Clark C. Lantz, PhD

Exposure to environmental toxicants alters lung structure and function and leads to chronic lung disease, including cancer. Current investigations are examining the effects of exposure to environmentally relevant doses of arsenic and uranium. Arsenic is a naturally occurring metalloid found in water, soil and air. Exposure to inorganic arsenic occurs worldwide, including the southwestern United States and Mexico, through environmental (contaminated drinking water, air, food and domestic fuel sources) and occupational exposures (smelting industries, pesticide production). Epidemiologic studies have associated arsenic exposure with an increased risk of multiple human cancers including lung, skin, bladder, kidney, liver and stomach cancers. In addition arsenic exposures are associated with non-malignant diseases, such as peripheral vascular disease, diabetes and chronic obstructive pulmonary disease.

Our current research is focusing on two models to examine the effects of arsenic in the lung. One model relies on exposure to arsenic during lung development, both in utero and postnatally. We have previously shown that exposure of pregnant female rats to arsenic in their drinking water until embryonic day 18 resulted in altered expression of extracellular matrix genes. In addition, genes involved in vascular development also appear to be targets. We are currently continuing exposure to arsenic after birth. In addition to cancer endpoints, arsenic exposures can also lead to noncancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic were found to alter airway reactivity to methacholine challenge. Alterations in air reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Alterations in matrix gene expression andairway smooth muscle were correlated with alterations in structure and lung function. Dietary folate supplementation reduced the arsenic induced functional alterations. This model system demonstrates that developmental exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary function in the adults and that dietary intervention strategies may be useful in reducing the adverse health effects caused by in utero and postnatal arsenic exposures.

A second model relies on chronic 4 to 8 week exposure of adult mice to arsenic in drinking water. We have evaluated alterations in mRNA and protein levels from animals exposed to 50 ppb. Again, extracellular matrix genes are among the classes of genes that are altered by this exposure. In addition, alterations in elastin and collagen deposition are being determined to link gene expression changes with phenotypic structural alterations in the lung. Data are also being analyzed using an annotated data base to identify pathways and transcriptional regulators that may be affected by the exposure to arsenic.

Research is also on going to identify protein alterations in lung lining fluid as biomarkers of exposure and effect prior to the development of disease following exposure to arsenic. This study uses the technology of proteomics to evaluate and identify biomarkers of chronic environmental exposure to arsenic by evaluating large numbers of proteins simultaneously. We are comparing alterations in protein expression in exposed human populations in Arizona and Mexico, human cell lines, and in vivo rodent studies. Patterns of alterations in protein expression, both common and unique to these different test systems, are being identified.

Finally, we are evaluating the chemical genotoxicity of uranium. In addition to its radioactive effects, uranium may also have adverse health effects because of its interactions with cellular macromolecules. We have found that uranium does directly interact with DNA and appears to form cross links. DNA damage caused by uranium does not appear to be mediated by induction of oxidative stress. Studies to define the interactions of uranium with DNA and proteins in the lung are continuing.