be underappreciated in contrast to ingestion. Analyses of these data will be used to help estimate the relative risks of metals from different exposures, e.g. eating contaminated food and water, inhaling airborne chat particles, or children playing in contaminated playgrounds.

Our studies have helped us understand molecular mechanisms of metal transport in both normal and mutant rats, and to elucidate mechanistic differences between manganese and iron absorption. Manganese transport into the blood can occur following inhalation of metal-containing particles. Intestinal manganese uptake is mediated by divalent metal transporter 1 (DMT1) and is upregulated by iron deficiency. Since iron status varies significantly within human populations, and DMT1 may mediate metal absorption from the respiratory tract, we tested the hypothesis that iron status may alter absorption of inhaled manganese and iron and explored the potential role of known iron transport proteins in lung metal absorption. Our studies have established that manganese and iron are absorbed by the lungs through different mechanistic pathways. We have also provided the first detailed analysis of the expression pattern and regulation of proteins involved in iron transport in the respiratory and olfactory epithelium. In situ analysis detected DMT1 mRNA in airway epithelium, airway macrophages and bronchus-associated lymphatic tissue (BALT). However, mRNA levels did not change in iron deficient rats. In iron oxide-exposed rats, local increases in DMT1 mRNA transcript were seen in iron oxide particle-containing macrophages and adjacent epithelial cells. These data are consistent with the model that DMT1 levels are differentially regulated in the lungs in response to iron-containing particles to enhance clearance of the metal from the lungs. This pattern of regulation was unexpected since upregulation of intestinal DMT1 is promoted by iron deficiency. We also identified, for the first time, the expression of DMT1 in olfactory epithelium, and cytolocalized its expression to basal endfeet of sustentacular cells using immunofluorescence microscopy. We studied olfactory absorption of 54Mn in Belgrade rats, an animal model of DMT1 deficiency, and established that transport of intranasally instilled metal from the nasal cavity to the blood was impaired. Moreover, this pathway of manganese absorption was enhanced in anemic rats and was enhanced relative to iron-sufficient controls. These findings are significant because they suggest that neurotoxicity of inhaled manganese may be modified by iron status.

We have also studied the role of DMT1 in neonatal absorption of iron using the Belgrade rat. We found that at time of weaning, impaired DMT1 function in the homozygous pups resulted in reduced absorption of 59Fe in the gut. However, total 59Fe absorption and retention in suckling pups were not different between the homozygous pups and their heterozygous siblings (with intact DMT1 function) when the 59Fe was injected intravenously to the lactating foster dams. Combined, these data suggest that at least during the early developmental period (during lactation), DMT1 function is not essential for iron assimilation from the milk.

The results of the soluble radioactive metal administration studies suggest that the absorbed dose of metals depends on the metal, the route of entry and duration and indicate that the importance of uptake from the nose and lungs may be under-appreciated. These data will be useful in assessing the relative risks for metal toxicity of various exposures to metals. The pharmacokinetic results from chat studies show differences in absorption, vascular kinetics and tissue retention of 59Fe or 65Zn from irradiated chat administered via different routes in rats. Significant differences were also observed as a function of particle size. Smaller, respirable chat had higher metal bioavailability when inhaled or ingested. Data from these studies will be used to assist in estimating the relative risks of metals from different exposures, e.g., eating contaminated food and water, inhaling airborne chat particles, or children playing in contaminated playgrounds. Our studies on molecular mechanisms of metal transport in both normal and mutant Belgrade rats are beginning to elucidate mechanistic differences between manganese and iron absorption in the nose, gut and lungs, and to explore other potential mechanisms in metal metabolism.


