University of Rochester

Environmental Health Sciences Center

Thomas A Gasiewicz, Ph.D.
tom_gasiewicz@urmc.rochester.edu
http://www2.envmed.rochester.edu/envmed/EHSC/index.html

Project Description

Questions continue to arise about the role of environmental agents as modulators of disease and dysfunction. The mission of the University of Rochester EHSC is to improve public health by defining the contribution and underlying mechanisms of environmental agents in health dysfunction and disease outcomes. These goals are achieved by a combination of research and community outreach and education. There are four research cores. The Pulmonary Toxicology Research Core focuses on the mechanisms and consequences of oxidative injury, inflammation and repair in the respiratory system using models ranging from genetically engineered mice to humans. Studies within the Neurotoxicology Research Core use molecular, genetic, neurochemical and behavioral approaches to determine the contributions of toxicant exposures to various diseases and dysfunctions of the nervous system and their mechanisms of action. A new Immunomodulators and Immunopathogenesis Research Core focuses on examining mechanisms and consequences of immunomodulation by environmental agents, with particular emphasis on T-cell immunobiology, autoimmune disease, cell cycle progression, and cell lineage commitment. The Osteotoxicology Research Core is examining the extent to which lead exposure serves as a risk factor for disturbances of the skeletal system, particularly osteoporosis. Scientific efforts of the research cores are promoted and assisted through five facility cores: Pathology Morphology Imaging, Biostatistics, University Facilities, Instrumentation, and Inhalation. Collaborations and new directions are significantly enhanced through a Pilot Project Program and an Enrichment Program that includes a Visiting Scientist Program and EHSC-sponsored seminars and conferences. The COEP has grown considerably in scope and impact through several community efforts and a range of pre-college science education programs for both teachers and students.

The current organization of the EHSC reflects significant growth and development that has included restructuring of research and facility cores, a new research core and facility core, recruitment of new faculty, and substantial enhancement of the COEP. Many of these advancements are directly attributable to the Pilot Project and Enrichment Programs.

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Program Highlights

Inhaled Ultrafine Particles Can Reach the Central Nervous System

Ultrafine particles (UFP < 100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of ambient airborne particles. Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial and alveolar regions due to diffusion. Previous studies indicate that UFP can translocate to interstitial sites in the respiratory tract in the rat as well as to extrapulmonary organs such as the liver within 4 to 24 hours post exposure. Additional studies were designed to determine whether translocation of inhaled UFP takes place to regions of the brain, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following exposure as opposed to other areas of the central nervous system. Using ultrafine elemental 13C particles (36 nm) generated from 13C graphite rods or manganese (Mn) oxide UFPs (30 nm), we demonstrated significant increases in UFPs in the olfactory bulb with lesser increases in the striatum, frontal cortex, and cerebellum. In the Mn study, lung lavage analysis showed no indications of lung inflammation, whereas increases in olfactory bulb tumor necrosis factor-a mRNA and protein were found 11 days after exposure, and to a lesser degree, in other brain regions with increased Mn levels. We conclude that the olfactory neuronal pathway is efficient for translocating inhaled UFPs to the central nervous system and that this can result in inflammatory changes. Access of inhaled UFPs to the central nervous system could have significant health consequences if they induce neurotoxic effects following environmental or occupational exposures.

Oberdoerster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. 2004. Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicol. 16: 437-45.

Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdoerster G. 2006. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ. Health Perspect. 114: 1172-8.

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Lead is a Risk Factor for Osteoporosis and Altered Fracture Healing

Lead exposure and musculoskeletal diseases represent two of the most widespread afflictions in the world. Lead contamination is still an insidious contaminant with serious disease-inducing potential. Evidence now shows that the effects of this metal are not mitigated by an apparent threshold effect, but rather adversely affect cognitive ability, renal function, hypertension, etc. in a continuum of decreasing exposures. Osteoporosis and osteoarthritis combined are by far the number one cause of disability in the United States. More than 40 million Americans are affected by arthritis and 28 million Americans are affected by osteoporosis. By 2020, the latter number is projected to increase to 80 million, or nearly 25% of the population. The data we have generated thus far on the effects of lead on bone cell activity has led to the formation of a hypothesis that environmental exposure prevents a person from attaining a high peak bone density during skeletal development. This is accomplished mechanistically by interfering with endochondrial bone formation and bone remodeling. Our findings predict that the accelerated maturation of growth plate tissues might actually lead to denser bone in lead exposed children at early ages (i.e. explaining the formation of "lead lines"), but that this premature growth plate closure would eventually hinder attainment of a high peak bone mass. Additionally, compromising osteoclast and osteoblast function would cause an individual to cross over a "fracture threshold" at an earlier age and predispose them to osteoporotic fractures. The effect of lead on cartilage and callus formation would also prevent the normal healing of fractures. Progress has been made in evaluating the mechanism by which lead adversely influences osteoblasts. We have uncovered at least three mechanisms by which lead affects the TGFb signaling pathway in osteoblasts, and ultimately the function of these cells. These three sites include an inhibition of receptor kinase activity, an up-regulation of Smurf2 levels, and an up regulation of Sno and Ski transcription factors levels. Be depressing kinase activity, Smad phosphorylation is compromised and the transactivation of genes necessary for inducing the osteoblast phenotype is blocked. Up-reguation of Smurf2 will lead to a depression of Smad pools and consequently will inhibit the pathway. Sno and Ski are repressors of TGFb function. Up-regulation of these molecules will have an inhibitory effect on the entire pathway. In summary, we have determined that lead, when administered in vivo, inhibits osteoblast progenitor cell generation but has no effect on osteoclast cell differentiation. This finding is consistent with the effects of lead on isolated osteoblasts and osteoclasts in vitro. By extension, these observations define a mechanism whereby lead may affect fracture healing and development of osteoporosis.

Campbell JR, Rosier RN, Novotny L, Puzas JE. The association between environmental lead exposure and bone density in children. Environ Health Perspect. 112:1200-3, 2005.

Carmouche J, O’Keefe RJ, Zuscik MJ, Puzas JE, Schwarz EM. Lead exposure inhibits fracture healing and is associated with increased chondrogenesis, delay in cartilage mineralization and a decrease in osteoprogenitor frequency. Environ. Health Perspect. 113: 749-55, 2005

Puzas JE, Campbell JR, O'Keefe RJ, Rosier RN. Lead toxicity in the skeleton and its role in osteoporosis. In "Nutrition and Bone Health" (M. F. Holick and B. Dawson-Hughes, Eds.), Humana Press, Totowa, NJ, 2005.

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