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1. SOC-V-06 New classification approach for Human Predictive Patch Test (HPPT) results under the UN GHS improves skin sensitisation potency sub-categorisation and weight-of-evidence assessments

Author

Herzler, M., primary, Abedini, J., additional, Allen, D., additional, Api, A.M., additional, Germolec, D., additional, Gordon, J., additional, Ko, H.-S., additional, Matheson, J., additional, Strickland, J., additional, Thierse, H.-J., additional, To, K., additional, Truax, J., additional, Vanselow, J.T., additional, and Kleinstreuer, N., additional

Published
2022
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3. Biomarkers of Oxidative Stress Study II: Are oxidation products of lipids, proteins, and DNA markers of CCl 4 poisoning?

Author

Kadiiska, M.B., Gladen, B.C., Baird, D.D., Germolec, D., Graham, L.B., Parker, C.E., Nyska, A., Wachsman, J.T., Ames, B.N., Basu, S., Brot, N., FitzGerald, G.A., Floyd, R.A., George, M., Heinecke, J.W., Hatch, G.E., Hensley, K., Lawson, J.A., Marnett, L.J., Morrow, J.D., Murray, D.M., Plastaras, J., Roberts, L.J., II, Rokach, J., Shigenaga, M.K., Sohal, R.S., Sun, J., Tice, R.R., Van Thiel, D.H., Wellner, D., Walter, P.B., Tomer, K.B., Mason, R.P., and Barrett, J.C.

Published
2005
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5. Biomarkers of Oxidative Stress Study II: Are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning?

Author

Kadiiska, M. B., Gladen, B. C., Baird, D. D., Germolec, D., Graham, L. B., Parker, C. E., Nyska, A., Wachsman, J. T., Ames, B. N., Basu, S., Brot, N., FitzGerald, G. A., Floyd, R. A., George, M., Heinecke, J. W., Hatch, G. E., Hensley, K., Lawson, J. A., Marnett, L. J., Morrow, J. D., Murray, D. M., Plastaras, J., Roberts, L. J., II, Rokach, J., Shigenaga, M. K., Sohal, R. S., Sun, J., Tice, R. R., Van Thiel, D. H., Wellner, D., Walter, P. B., Tomer, K. B., Mason, R. P., and Barrett, J. C.

Published
2005
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12. Report of the exploratory meeting regarding epidemiology of occupational and environmental factors associated with autoimmunity, Bilthoven, May 10-12, 2000

Author

van Loveren H, Vos JG, Germolec D, Simeonova PP, Eijkemanns G, and LPI

Subjects
epidemiology of autoimmunity, immunotoxicity, autoimmune assessment, autoimmunity, autoimmune diseases, methodology
Abstract

Van 10-12 Mei 2000 werd in Bilthoven een wetenschappelijke bijeenkomst gehouden, getiteld "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity". Het doel was te bepalen wat de optimale methodologie zou zijn voor het vaststellen van autoimmuniteit die is geassocieerd met blootstelling aan agentia op de werkplek of aan omgevingsfactoren. Bovendien werd de mogelijkheid besproken om in interdisciplinaire samenwerkingsverbanden dergelijke associaties te onderzoeken, gericht op silica, hexachlorobenzeen, en ultraviolette straling. Deze agentia werden geselecteerd omdat er aanwijzingen zijn dat zij een invloed hebben op autoimmuniteit in de bevolking. Er werd een aantal aanbevelingen gedaan: 1) systematische epidemiologische gegevens betreffende autoimmuniteit en autoimmuunziekten dienen te worden vergaard; 2) het opzetten van data bestanden betreffende autoimmuunaandoeningen dient te worden bevorderd; 3) er dient een internationaal geaccepteerde standaard voor diagnostische criteria voor autoimmuunziekten te worden ontwikkeld; 4) sociale en economische repercussies van autoimmuunziekten dienen in kaart te worden; 5) methoden om blootstelling vast te stellen en de gegevens te gebruiken in epidemiologische studies dienen te worden gestandaardiseerd; 6) laboratoriummethoden om biologische responsen te meten dienen te worden gestandaardiseerd; en 7) het opnemen van indicatoren van autoimmuneit en autoimmuunziekten alsmede relevante blootstellingen in lopende epidemiologische studies dient te worden bevorderd.

