Because of their escalating uses in industrial and biomedical applications, humans are increasing... more Because of their escalating uses in industrial and biomedical applications, humans are increasingly exposed to nanoparticles in occupational and other environmental settings. However, the environmental safety and health impact of such particles have not been elucidated. Previously, we have shown that many nanoparticles of metallic and non-metallic oxides exert cytotoxicity in human and other mammalian neural and non-neural cells. In this study, we have investigated the hypothesis that apoptosis is one mechanism underlying the toxicity of zinc oxide (ZnO) nanoparticles in human neuroblastoma SK-NSH (neurons-like) and astrocytoma U87 (astrocytes-like) cells. Our results demonstrate the nanoparticles induced dose-related decreases in survival of both cell types. Furthermore, flow cytometric findings reveal that at higher treatment concentrations of 20-50 μg/mL of ZnO nanoparticles, both SK-N-SH and U87 cells were undergoing apoptosis and necrosis. However, significant proportions of SK...
Journal of occupational and environmental medicine, 2017
This article describes radiologic and pulmonary function findings among miners exposed to Libby a... more This article describes radiologic and pulmonary function findings among miners exposed to Libby amphibole. Computed tomography permits the detection of the characteristic thin, lamellar pleural thickening (LPT). Individuals who worked at the mine for a minimum of 6 months had chest CT and pulmonary function tests. Pleural thickening was noted in 223 (87%) of the 256 miners, parenchymal abnormalities in 49 (19%). LPT, found in 151 (68%), was associated with low values of forced vital capacity and diffusion capacity and significantly lower values in all pulmonary function tests when associated with parenchymal abnormalities. Eighty-seven percent of miners exposed to Libby Amphibole had pleural abnormalities on CT. LPT alone, and more so with parenchymal abnormalities, resulted in decreased pulmonary function. The importance of this easily-missed LPT is demonstrated by its high frequency and significant functional effects.
Autism Spectrum Disorders (ASD) are complex neurological disorders for which the prevalence in th... more Autism Spectrum Disorders (ASD) are complex neurological disorders for which the prevalence in the U.S. is currently estimated to be 1 in 50 children. A majority of cases of idiopathic autism in children likely result from unknown environmental triggers in genetically susceptible individuals. These triggers may include maternal exposure of a developing embryo to environmentally relevant minute concentrations of psychoactive pharmaceuticals through ineffectively purified drinking water. Previous studies in our lab examined the extent to which gene sets associated with neuronal development were up- and down-regulated (enriched) in the brains of fathead minnows treated with psychoactive pharmaceuticals at environmental concentrations. The aim of this study was to determine whether similar treatments would alter in vitro expression of ASD-associated synaptic proteins on differentiated human neuronal cells. Human SK-N-SH neuroblastoma cells were differentiated for two weeks with 10μM ret...
This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a no... more This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a non-typical set of health outcomes not generally reported for asbestos, including systemic autoimmunity and an unusual and devastating lamellar pleural thickening that progresses to severe pulmonary dysfunction and death. Further, mineral fiber mixtures with some similarities to LAA have recently been discovered in southern Nevada and northwestern Arizona, where the material exists in extensive recreational areas and is present in yards, roads, parking lots and school yards. The objective was to compare the health outcomes in mice exposed to either LAA or the fibrous amphiboles collected in Arizona at the Lake Mead National Recreational Area at very low doses to represent environmental exposures. In this study, the fibrous amphibole asbestos sample from Arizona (AzA) is composed of winchite (69%), actinolite (22%), and non-amphibole minerals (9%) and has a mean aspect ratio of 16.7±0.9. Fi...
Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies ... more Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies (MCAA). These MCAA have been linked with pleural fibrotic disease in the asbestos exposed community of Libby, Montana, and induce collagen deposition by cultured mesothelial cells. However, the exact intracellular mechanism by which these autoantibodies cause an increase in collagen deposition remains unknown. This study sought to gain insight into the transcription factors involved in the collagen production after human mesothelial cells are exposed to MCAA. In this study, transcription factor activation profiles were generated from human mesothelial cells (Met5A) treated with serum from Libby subjects, and were compared to cells treated with serum cleared of IgG, and therefore containing no MCAA. Analysis of those profiles indicated C/EBP-beta and hypoxia inducible factor 1 alpha (HIF-1α) are significantly increased in the nucleus, indicating activation, due to MCAA exposure compared t...
Despite a body of evidence supporting an association between asbestos exposure and autoantibodies... more Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA), a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a) a lack of statistical power due to relatively small or diffuse exposure cohorts, (b) exposure misclassification, (c) latency of clinical disease, (d) mild or subclinical entities that remain undetected or masked by other pathologies, or (e) effects that are specific to...
