Clark Lantz

Clark Lantz

Professor, Cellular and Molecular Medicine
Investigator, Center for Toxicology
Professor, Public Health
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-6084

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 These changes were specific for exposure during development and were not reversible if arsenic was withdrawn.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

Publications

Hays, A. M., Lantz, R. C., Rodgers, L. S., Sollome, J. J., Vaillancourt, R. R., Andrew, A. S., Hamilton, J. W., & Camenisch, T. D. (2008). Arsenic-induced decreases in the vascular matrix. Toxicologic pathology, 36(6), 805-17.

Chronic ingestion of arsenic is associated with increased incidence of respiratory and cardiovascular diseases. To investigate the role of arsenic in early events in vascular pathology, C57BL/6 mice ingested drinking water with or without 50 ppb sodium arsenite (AsIII) for four, five, or eight weeks. At five and eight weeks, RNA from the lungs of control and AsIII-exposed animals was processed for microarray. Sixty-five genes were significantly and differentially expressed. Differential expression of extracellular matrix (ECM) gene transcripts was particularly compelling, as 91% of genes in this category, including elastin and collagen, were significantly decreased. In additional experiments, real-time RT-PCR showed an AsIII-induced decrease in many of these ECM gene transcripts in the heart and NIH3T3 fibroblast cells. Histological stains for collagen and elastin show a distinct disruption in the ECM surrounding small arteries in the heart and lung of AsIII-exposed mice. Immunohistochemical detection of alpha-smooth muscle actin in blood vessel walls was decreased in the AsIII-exposed animals. These data reveal a functional link between AsIII exposure and disruption in the vascular ECM. These AsIII-induced early pathological events may predispose humans to respiratory and cardiovascular diseases linked to chronic low-dose AsIII exposure.

Yellowhair, M., & Lantz, R. C. (2017). Characterization of uranyl acetate-induced DNA damage in Chinese Hamster ovary repair deficient cell lines. Toxicological Science.
Gonzalez-Cortes, T., Recio-Vega, R., Lantz, R. C., & Chau, B. T. (2017). DNA methylation of extracellular matrix remodeling genes in children exposed to arsenic. Toxicology and applied pharmacology, 329, 140-147.

Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

Lantz, R. C., Chau, B., Sarihan, P., Witten, M. L., Pivniouk, V. I., & Chen, G. J. (2009). In utero and postnatal exposure to arsenic alters pulmonary structure and function. Toxicology and applied pharmacology, 235(1), 105-13.

In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous 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 (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airway 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. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 microm in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.

de la Vega, M. R., Dodson, M., Gross, C., Manzour, H., Lantz, R. C., Chapman, E., Wang, T., Black, S. M., Garcia, J. G., & Zhang, D. D. (2016). Role of Nrf2 and Autophagy in Acute Lung Injury. Current pharmacology reports, 2(2), 91-101.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.