Published
2012

13. Linking environmental agents and autoimmune disease: an agenda for future research

Author

Selgrade, M K, Cooper, G S, Germolec, D R, and Heindel, J J

Subjects
Research Article
Abstract

Autoimmune diseases are influenced by multiple factors including genetics, age, gender, reproductive status, hormones, and potential environmental contaminants. A workshop, "Linking Environmental Agents and Autoimmune Diseases," was convened at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 1-3 September 1998, to review current knowledge about links between environmental exposures and autoimmune disease, to identify and prioritize research needs, and to develop an integrated, multidisciplinary research agenda. Participants spent the last half-day of the workshop in small group discussions for the purpose of developing consensus on research needs. Research needs identified were a) develop research tools needed to explore links between environmental agents and autoimmune disease; b) establish a disease registry or surveillance system; c) develop and validate strategies for screening chemicals for the potential to induce or exacerbate autoimmune disease; d) develop an emergency response strategy to gain information from accidental exposures; and e) conduct hypothesis-driven research in occupationally exposed groups and/or in experimental animals. There was consensus that meetings like this workshop and projects that facilitate interactions between specialties should be encouraged. A multidisciplinary approach is needed to address this problem.

Published
1999

14. Influence of Aspergillus fumigatus conidia viability on murine pulmonary micro RNA and m RNA expression following subchronic inhalation exposure.

Author

Croston, T. L., Nayak, A. P., Lemons, A. R., Goldsmith, W. T., Gu, J. K., Germolec, D. R., Beezhold, D. H., and Green, B. J.

Subjects
MICROBIOLOGICAL aerosols, ASPERGILLUS fumigatus, MICRORNA, MESSENGER RNA, IMMUNE response, FUNGAL gene expression, LABORATORY mice
Abstract

Background Personal exposure to fungal bioaerosols derived from contaminated building materials or agricultural commodities may induce or exacerbate a variety of adverse health effects. The genomic mechanisms that underlie pulmonary immune responses to fungal bioaerosols have remained unclear. Objective The impact of fungal viability on the pulmonary micro RNA and messenger RNA profiles that regulate murine immune responses was evaluated following subchronic inhalation exposure to Aspergillus fumigatus conidia. Methods Three groups of naïve B6C3F1/N mice were exposed via nose-only inhalation to A. fumigatus viable conidia, heat-inactivated conidia (HIC), or HEPA-filtered air twice a week for 13 weeks. Total RNA was isolated from whole lung 24 and 48 h postfinal exposure and was further processed for gene expression and micro RNA array analysis. The molecular network pathways between viable and HIC groups were evaluated. Results Comparison of data sets revealed increased Il4, Il13 and Il33 expression in mice exposed to viable vs. HIC. Of 415 micro RNAs detected, approximately 50% were altered in mice exposed to viable vs. HIC 48 h postexposure. Significantly down-regulated ( P ≤ 0.05) miR-29a-3p was predicted to regulate TGF-β 3 and Clec7a, genes involved in innate responses to viable A. fumigatus. Also significantly down-regulated ( P ≤ 0.05), miR-23b-3p regulates genes involved in pulmonary IL-13 and IL-33 responses and SMAD2, downstream of TGF-β signalling. Using Ingenuity Pathway Analysis, a novel interaction was identified between viable conidia and SMAD2/3. Conclusions and Clinical Relevance Examination of the pulmonary genetic profiles revealed differentially expressed genes and micro RNAs following subchronic inhalation exposure to A. fumigatus. Micro RNAs regulating genes involved in the pulmonary immune responses were those with the greatest fold change. Specifically, germinating A. fumigatus conidia were associated with Clec7a and were predicted to interact with Il13 and Il33. Furthermore, altered micro RNAs may serve as potential biomarkers to evaluate fungal exposure. [ABSTRACT FROM AUTHOR]

Published
2016
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16. Biomarkers of oxidative stress study II : are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning?