The Immunotoxicology Specialty Section of the Society of Toxicology (SOT) celebrated the 50(th) A... more The Immunotoxicology Specialty Section of the Society of Toxicology (SOT) celebrated the 50(th) Anniversary of the SOT by constructing a poster to highlight the milestones of Immunotoxicology during that half-century period. This poster was assembled by an ad hoc committee and intertwines in words, citations, graphics, and photographs our attempts to capture a timeline reference of the development and progressive movement of immunotoxicology across the globe. This poster was displayed during the 50(th) Annual SOT Meeting in Washington DC in March, 2011. The poster can be accessed by any Reader at the SOT Website via the link http://www.toxicology.org/AI/MEET/AM2011/posters_rcsigss.asp#imss. We dedicate this poster to all of the founders and the scientists that followed them who have made the discipline of Immunotoxicology what it is today.
Recent advances in genomics-based identification of gene families and gene polymorphisms associat... more Recent advances in genomics-based identification of gene families and gene polymorphisms associated with immune system dysfunction have answered basic questions in immunology and have begun to move forward our understanding of immune-related disease processes. In toxicology, "omic" technologies have the potential to replace or supplement current immunotoxicological screening procedures, to provide insight into potential mode or mechanisms of action, and to provide data suitable for risk assessment. The application of omic technologies to the study of the immune system also has great potential to appreciably impact the diagnosis and treatment of immune-related diseases. This review focuses on the use of omic technologies in immunopharmacology and immunotoxicology, specifically considering the potential for these technologies to impact chemical hazard identification, risk characterization and risk assessment, and the development and application of novel therapeutics. The state of the science of omics technologies and the immune system is addressed in terms of a continuum of understanding of how omics technologies can and cannot yet be applied in the various aspects of immunopharmacology and immunotoxicology. Additionally, information gaps are identified that, once addressed, will move each area further down the continuum of understanding.
Because of their escalating uses in industrial and biomedical applications, humans are increasing... more Because of their escalating uses in industrial and biomedical applications, humans are increasingly exposed to nanoparticles in occupational and other environmental settings. However, the environmental safety and health impact of such particles have not been elucidated. Previously, we have shown that many nanoparticles of metallic and non-metallic oxides exert cytotoxicity in human and other mammalian neural and non-neural cells. In this study, we have investigated the hypothesis that apoptosis is one mechanism underlying the toxicity of zinc oxide (ZnO) nanoparticles in human neuroblastoma SK-NSH (neurons-like) and astrocytoma U87 (astrocytes-like) cells. Our results demonstrate the nanoparticles induced dose-related decreases in survival of both cell types. Furthermore, flow cytometric findings reveal that at higher treatment concentrations of 20-50 μg/mL of ZnO nanoparticles, both SK-N-SH and U87 cells were undergoing apoptosis and necrosis. However, significant proportions of SK...
Journal of occupational and environmental medicine, 2017
This article describes radiologic and pulmonary function findings among miners exposed to Libby a... more This article describes radiologic and pulmonary function findings among miners exposed to Libby amphibole. Computed tomography permits the detection of the characteristic thin, lamellar pleural thickening (LPT). Individuals who worked at the mine for a minimum of 6 months had chest CT and pulmonary function tests. Pleural thickening was noted in 223 (87%) of the 256 miners, parenchymal abnormalities in 49 (19%). LPT, found in 151 (68%), was associated with low values of forced vital capacity and diffusion capacity and significantly lower values in all pulmonary function tests when associated with parenchymal abnormalities. Eighty-seven percent of miners exposed to Libby Amphibole had pleural abnormalities on CT. LPT alone, and more so with parenchymal abnormalities, resulted in decreased pulmonary function. The importance of this easily-missed LPT is demonstrated by its high frequency and significant functional effects.
Autism Spectrum Disorders (ASD) are complex neurological disorders for which the prevalence in th... more Autism Spectrum Disorders (ASD) are complex neurological disorders for which the prevalence in the U.S. is currently estimated to be 1 in 50 children. A majority of cases of idiopathic autism in children likely result from unknown environmental triggers in genetically susceptible individuals. These triggers may include maternal exposure of a developing embryo to environmentally relevant minute concentrations of psychoactive pharmaceuticals through ineffectively purified drinking water. Previous studies in our lab examined the extent to which gene sets associated with neuronal development were up- and down-regulated (enriched) in the brains of fathead minnows treated with psychoactive pharmaceuticals at environmental concentrations. The aim of this study was to determine whether similar treatments would alter in vitro expression of ASD-associated synaptic proteins on differentiated human neuronal cells. Human SK-N-SH neuroblastoma cells were differentiated for two weeks with 10μM ret...
