Influence of the Ah locus on the humoral immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Evidence for Ah-receptor-dependent and Ah-receptor-independent mechanisms of immunosuppression

Kerkvliet, Nancy I.; Steppan, Linda B.; Brauner, Julie A.; Deyo, James A.; Henderson, Marilyn C.; Tomar, Rajpal S.; Buhler, Donald R.

doi:10.1016/0041-008x(90)90356-y

Cited by 111 publications

(56 citation statements)

References 29 publications

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“…B lymphocytes, which mature in the bursa of Fabricius in birds and the bone marrow or Peyer's patches in mammals, produce antibodies that destroy invading microorganisms. High doses of HAHs suppress antibody responses (22,23,28,42,44,45,(48)(49)(50). HAHs reduce concentrations of retinol [vitamin A] and thyroxine (51)(52)(53)(54), which are important for immune function (55)(56)(57).…”

Section: Introductionmentioning

confidence: 99%

Organochlorine-Associated Immunosuppression in Prefledgling Caspian Terns and Herring Gulls from the Great Lakes: An Ecoepidemiological Study

Grasman¹,

Fox²,

Scanlon³

et al. 1996

Environmental Health Perspectives

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The objectives of this study were to determine whether contaminant-associated immunosuppression occurs in prefledgling herring gulls and Caspian terns from the Great Lakes and to evaluate immunological biomarkers for monitoring health effects in wild birds. During 1992 to 1994, immunological responses and related variables were measured in prefledgling chicks at colonies distributed across a broad gradient of organochlorine contamination (primarily polychlorinated biphenyls), which was measured in eggs. The phytohemagglutinin skin test was used to assess T-lymphocyte function. In both species, there was a strong exposure-response relationship between organochlorines and suppressed T-cell-mediated immunity. Suppression was most severe (30-45%) in colonies in Lake Ontario (1992) and Saginaw Bay (1992)(1993)(1994) for both species and in western Lake Erie (1992) for herring gulls. Both species exhibited biologically significant differences among sites in anti-sheep red blood cells antibody titers, but consistent exposure-response relationships with organochlorines were not observed. In Caspian terns and, to a lesser degree, in herring gulls, there was an exposure-response relationship between organochlorines and reduced plasma retinol (vitamin A). In 1992, altered white blood cell numbers were associated with elevated organochlorine concentrations in Caspian terns but not herring gulls. The immunological and hematological biomarkers used in this study revealed contaminantassociated health effects in wild birds. An epidemiological analysis strongly supported the hypothesis that suppression of T-cell-mediated immunity was associated with high perinatal exposure to persistent organochlorine contaminants.Environ Health Perspect 104(Suppl 4): 829-842 (1996)

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Section: Introductionmentioning

confidence: 99%

Organochlorine-Associated Immunosuppression in Prefledgling Caspian Terns and Herring Gulls from the Great Lakes: An Ecoepidemiological Study

Grasman¹,

Fox²,

Scanlon³

et al. 1996

Environmental Health Perspectives

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“…TCDD exposure during mouse embryogenesis causes craniofacial anomalies, such as cleft palate, and hydronephrosis (6), whereas in adult rodents, TCDD causes an elevated incidence of hepatic carcinoma and pulmonary and skin tumors (7)(8)(9). Other consequences of TCDD exposure include disturbances of lipid metabolism, cardiovascular and craniofacial abnormalities during fish development (10,11), and immunotoxic (12), reproductive, and endocrine effects (13)(14)(15)(16), some of which appear to be present also in exposed humans (17)(18)(19).…”

mentioning

confidence: 99%

Aromatic Hydrocarbon Receptor Interaction with the Retinoblastoma Protein Potentiates Repression of E2F-dependent Transcription and Cell Cycle Arrest