Author

Kadiiska, M B, Gladen, B C, Baird, D D, Germolec, D, Graham, L B, Parker, C E, Nyska, A, Wachsman, J T, Ames, B N, Basu, S, Brot, N, Fitzgerald, G A, Floyd, R A, George, M, Heinecke, J W, Hatch, G E, Hensley, K, Lawson, J A, Marnett, L J, Morrow, J D, Murray, D M, Plastaras, J, Roberts, L J, Rokach, J, Shigenaga, M K, Sohal, R S, Sun, J, Tice, R R, Van Thiel, D H, Wellner, D, Walter, P B, Tomer, K B, Mason, R P, Barrett, J C, Kadiiska, M B, Gladen, B C, Baird, D D, Germolec, D, Graham, L B, Parker, C E, Nyska, A, Wachsman, J T, Ames, B N, Basu, S, Brot, N, Fitzgerald, G A, Floyd, R A, George, M, Heinecke, J W, Hatch, G E, Hensley, K, Lawson, J A, Marnett, L J, Morrow, J D, Murray, D M, Plastaras, J, Roberts, L J, Rokach, J, Shigenaga, M K, Sohal, R S, Sun, J, Tice, R R, Van Thiel, D H, Wellner, D, Walter, P B, Tomer, K B, Mason, R P, and Barrett, J C

Published
2005

19. Report of the exploratory meeting regarding epidemiology of occupational and environmental factors associated with autoimmunity, Bilthoven, May 10-12, 2000

Author

LPI, van Loveren H, Vos JG, Germolec D, Simeonova PP, Eijkemanns G, LPI, van Loveren H, Vos JG, Germolec D, Simeonova PP, and Eijkemanns G

Abstract

RIVM rapport:Van 10-12 Mei 2000 werd in Bilthoven een wetenschappelijke bijeenkomst gehouden, getiteld "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity". Het doel was te bepalen wat de optimale methodologie zou zijn voor het vaststellen van autoimmuniteit die is geassocieerd met blootstelling aan agentia op de werkplek of aan omgevingsfactoren. Bovendien werd de mogelijkheid besproken om in interdisciplinaire samenwerkingsverbanden dergelijke associaties te onderzoeken, gericht op silica, hexachlorobenzeen, en ultraviolette straling. Deze agentia werden geselecteerd omdat er aanwijzingen zijn dat zij een invloed hebben op autoimmuniteit in de bevolking. Er werd een aantal aanbevelingen gedaan: 1) systematische epidemiologische gegevens betreffende autoimmuniteit en autoimmuunziekten dienen te worden vergaard; 2) het opzetten van data bestanden betreffende autoimmuunaandoeningen dient te worden bevorderd; 3) er dient een internationaal geaccepteerde standaard voor diagnostische criteria voor autoimmuunziekten te worden ontwikkeld; 4) sociale en economische repercussies van autoimmuunziekten dienen in kaart te worden; 5) methoden om blootstelling vast te stellen en de gegevens te gebruiken in epidemiologische studies dienen te worden gestandaardiseerd; 6) laboratoriummethoden om biologische responsen te meten dienen te worden gestandaardiseerd; en 7) het opnemen van indicatoren van autoimmuneit en autoimmuunziekten alsmede relevante blootstellingen in lopende epidemiologische studies dient te worden bevorderd., An "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity" was organized in Bilthoven the Netherlands, from May 10-12, 2000. The aim was to determine the optimal methodology for assessment of autoimmunity associated with occupational or environmental exposures in the human population, and to set up interdisciplinary and collaborative epidemiological studies to investigate the association of exposure to silica, hexachlorobenzene, ultraviolet radiation, and other agents with autoimmunity and autoimmune diseases in the human population. These agents were selected as carrying particular suspicion at present. Several recommendations were made: 1) systematic descriptive epidemiological data on autoimmunity and autoimmune disorders are required; 2) the establishment of disease-reporting registries should be encouraged; 3) the development of internationally accepted standard diagnostic criteria for all autoimmune diseases should be encouraged; 4) the social impact of these disorders should be evaluated and estimations of direct and indirect economic costs should also be made; 5) the methods of exposure assessment used in epidemiological studies should be standardized; 6) laboratory methods for measurement of biological responses should be standardized; and 7) the inclusion of indicators of autoimmunity and autoimmune diseases and of relevant environmental exposures in ongoing epidemiological studies should be encouraged.