Journal Articles on this Report : 12 Displayed | Download in RIS Format

Other subproject views: All 12 publications 12 publications in selected types All 12 journal articles
Other center views: All 35 publications 26 publications in selected types All 25 journal articles
Type Citation Sub Project Document Sources
Journal Article Arora M, Weuve J, Schwartz J, Wright RO. Association of environmental cadmium exposure with pediatric dental caries. Environmental Health Perspectives 2008;116(6):821-825. R831725 (2007)
R831725 (2009)
R831725C001 (2007)
R831725C001 (2008)
R831725C003 (2007)
R831725C004 (2007)
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  • Journal Article Brain JD, Heilig E, Donaghey TC, Knutson MD, Wessling-Resnick M, Molina RM. Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe. American Journal of Respiratory Cell and Molecular Biology 2006;34(3):330-337. R831725 (2005)
    R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2005)
    R831725C003 (2007)
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  • Journal Article Heilig EA, Thompson KJ, Molina RM, Ivanov AR, Brain JD, Wessling-Resnick M. Manganese and iron transport across pulmonary epithelium. American Journal of Physiology–Lung Cellular and Molecular Physiology 2006;290(6):L1247-L1259. R831725 (2005)
    R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
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  • Journal Article Heilig E, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats. American Journal of Physiology–Lung Cellular and Molecular Physiology 2005;288(5):L887-L893. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2005)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Hu H, Shine J, Wright RO. The challenge posed to children’s health by mixtures of toxic waste: the Tar Creek Superfund Site as a case-study. Pediatric Clinics of North America 2007;54(1):155-175. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Schaider LA, Senn DB, Brabander DJ, McCarthy KD, Shine JP. Characterization of zinc, lead, and cadmium in mine waste: implications for transport, exposure, and bioavailability. Environmental Science and Technology 2007;41(11):4164-4171. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Surkan PJ, Schnaas L, Wright RJ, Tellez-Rojo MM, Lamadrid-Figueroa H, Hu H, Hernandez-Avila EM, Bellinger DC, Schwartz J, Perroni E, Wright RO. Maternal self-esteem, exposure to lead, and child neurodevelopment. NeuroToxicology 2008;29(2):278-285. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C001 (2008)
    R831725C003 (2007)
    R831725C004 (2007)
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  • Journal Article Thompson K, Molina RM, Brain JD, Wessling-Resnick M. Belgrade rats display liver iron loading. Journal of Nutrition 2006;136(12):3010-3014. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
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  • Journal Article Thompson K, Molina R, Donaghey T, Brain JD, Wessling-Resnick M. The influence of high iron diet on rat lung manganese absorption. Toxicology and Applied Pharmacology 2006;210(1-2):17-23. R831725 (2005)
    R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
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  • Journal Article Thompson K, Molina RM, Donaghey T, Schwob JE, Brain JD, Wessling-Resnick M. Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. FASEB Journal 2007;21(1):223-230. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
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  • Journal Article Thompson K, Molina RM, Donaghey T, Brain JD, Wessling-Resnick M. Iron absorption by Belgrade rat pups during lactation. American Journal of Physiology-Gastrointestinal and Liver Physiology 2007;293(3):G640-G644. R831725 (2007)
    R831725 (2009)
    R831725C001 (2007)
    R831725C003 (2007)
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  • Journal Article Wright RO, Baccarelli A. Metals and neurotoxicology. The Journal of Nutrition 2007;137(12):2809-2813. R831725 (2007)
    R831725 (2009)
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    R831725C003 (2007)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Waste, Environmental Chemistry, Health Risk Assessment, Hazardous Waste, Biochemistry, Children's Health, Hazardous, Risk Assessment, community-based intervention, fate and transport , developmental toxicity, animal model, lead, Human Health Risk Assessment, neurodevelopmental toxicity, iron, manganese, children's environmental health, cadmium, mining waste, metal wastes, metals, human health risk, metal contamination

    Progress and Final Reports:

    Original Abstract
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006
  • 2008 Progress Report
  • 2009
  • Final

  • Main Center Abstract and Reports:

    R831725    Harvard Center for Children’s Environmental Health and Disease Prevention Research

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R831725C001 Metals, Nutrition, and Stress in Child Development
    R831725C002 Exposure Assessment of Children and Metals in Mining Waste: Composition, Environmental Transport, and Exposure Patterns
    R831725C003 Manganese, Iron, Cadmium, and Lead Transport from the Environment to Critical Organs During Gestation and Early Development in a Rat Model
    R831725C004 Metals Neurotoxicity Research Project