This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a no... more This project developed from studies demonstrating that Libby Amphibole Asbestos (LAA) causes a non-typical set of health outcomes not generally reported for asbestos, including systemic autoimmunity and an unusual and devastating lamellar pleural thickening that progresses to severe pulmonary dysfunction and death. Further, mineral fiber mixtures with some similarities to LAA have recently been discovered in southern Nevada and northwestern Arizona, where the material exists in extensive recreational areas and is present in yards, roads, parking lots and school yards. The objective was to compare the health outcomes in mice exposed to either LAA or the fibrous amphiboles collected in Arizona at the Lake Mead National Recreational Area at very low doses to represent environmental exposures. In this study, the fibrous amphibole asbestos sample from Arizona (AzA) is composed of winchite (69%), actinolite (22%), and non-amphibole minerals (9%) and has a mean aspect ratio of 16.7±0.9. Fi...
Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies ... more Amphibole asbestos exposure is associated with the production of mesothelial cell autoantibodies (MCAA). These MCAA have been linked with pleural fibrotic disease in the asbestos exposed community of Libby, Montana, and induce collagen deposition by cultured mesothelial cells. However, the exact intracellular mechanism by which these autoantibodies cause an increase in collagen deposition remains unknown. This study sought to gain insight into the transcription factors involved in the collagen production after human mesothelial cells are exposed to MCAA. In this study, transcription factor activation profiles were generated from human mesothelial cells (Met5A) treated with serum from Libby subjects, and were compared to cells treated with serum cleared of IgG, and therefore containing no MCAA. Analysis of those profiles indicated C/EBP-beta and hypoxia inducible factor 1 alpha (HIF-1α) are significantly increased in the nucleus, indicating activation, due to MCAA exposure compared t...
Despite a body of evidence supporting an association between asbestos exposure and autoantibodies... more Despite a body of evidence supporting an association between asbestos exposure and autoantibodies indicative of systemic autoimmunity, such as antinuclear antibodies (ANA), a strong epidemiological link has never been made to specific autoimmune diseases. This is in contrast with another silicate dust, crystalline silica, for which there is considerable evidence linking exposure to diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Instead, the asbestos literature is heavily focused on cancer, including mesothelioma and pulmonary carcinoma. Possible contributing factors to the absence of a stronger epidemiological association between asbestos and autoimmune disease include (a) a lack of statistical power due to relatively small or diffuse exposure cohorts, (b) exposure misclassification, (c) latency of clinical disease, (d) mild or subclinical entities that remain undetected or masked by other pathologies, or (e) effects that are specific to...
The Immunotoxicology Specialty Section of the Society of Toxicology (SOT) celebrated the 50(th) A... more The Immunotoxicology Specialty Section of the Society of Toxicology (SOT) celebrated the 50(th) Anniversary of the SOT by constructing a poster to highlight the milestones of Immunotoxicology during that half-century period. This poster was assembled by an ad hoc committee and intertwines in words, citations, graphics, and photographs our attempts to capture a timeline reference of the development and progressive movement of immunotoxicology across the globe. This poster was displayed during the 50(th) Annual SOT Meeting in Washington DC in March, 2011. The poster can be accessed by any Reader at the SOT Website via the link http://www.toxicology.org/AI/MEET/AM2011/posters_rcsigss.asp#imss. We dedicate this poster to all of the founders and the scientists that followed them who have made the discipline of Immunotoxicology what it is today.
Recent advances in genomics-based identification of gene families and gene polymorphisms associat... more Recent advances in genomics-based identification of gene families and gene polymorphisms associated with immune system dysfunction have answered basic questions in immunology and have begun to move forward our understanding of immune-related disease processes. In toxicology, "omic" technologies have the potential to replace or supplement current immunotoxicological screening procedures, to provide insight into potential mode or mechanisms of action, and to provide data suitable for risk assessment. The application of omic technologies to the study of the immune system also has great potential to appreciably impact the diagnosis and treatment of immune-related diseases. This review focuses on the use of omic technologies in immunopharmacology and immunotoxicology, specifically considering the potential for these technologies to impact chemical hazard identification, risk characterization and risk assessment, and the development and application of novel therapeutics. The state of the science of omics technologies and the immune system is addressed in terms of a continuum of understanding of how omics technologies can and cannot yet be applied in the various aspects of immunopharmacology and immunotoxicology. Additionally, information gaps are identified that, once addressed, will move each area further down the continuum of understanding.
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Papers by Jean McClellan