Published
2000

20. Report of the exploratory meeting regarding epidemiology of occupational and environmental factors associated with autoimmunity, Bilthoven, May 10-12, 2000

Author

NIEHS, CDC/NIOSH, IPCS/WHO, LSHTM, LPI, Loveren H van, Vos JG, Germolec D, Simeonova PP, Eijkemanns G, NIEHS, CDC/NIOSH, IPCS/WHO, LSHTM, LPI, Loveren H van, Vos JG, Germolec D, Simeonova PP, and Eijkemanns G

Abstract

RIVM rapport:An "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity" was organized in Bilthoven the Netherlands, from May 10-12, 2000. The aim was to determine the optimal methodology for assessment of autoimmunity associated with occupational or environmental exposures in the human population, and to set up interdisciplinary and collaborative epidemiological studies to investigate the association of exposure to silica, hexachlorobenzene, ultraviolet radiation, and other agents with autoimmunity and autoimmune diseases in the human population. These agents were selected as carrying particular suspicion at present. Several recommendations were made: 1) systematic descriptive epidemiological data on autoimmunity and autoimmune disorders are required; 2) the establishment of disease-reporting registries should be encouraged; 3) the development of internationally accepted standard diagnostic criteria for all autoimmune diseases should be encouraged; 4) the social impact of these disorders should be evaluated and estimations of direct and indirect economic costs should also be made; 5) the methods of exposure assessment used in epidemiological studies should be standardized; 6) laboratory methods for measurement of biological responses should be standardized; and 7) the inclusion of indicators of autoimmunity and autoimmune diseases and of relevant environmental exposures in ongoing epidemiological studies should be encouraged., Van 10-12 Mei 2000 werd in Bilthoven een wetenschappelijke bijeenkomst gehouden, getiteld "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity". Het doel was te bepalen wat de optimale methodologie zou zijn voor het vaststellen van autoimmuniteit die is geassocieerd met blootstelling aan agentia op de werkplek of aan omgevingsfactoren. Bovendien werd de mogelijkheid besproken om in interdisciplinaire samenwerkingsverbanden dergelijke associaties te onderzoeken, gericht op silica, hexachlorobenzeen, en ultraviolette straling. Deze agentia werden geselecteerd omdat er aanwijzingen zijn dat zij een invloed hebben op autoimmuniteit in de bevolking. Er werd een aantal aanbevelingen gedaan: 1) systematische epidemiologische gegevens betreffende autoimmuniteit en autoimmuunziekten dienen te worden vergaard; 2) het opzetten van data bestanden betreffende autoimmuunaandoeningen dient te worden bevorderd; 3) er dient een internationaal geaccepteerde standaard voor diagnostische criteria voor autoimmuunziekten te worden ontwikkeld; 4) sociale en economische repercussies van autoimmuunziekten dienen in kaart te worden; 5) methoden om blootstelling vast te stellen en de gegevens te gebruiken in epidemiologische studies dienen te worden gestandaardiseerd; 6) laboratoriummethoden om biologische responsen te meten dienen te worden gestandaardiseerd; en 7) het opnemen van indicatoren van autoimmuneit en autoimmuunziekten alsmede relevante blootstellingen in lopende epidemiologische studies dient te worden bevorderd.

Published
2000

27. Report of the Bilthoven Symposium: Advancement of epidemiological studies in assessing the human health effects of immunotoxic agents in the environment and the workplace

Author

LPI-RIVM, National Institute of Environmental Health Sciences NIEHS(USA), American Crop Protection Association ACPA(USA), Environmental Protection Agency EPA(USA), Centers for Disease Control and Prevention CDCP(USA), European Commission EC(Belgie), World Resources Institute WRI(USA), World Health Organization WHO(Zwitserland), Centers for Disease Control CDC(USA), Loveren H van, Germolec D, Koren HS, Luster MI, Nolan C, Repetto R, Smith E, Vos JG, Vogt RF, LPI-RIVM, National Institute of Environmental Health Sciences NIEHS(USA), American Crop Protection Association ACPA(USA), Environmental Protection Agency EPA(USA), Centers for Disease Control and Prevention CDCP(USA), European Commission EC(Belgie), World Resources Institute WRI(USA), World Health Organization WHO(Zwitserland), Centers for Disease Control CDC(USA), Loveren H van, Germolec D, Koren HS, Luster MI, Nolan C, Repetto R, Smith E, Vos JG, and Vogt RF

