CHEEC Seed Grants: FY 2007

Paraquat-Mediated Generation of Endogenous Neurotoxins Resulting from Dopamine Oxidation
J. Doorn, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa

Exploratory Studies of a Novel Pathway for the Formation of halo-organic "Disinfection By-Products" 
R. Valentine, Department of Civil and Environmental Engineering, University of Iowa

Arsenic speciation in Iowa's groundwater and surface water 
D. Simmons, University Hygienic Laboratory, University of Iowa

Determining the Mechanistic Effects of the Physical Properties of Nanocrystalline Zeolites on Cell Toxicity
A. Salem, Department of Pharmaceutics, S. Larsen, Department of Chemistry, The University of Iowa

Mechanisms of Perfluorooctanesulfonamide- Induced Oxidative Stress in Female Rats 
W. Xie, H Lehmler, Department of Occupational and Environmental Health, D. Spitz, Department of Radiation Oncology, The University of Iowa

 


Paraquat-Mediated Generation of Endogenous Neurotoxins Resulting from Dopamine Oxidation 
Investigator: J. Doorn, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa
Exposure to environmental chemicals is a known risk factor for Parkinson's Disease (PD). Specifically, chemicals used in agriculture, (e.g. paraquat), are associated with PD. However, the exact relationship between exposure and disease is not known, and the underlying mechanism remains to be elucidated. Recent evidence suggests oxidative stress, but it is not known how these agents (e.g. paraquat) produce specific death of DA neurons as observed in PD. A potential mechanism may involve DA-derived endogenous neurotoxins, which would be found in DA regions of the brain. In this proposal, it is hypothesized that exposure of brain mitochondria to the herbicide paraquat results in accumulation of oxidized DA, specifically, DOPAL and/or the DA-quinone, yielding protein modification by these reactive compounds. Therefore, the studies described in this application seek to establish a mechanistic link between exposure to paraquat and aberrant levels of neurotoxic DA oxidation products proposed to participate in PD pathogenesis.

Exploratory Studies of a Novel Pathway for the Formation of halo-organic "Disinfection By-Products" 
Investigator: R. Valentine, Department of Civil and Environmental Engineering, University of Iowa
It is hypothesized that metal oxides may exist in some drinking water distribution systems capable of oxidizing iodide and possibly bromide producing species that can react with natural organic to form halo-organic compounds of possible health concerns. This hypothesis is based on recently obtained experimental evidence indicating that lead oxide (PbO2), an oxide that can accumulate in distribution systems and on household plumbing fixtures, has the capacity to oxidize iodide. The primary objectives of this research are to demonstrate proof-of-concept of this novel reaction pathway, and to investigate factors that influence the extent and rates of the reactions. Studies will initially focus on the lead oxide-iodide-NOM system and measurement of selected iodo-organic compounds. Additional studies will be conducted using several other oxides. If iodide is found reactive, then oxidation of bromide will also be evaluated to determine if formation of bromo-organic compounds is also possible at environmentally relevant conditions.

Publication:  Lin YP, Washburn MP, Valentine RL; Reduction of Lead Oxide (PbO2) by Iodide and formation of Iodoform in the PbO2/I-/Nom system. Environ Sci Technol. 2008; 42:2919-2924.

Arsenic speciation in Iowa's groundwater and surface water
Investigator: D. Simmons, University Hygienic Laboratory, University of Iowa 
Arsenic (As) is a highly regulated trace element due to its adverse health effects. The University Hygienic Laboratory has closely monitored total arsenic concentrations in Iowa's surface (lakes, rivers, streams, etc.) and groundwater; elevated levels of arsenic have been detected in the past. Different As species, including inorganic and organoarsenic species, have different toxicities and bioavailabilities. We propose a pilot study to take an initial assessment of As speciation in both groundwater and surface water from a variety of Iowa sites. A hyphenated technique, coupling Inductively SCoupled Plasma - Mass Spectrometry (ICP-MS) with a liquid chromatographic (LC) separation, will facilitate the analytical tasks. Some water chemistry parameters and their influence on arsenic speciation will also be investigated. Joining with the Iowa Statewide Rural Well Water Survey Phase II (SWRL 2), it is expected that this study will lead to a more comprehensive arsenic environmental chemistry study in the rural environment.

Determining the Mechanistic Effects of the Physical Properties of Nanocrystalline Zeolites on Cell Toxicity 
A. Salem, Department of Pharmaceutics, S. Larsen, Department of Chemistry, The University of Iowa 
The rapid growth and development in the synthesis of nanomaterials with carefully controlled properties, such as size and shape, surface area and composition has led to a burgeoning of potential applications for these nanomaterials. However, the toxicological effects of these materials such as nanocrystalline zeolites have not yet been systematically investigated and assessed with respect to their properties. In this proposal, the impact of size, surface chemistry, composition and porosity of nanocrystalline zeolites on the mechanism of death in lung epithelial cells will be investigated.

Publication:  Petushkov A, Intra J, Graham JB, Larsen SC, Salem AK; Effect of Crystal Size and Surface Functionalization on the Cytotoxicity of Silicalite-1 Nanoparticles. Chem. Res. Toxicol. 2009; 22:1359-1368.

Mechanisms of Perfluorooctanesulfonamide- Induced Oxidative Stress in Female Rats 
W. Xie, H. Lehmler, Department of Occupational and Environmental Health, D. Spitz, Department of Radiation Oncology, The University of Iowa
Perfluorinated compounds such as perfluorooctanesulfonamides (PFOSAs) are emerging as an important class of environmentally persistent chemicals. Our knowledge of their mechanisms of toxicity is very limited. Exposure to these chemicals has been associated with developmental toxicity in several animal models. Based on the observation that PFOSAs are peroxisome proliferators and cause mitochondrial dysfunction we hypothesize that oral exposure to a typical PFOSA such as N-EtFOSE (N-ethyl perfluorooctanesulfonamidoethanol) may cause oxidative stress in vivo. We will test this hypothesis by measuring markers of oxidative stress and the activity of enzyme in selected organs. This pilot study will answer important questions regarding the toxicity of PFOSAs and allow us to design further investigations of the mechanisms of their toxicity.

Publications:  Xie W, Ludewig G, Wang K, Lehmler HJ; Model and cell membrane partitioning of perfluorooctanesulfonate is independent of the lipid chain length; Colloids Surf B Biointerfaces 2010 Mar1;76(1): 128-36.

Xie W, Bothun GD, Lehmler HJ; Partitioning of perfluorooctanoate into phosphatidylcholine bilayers is chain length-independent; J Chem Phys Lipids 2010 Mar; 163(3): 300-8.

Xie W, Kania-Korwel I, Tharappel JC, Telu S, Coleman MC, Glauert HP, Kannan K, Mariappan SVS, Spitz DR, Weydert J, Lehmler HJ; Subacute exposure to N-ethyl perfluorooctanesulfonamidoethanol results in the formation of perfluorooctanesulfonate and alters superoxide dismutase activity in female rats; Arch Toxicol 2009; 83:909-924.