Objectives of Project: 1. Establish practical applications of new and emerging magnetic resonance imaging technologies to experimental toxicology and carcinogenesis. 2. Establish rapid data acquisition schemes and new techniques to allow in vivo microscopy in experimental laboratory animals. 3. Establish techniques for non-invasive histology on blocks of fixed tissue specimens (ex vivo imaging). 4. Develop methods for MR phenotyping of genetically modified mice with provision for investigators to access MR images via the internet. Background and Significance: Magnetic resonance imaging techniques provide the opportunity to visualize interal organs at microscopic resolution in live as well as perfused-fixed animals and to study the effects of environmental important chemicals on tissue perturbations. Advanced techniques continue to be developed by Dr. G. Allan Johnson of Duke Medical Center. Currently used technology permits tissue reolution of less than 50 microns. Current work with hyperpolarized helium as a paramagnetic contrast agent potentially can provide resolution of individual alveoli in live rodent lungs and will be applied to a project involving experimental emphysema. These magnetic resonance imaging techniques offer great promise in following the progression and regression of toxic and carcinogenic processes in experimental animals without the need to kill animals at interim time points in order to study pathogenesis. Current efforts to create MR mouse atlases for commonly used strains will aid investigators who utilize MR imaging for phenotyping genetically modified mice. Achievements: 1. Techniques continue to be refined for use of hyperpolarized helium in imaging fine structures of the lung in live animals. Initial images show fine detail at all levels of branching airways. 2. Images of fixed liver specimens from rats treated with the hepatotoxicant bromobenzene have shown definition of hepatic lobules and tissue alterations at low doses where conventional histopathology does not detect lesions. A dose response and time course of bromobenzene-induced hepatotoxicity in fixed liver specimens has been published in the journal Hepatology. 3. An initial pilot study to utilize MR imaging for rat teratology studies has been completed and data are currently being analyzed. Gadolinium contrast agent was introduced into the pregnant dams at day 19 of gestation and crossed the placental barrier to provide enhanced contrast in the fetuses. Image acquisition parameters are being refined in anticipation of a future teratology study. 4. We are currently defining the normal MR anatomy of perfused-fixed whole mice to provide an on-line atlas for investigators who will ultimately utilize MR imaging for phenotyping genetically modified mice. Future Efforts: Studies of experimentally induced emphysema have just begun with a rat model. Once the pathologic features and reproducibility of the model manipulation and the parameters and sensitivity of the MRI techniques have been established, studies will begin on environmentally induced or exacerbated emphysema in animal models. Specifically, the effect of environmentally relevant particulates on lung pathophysiology will be studied in collaboration with investigators from the EPA. Additional applications of MR imaging to meet the needs of neuroscientists and toxicologist in the ETP will be explored. Potential applications will be discussed at the August 2001 ETP Retreat. These efforts have so far involved a minimum expenditure of NIEHS resources and offer the opportunity to be on the cutting edge of small animal magnetic resonance imaging technology.