Abstract

RIVM rapport:Van 12-14 november 1997 werd in Bilthoven een wetenschappelijk symposium gehouden, getiteld 'Epidemiology of Immunotoxicity'. De aanleiding voor dit symposium was een publicatie van een rapport van een WHO/IPCS Task Group meeting getiteld 'Principles and methods for assessing direct immunotoxicity associated with exposure to chemicals' (WHO, 1996), een rapport van het World Resources Institute (WRI 1996) dat inging op mogelijke immuunsuppressieve effecten van pesticiden in de bevolking van ontwikkelingslanden, en een workshop getiteld 'Environment and Immunity' georganiseerd door de Europese Unie (EU, 1997). Het thema van deze activiteiten was de behoefte aan goed opgezette epidemiologische studies van immunotoxiciteit. Experts op het gebied van de epidemiologie, klinische immunologie en immunotoxicologie die aan het symposium deelnamen werd gevraagd om consensus te bereiken ten aanzien van de meest adequate aanpak om immunotoxicitiet in de mens vast te stellen. Het symposium illustreerde de meerwaarde van 'kruisbestuiving' - het samenkomen van ideeen - i.e. het beste resultaat in termen van design, uitvoering en interpretatie van een complexe wetenschappelijke vraagstelling. De conclusie van het symposium was dat epidemiologie een essentiele methode is om immunotoxiciteit in mensen vast te kunnen stellen. Elke epidemiologische studie dient gepaard te gaan met valide informatie ten aanzien van blootstelling, gezondheidseffecten, en 'confounders'. Hoewel vragenlijsten en dagboeken belangrijke middelen zijn in de epidemiologie, zijn directe en kwantitatieve biologische metingen te prefereren. Indien mogelijk zijn longitudinale studies, waarbij de personen gedurende een tijd die lang genoeg is om gezondheidseffecten die verband houden met veranderingen in immuunfuncties vast te stellen worden vervolgd, te prefereren. Hoewel dergelijke studies prospectief van aard zijn, zijn retrospectieve studies, waarbij gebruik wordt gemaakt van monsters die verkregen zijn van person, A scientific symposium 'Epidemiology of Immunotoxicity' was held in Bilthoven, the Netherlands, on November 12-14, 1997. This symposium was stimulated by publication of the report of a 1994 WHO/IPCS Task Group meeting on principles and methods for assessing direct immunotoxicity associated with exposure to chemicals (WHO, 1996), a report by the World Resources Institute (WRI 1996) that raised concern about the immunosuppressive effects of pesticides on exposed populations in developing countries, and a workshop on 'Environment and Immunity' organized by the European Union (EU, 1997). A common theme among these reports was the need for well designed epidemiological studies on immunotoxicity. Experts in epidemiology, clinical immunology, and immunotoxicology who participated were asked to reach consensus on the most useful approaches to assess immunotoxic effects in humans. The symposium demonstrated the benefits which can be derived from 'cross-fertilization' - a meeting of the minds and sharing of ideas - i.e. the best product in terms of design, conduct, and interpretation of a complex scientific issue. The meeting concluded that epidemiology is an essential method for assessing immunotoxicity in humans. Every epidemiologic study should have valid measures of exposures, confounders and health endpoints. Although questionnaires and diaries are important and valuable tools in epidemiology, direct and quantitative biological measures are preferred. When possible, a longitudinal study design in which study subjects are observed over a time sufficient to assess the health outcomes associated with immunotoxic exposures and alterations in immune functions is preferable. While such studies are most often prospective, retrospective studies, using banked specimens from individuals who develop immune related disease, would be useful if exposure assessment is objective and quantifiable. A longitudinal study design may be most suitable where infections are the health consequenc

Published
1998

40. Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice.

Author

Guo, Tai L., McCay, J. Ann, Zhang, Ling X., Brown, Ronnetta D., Li You, Karrow, Niel A., Germolec, Dori R., White Jr., Kimber L., Guo, T L, McCay, J A, Zhang, L X, Brown, R D, You, L, Karrow, N A, Germolec, D R, and White, K L Jr

