Clark Lantz
Investigator, Center for Toxicology
Professor, BIO5 Institute
Professor, Cellular and Molecular Medicine
Professor, Public Health
Primary Department
Department Affiliations
(520) 626-6716
Work Summary
We are interested in the effects of early life exposures to environmental toxicants on lung growth and development. We determine if the early life exposures leads to adult disease.
Research Interest
R. Clark 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 through environmental (contaminated drinking water, air, food and domestic fuel sources) and occupational exposures (smelting industries, pesticide production). In addition to its association with non-malignant diseases, arsenic is of major worldwide health concern because of its carcinogenic potential in humans. Epidemiologic studies have associated arsenic exposure with an increased risk of multiple human cancers including lung, skin, bladder, kidney, liver and stomach cancers. 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 shown that exposure of pregnant female mice and their offspring to 50 or 100 ppb as arsenic in drinking water resulted in altered pulmonary function in 28 day old animals. Airways were more responsive to bronchoconstriction. These changes were specific for exposure during development and were not reversible if arsenic was withdrawn. Associated with these functional changes, arsenic exposure resulted in a dose-dependent increase in airway smooth muscle and alterations in airway connective tissue expression. We are currently analyzing mediators that may be involved in this response to arsenic. In addition, we are beginning investigations into the effect of inhalation of arsenic on lung development. We are also currently using in vitro airway epithelial cell cultures to determine the effects of arsenic on wound repair and epithelial barrier function. In collaboration with Dr. Scott Boitano, we have been able to show that arsenic inhibits wound repair. This may be due in part to arsenic- induced alteration in calcium signaling. We have also been able to show that arsenic alters expression of epithelial junctional proteins and decreases epithelial barrier resistance. Research is also on going to identify protein alterations in lung lining fluid as biomarkers of exposure and effect. 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, will be 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 causes DNA damage through forming adducts which results in single strand breaks. In addition, uranium also inhibits double strand break DNA repair in airway epithelial cells. Keywords: pulmonary toxicology, arsenic, early life exposures


Beamer, P., Loh, M. M., Klimecki, W., Ornelas Van Horne, Y., Sugeng, A. J., Lothrop, N. Z., Billheimer, D. D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. (2016). Association of children's urinary CC16 levels with arsenic concentrations in multiple environmental media. International Journal of Environmental Research and Public Health.
BIO5 Collaborators
Paloma Beamer, Dean Billheimer, Stefano Guerra, Walter Klimecki, Clark Lantz, Fernando Martinez
Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Response to García-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. International journal of environmental research and public health, 13(10).
BIO5 Collaborators
Paloma Beamer, Dean Billheimer, Stefano Guerra, Walter Klimecki, Clark Lantz, Fernando Martinez

We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. García Nieto.[...].

Burgess, J. L., Kurzius-Spencer, M., Poplin, G. S., Littau, S. R., Kopplin, M. J., Stürup, S., Boitano, S., & Clark Lantz, R. (2015). Environmental arsenic exposure, selenium and sputum alpha-1 antitrypsin. Journal of exposure science & environmental epidemiology, 24(2), 150-5.
BIO5 Collaborators
Scott A Boitano, Jefferey L Burgess, Clark Lantz

Exposure to arsenic in drinking water is associated with increased respiratory disease. Alpha-1 antitrypsin (AAT) protects the lung against tissue destruction. The objective of this study was to determine whether arsenic exposure is associated with changes in airway AAT concentration and whether this relationship is modified by selenium. A total of 55 subjects were evaluated in Ajo and Tucson, Arizona. Tap water and first morning void urine were analyzed for arsenic species, induced sputum for AAT and toenails for selenium and arsenic. Household tap-water arsenic, toenail arsenic and urinary inorganic arsenic and metabolites were significantly higher in Ajo (20.6±3.5 μg/l, 0.54±0.77 μg/g and 27.7±21.2 μg/l, respectively) than in Tucson (3.9±2.5 μg/l, 0.16±0.20 μg/g and 13.0±13.8 μg/l, respectively). In multivariable models, urinary monomethylarsonic acid (MMA) was negatively, and toenail selenium positively associated with sputum AAT (P=0.004 and P=0.002, respectively). In analyses stratified by town, these relationships remained significant only in Ajo, with the higher arsenic exposure. Reduction in AAT may be a means by which arsenic induces respiratory disease, and selenium may protect against this adverse effect.

Burgess, J. L., Fierro, M. A., Lantz, R. C., Hysong, T. A., Fleming, J. E., Gerkin, R., Hnizdo, E., Conley, S. M., & Klimecki, W. (2004). Longitudinal decline in lung function: Evaluation of interleukin-10 genetic polymorphisms in firefighters. Journal of Occupational and Environmental Medicine, 46(10), 1013-1022.
BIO5 Collaborators
Jefferey L Burgess, Walter Klimecki, Clark Lantz
Olsen, C. E., Liguori, A. E., Zong, Y., Lantz, R. C., Burgess, J. L., & Boitano, S. (2008). Arsenic upregulates MMP-9 and inhibits wound repair in human airway epithelial cells. American journal of physiology. Lung cellular and molecular physiology, 295(2), L293-302.
BIO5 Collaborators
Scott A Boitano, Jefferey L Burgess, Clark Lantz

As part of the innate immune defense, the polarized conducting lung epithelium acts as a barrier to keep particulates carried in respiration from underlying tissue. Arsenic is a metalloid toxicant that can affect the lung via inhalation or ingestion. We have recently shown that chronic exposure of mice or humans to arsenic (10-50 ppb) in drinking water alters bronchiolar lavage or sputum proteins consistent with reduced epithelial cell migration and wound repair in the airway. In this report, we used an in vitro model to examine effects of acute exposure of arsenic (15-290 ppb) on conducting airway lung epithelium. We found that arsenic at concentrations as low as 30 ppb inhibits reformation of the epithelial monolayer following scrape wounds of monolayer cultures. In an effort to understand functional contributions to epithelial wound repair altered by arsenic, we showed that acute arsenic exposure increases activity and expression of matrix metalloproteinase (MMP)-9, an important protease in lung function. Furthermore, inhibition of MMP-9 in arsenic-treated cells improved wound repair. We propose that arsenic in the airway can alter the airway epithelial barrier by restricting proper wound repair in part through the upregulation of MMP-9 by lung epithelial cells.