Puga

Barnes

Dalton

et al. 2000

Journal of Biological Chemistry

281

221

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Polyhalogenated aromatic hydrocarbons, of which 2,3,7,8-tetrachloro-p-dioxin (TCDD) is the prototype compound, elicit a variety of toxic, teratogenic, and carcinogenic responses in exposed animals and in humans.In cultured cells, TCDD shows marked effects on the regulation of cell cycle progression, including thymocyte apoptosis, induction of keratinocyte proliferation and terminal differentiation, and inhibition of estrogendependent proliferation in breast cancer cells. The presence of an LXCXE domain in the dioxin aromatic hydrocarbon receptor (AHR), suggested that the effects of TCDD on cell cycle regulation might be mediated by protein-protein interactions between AHR and the retinoblastoma protein (RB). Using the yeast two-hybrid system, AHR and RB were in fact shown to bind to each other. In vitro pull-down experiments with truncated AHR peptides indicated that at least two separate AHR domains form independent complexes with hypophosphorylated RB. Coimmunoprecipitation of whole cell lysates from human breast carcinoma MCF-7 cells, which express both proteins endogenously, revealed that AHR associates with RB in vivo only after receptor transformation and nuclear translocation. However, the AHR nuclear translocator and transcriptional heterodimerization partner, is not required for (nor is it a part of) the AHR⅐RB complexes detected in vitro. Ectopic expression of AHR and RB in human osteosarcoma SAOS-2 cells, which lack endogenous expression of both proteins, showed that AHR synergizes with RB to repress E2F-dependent transcription and to induce cell cycle arrest. Furthermore, AHR partly blocked T-antigen-mediated reversal of RB-dependent transcriptional repression. These results uncover a potential function for the AHR in cell cycle regulation and suggest that this function may be that of serving as an environmental sensor that signals cell cycle arrest when cells are exposed to certain environmental toxicants.

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“…Although very little is known about the endogenous function of the AhR in the immune system, TCDD has a very profound effect on immune function. In fact, T cell-dependent responses and host resistance to infection are extremely sensitive targets for modulation by AhR agonists (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Although the molecular mechanisms that underlie these effects are not entirely clear, epidemiological data suggest that exposure to pollutants that contain AhR agonists correlates with diminished host resistance, altered immune function, and an increased incidence of influenza and other respiratory infections (27)(28)(29), suggesting a possible cause and effect relationship between exposure to AhR ligands and altered host resistance to infection.…”

mentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

Lawrence

Roberts

Neumiller

et al. 2006

The Journal of Immunology

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The response of CD8+ T cells to influenza virus is very sensitive to modulation by aryl hydrocarbon receptor (AhR) agonists; however, the mechanism underlying AhR-mediated alterations in CD8+ T cell function remains unclear. Moreover, very little is known regarding how AhR activation affects anamnestic CD8+ T cell responses. In this study, we analyzed how AhR activation by the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the in vivo distribution and frequency of CD8+ T cells specific for three different influenza A virus epitopes during and after the resolution of a primary infection. We then determined the effects of TCDD on the expansion of virus-specific memory CD8+ T cells during recall challenge. Adoptive transfer of AhR-null CD8+ T cells into congenic AhR+/+ recipients, and the generation of CD45.2AhR−/−→CD45.1AhR+/+ chimeric mice demonstrate that AhR-regulated events within hemopoietic cells, but not directly within CD8+ T cells, underlie suppressed expansion of virus-specific CD8+ T cells during primary infection. Using a dual-adoptive transfer approach, we directly compared the responsiveness of virus-specific memory CD8+ T cells created in the presence or absence of TCDD, which revealed that despite profound suppression of the primary response to influenza virus, the recall response of virus-specific CD8+ T cells that form in the presence of TCDD is only mildly impaired. Thus, the delayed kinetics of the recall response in TCDD-treated mice reflects the fact that there are fewer memory cells at the time of reinfection rather than an inherent defect in the responsive capacity of virus-specific memory CD8+ cells.

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Influence of the Ah locus on the humoral immunotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Evidence for Ah-receptor-dependent and Ah-receptor-independent mechanisms of immunosuppression

Cited by 111 publications

References 29 publications

Organochlorine-Associated Immunosuppression in Prefledgling Caspian Terns and Herring Gulls from the Great Lakes: An Ecoepidemiological Study

Organochlorine-Associated Immunosuppression in Prefledgling Caspian Terns and Herring Gulls from the Great Lakes: An Ecoepidemiological Study

Aromatic Hydrocarbon Receptor Interaction with the Retinoblastoma Protein Potentiates Repression of E2F-dependent Transcription and Cell Cycle Arrest

Aryl Hydrocarbon Receptor Activation Impairs the Priming but Not the Recall of Influenza Virus-Specific CD8+ T Cells in the Lung

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