Subjects
TUMORS, MICE, ANIMAL models in research
Abstract

The isoflavone genistein (4,7,4'-trihydroxyisoflavone) is a phytoestrogen found in high levels in soy products that has been associated with decreased incidences of breast and prostate cancers. The potential effects of genistein on the immune system were evaluated in adult female B6C3F1 mice. Groups of mice were exposed to vehicle or genistein by gavage for 28 d. The doses of genistein used were 2, 6 and 20 mg/kg body. Consistent with the chemopreventive effect of genistein, exposure to this compound significantly increased host resistance to B16F10 tumor as reflected by a decrease in the number of lung tumor nodules after tumor cell injection at the middle and high dose levels. Inhibition of B16F10 tumor formation was not due to a direct effect of serum genistein and/or its metabolites on the proliferation of B16F10 tumor cells. When innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell activity was observed in genistein-treated mice with significant changes observed at the middle and high dose levels. Furthermore, in vitro interleukin (IL)-2-stimulated natural killer (NK) cell activity was significantly enhanced in the high genistein dose group, although the basal NK cell activity was not affected. Although no affect on the mixed lymphocyte responses and anti-CD3 antibody-mediated splenocyte proliferation was observed, exposure to genistein significantly increased basal splenocyte proliferation. Exposure to genistein did not alter the activity of the mononuclear phagocyte system and the cytotoxic/cytostatic function of thioglycollate-recruited peritoneal cells on B16F10 tumor cells. Finally, exposure to genistein did not produce biologically meaningful changes in spleen immunoglobulin (Ig)M and IgG antibody-forming cell responses. In conclusion, genistein enhanced host resistance as evaluated in the B16F10 tumor model, which may be related to the increases in the activities of cytotoxic T cells and NK cells. [ABSTRACT FROM AUTHOR]

Published
2001
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41. Report of the Bilthoven Symposium: Advancement of Epidemiological Studies in Assessing the Human Health Effects of Immunotoxic Agents in the Environment and the Workplace.

Author

Loveren, H. Van, Germolec, D., Koren, H. S., Luster, M. I., Nolan, C., Repetto, R., Smith, E., Vos, J. G., and Vogt, R. F.

Subjects
*CONFERENCES & conventions, *IMMUNOTOXICOLOGY, *EPIDEMIOLOGY
Abstract

Highlights the symposium on Epidemiology of Immunotoxicity in Bilthoven, Netherlands. Advancement of the epidemiological studies in assessing the human health; Effects of immunotoxic agents in the environment and the workplace; Importance of questionnaires and diaries as valuable tools in epidemiology.

Published
1999
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42. Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators.

Author

Rose, M L, Germolec, D R, Schoonhoven, R, and Thurman, R G

Abstract

WY-14,643 [4-chloro-6-(2,3-xylidino)pyrimidinylthio-acetic acid] is a well-known non-genotoxic carcinogen and peroxisome proliferator that causes liver cancer in rodents by unknown mechanisms. Its ability to sustain elevated rates of hepatocyte DNA synthesis is most likely pivotal in the ultimate development of tumors. The source of this mitogenic stimulus following treatment of rats with WY-14,643 has been hypothesized to be Kupffer cells, the resident hepatic macrophages, since they are activated by peroxisome proliferators in vivo. Therefore, these studies were designed to determine if Kupffer cells are causally responsible for WY-14 643-induced increases in hepatocyte DNA synthesis in vivo. WY-14,643 (100 mg/kg) increased DNA synthesis 8-fold 24 h after treatment; however, inactivation of Kupffer cells with methyl palmitate, a nonhydrolyzable fatty acid ester and known Kupffer cell inhibitor, completely prevented the mitogenic effect of WY-14,643. On the other hand, the ability of WY-14,643 to induce peroxisomes was not affected by methyl palmitate. These data demonstrate that induction of peroxisomes is not dependent on factors from Kupffer cells and support the idea that stimulation of DNA synthesis and induction of peroxisomes occur via distinct mechanisms. Additionally, WY-14,643 increased liver mRNA transcripts of the hepatocyte mitogen tumor necrosis factor alpha (TNF alpha) more than twofold. This increase was also prevented by inactivating Kupffer cells with methyl palmitate. Therefore, it is concluded that Kupffer cells are causally responsible for WY-14,643-induced increases in hepatocyte DNA synthesis most likely by increasing production of TNF alpha, a hepatic mitogen. [ABSTRACT FROM PUBLISHER]

Published
1997
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43. Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY-14,643.

Author

Bojes, H K, Germolec, D R, Simeonova, P, Bruccoleri, A, Schoonhoven, R, Luster, M I, and Thurman, R G

Abstract

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643. [ABSTRACT FROM PUBLISHER]

Published
1997
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44. Effect of Chronic Exposure of PCB (Aroclor 1254) on Specific and Nonspecific Immune Parameters in the Rhesus (Macaca mulatta) Monkey.

Author

TRYPHONAS, H., LUSTER, M. I., SCHIFFMAN, G., DAWSON, L.-L., HODGEN, M., GERMOLEC, D., HAYWARD, S., BRYCE, F., LOO, J. C. K., MANDY, F., and ARNOLD, D. L.

Abstract

Effects of Chronic Exposure of PCB (Aroclor 1254) on Specific and Nonspecific Immune Parameters in the Rhesus () Monkey. Tryphonas, H., Luster, M. I., Schiffman, G., Dawson, L.-L., Hodgen, M., Germolec, D., Hayward, S., Bryce, F., Loo, J. C. K., Mandy, F., and Arnold, D. L. (1991). . , 773–786. The immunomodulatory effects of low-level, chronic polychlorinated biphenyl PCB; (Aroclor 1254) exposure were investigated in female rhesus () monkeys. Five groups of monkeys (initially 16 monkeyS/group) were orally administered PCB at levels of 0, 5, 20, 40, or 80 μg/kg body wt/day. Tests for immunomodulation were initiated after 55 months of exposure to PCBs. Statistically significant observed immune changes included a dose-related decrease in the anamnestic (IgM and IgG) response to sheep red blood cells. Conversely, the antibody response to pneumococcus antigen did not differ significantly across the test groups. A statistically significant dose-related decrease in lymphoproliferation was noted with increasing doses of PCBs when phytohemagglutinin and Concanavalin A, but not when pokeweed mitogen, were used as mitogens. A trend toward reduced peak chemiluminescence (mV/min) was observed in zymosan-activated peripheral blood monocytes. The time to peak chemiluminescence of phorbol myristate acetate activation was statistically increased in a dose-response fashion. Flow cytometric analysis results of peripheral blood lymphocytes using the markers CD4, CD8, and CD20 were similar across the test groups. The mean percentage levels for the CD2 marker in the treated groups were statistically lower than the mean in the control, while absolute numbers for CD2 were similar across the test groups. Serum hydrocortisone levels did not differ among the test groups. Taken together these results indicate that low-level, chronic PCB exposure alters a number of rhesus monkey immune system components and that these effects may be due to altered T-cell and/or macrophage function. These data may be of use in extrapolating potential human health effects following chronic PCB exposure. [ABSTRACT FROM PUBLISHER]

Published
1991

47. Endotoxin (Lipopolysaccharide)-Induced Nitric Oxide Production in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Treated Fischer Rats:  Detection of Nitrosyl Hemoproteins by EPR Spectroscopy

Author

Glover, R. E., Germolec, D. R., Patterson, R., Walker, N. J., Lucier, G. W., and Mason, R. P.

Abstract

Electron paramagnetic resonance (EPR) spectroscopy was used to study the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on endotoxin (lipopolysaccharide)-induced nitric oxide (NO) production in Fischer rats. We found that rats treated with 50 μg/kg TCDD had increased sensitivity to endotoxin, resulting in an approximately 2-fold increase in the level of NO production detected as nitrosylhemoglobin (HbNO) in venous blood. At lower concentrations (≤5 μg/kg), TCDD did not affect the endotoxin-induced NO production. The TNF-α serum concentration was found to parallel that of NO. TCDD alone did not induce the production of detectable HbNO or TNF-α. We found that TCDD induced a dose-dependent increase in the EPR signal intensity of (Fe3+) low-spin methemoprotein complexes found in the liver and kidney. These species with EPR resonance at g = 2.43, 2.26, and 1.92 are attributed to low-spin Fe3+ in cytochromes P450 and P420. Our data confirm previous studies that have shown that TCDD induces a dose-dependent increase in the production of some cytochrome P450 enzymes. However, in rats that were subsequently challenged with endotoxin, a smaller increase in the EPR intensity of these species was observed. The decrease in the low-spin Fe3+ cytochrome P450 EPR signal in endotoxin-challenged rats could be due to one or more of the following occurring:  (1) cytochrome destruction, (2) reduction of the ferric to the ESR-silent ferrous oxidation state of cytochromes by nitric oxide, and/or (3) formation of ferrous nitrosyl cytochrome complexes that contribute, in part, to the characteristic five-coordinate nitrosyl hemoprotein triplet also observed in these tissues. Since low concentrations of endotoxin can leak from the gut lumen into the systemic circulation, this investigation explores the possibility that endotoxin interaction with TCDD may be, in part, responsible for the effects of TCDD observed in these tissues.

Published
2000

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