Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in strains of mice with different susceptibility to induction of aryl hydrocarbon hydroxylase

doi:10.1016/0041-008X(83)90288-0

Toxicology and Applied Pharmacology

Volume 68, Issue 3, May 1983, Pages 434-441

https://doi.org/10.1016/0041-008X(83)90288-0 Get rights and content

Abstract

Mouse strains with different susceptibility to aryl hydrocarbon hydroxylase (AHH) induction and with different levels and/or affinity for a specific cytosolic binding protein (“receptor”) were used to investigate the immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Humoral antibody production was strongly inhibited in $C57B1 6$ and $C3H HeN$ mice (more susceptible strains) with very low, single doses of TCDD (1.2 μg/kg), while other strains ( $DBA 2$ and AKR) required higher doses (at least 6 μg/kg) to be partially suppressed. Longer exposure (8 weeks) did not increase the sensitivity of $DBA 2$ mice. A good correlation between the degree of enzyme inducibility and immunosuppression was observed in studies with B6D2F1 mice and backcrosses. Similar results were obtained with 2,3,7,8-tetrachlorodibenzo-furan (TCDF), the most powerful competitor for TCDD “receptor” in vitro and in vivo. TCDD immnotoxic effects appeared to be associated with the presence of a specific cytosolic binding protein which mediates AHH induction.

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The Aryl Hydrocarbon Receptor and Immunity
2018, Comprehensive Toxicology: Third Edition
The aryl hydrocarbon receptor (AhR), originally discovered as a xenobiotic receptor involved in upregulating metabolic enzymes, has become increasingly linked to physiological processes such as cell cycle regulation and cellular differentiation as well as disease states associated with these processes. The immune system is composed of numerous effector cells and protein mediators with specialized functions, all of which are highly dependent on cell cycle regulation and cellular differentiation and therefore offer a plethora of potential targets for modulation by the AhR. Indeed, the vast majority of studies support a direct or indirect influence of the AhR in most aspects of immunity. The focus of this chapter is to discuss these studies. Although AhR activation by dioxin and nondioxin ligands is a primary method for evaluating AhR-mediated effects, there is the possibility for off-target effects by AhR ligands (i.e., not AhR mediated) or for effects that do not accurately reflect the physiological function of the AhR (i.e., exogenous vs. endogenous ligands). Therefore, more emphasis will be given to immune effects that have been demonstrated to be AhR dependent by either the use of a chemical AhR antagonist or the knockdown or knockout of the AhR.
An evaluation of benchmark dose methodology for non-cancer continuous-data health effects in animals due to exposures to dioxin (TCDD)
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The U.S. Environmental Protection Agency (EPA) has conducted extensive reviews and analyses of health effects associated with exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Because the carcinogenicity of TCDD has received considerable attention from EPA and others, this paper focuses on animal data for non-cancer health effects that sometimes appear to be almost as sensitive as cancer to TCDD exposures. Benchmark dose (BMD) methodology can be used to identify point-of-departure (POD) estimates for use in derivation of reference doses or evaluation of margins of exposure. However, selection of an appropriate BMD methodology for assessment of non-cancer data, which are usually continuous (non-quantal), needs to be considered. One option available for a benchmark dose is to use a small percentage change in the mean response relative to the estimated maximum effect of TCDD at large doses. The benchmark based on a change estimated to equal 1% of the estimated maximum change from background to the asymptotic response at large doses (denoted as the relative ED₀₁) was used by EPA in a reassessment of TCDD health risks. A lower confidence limit (LED₀₁) could serve as a point of departure for setting a reference dose (RfD). This is a somewhat arbitrary effect level, generally within the background range of variation among unexposed animals, with an unknown risk. An alternative approach is recommended in which the risk of abnormal levels can be estimated. For continuous-data effects, a low and/or high percentile (e.g., 1st and/or 99th) in unexposed control animals can be used to define abnormal (not necessarily adverse) levels. From a dose–response curve and the standard deviation, it is possible to estimate the excess risk (proportion) of animals with abnormal levels as a function of dose for normally distributed levels. With this approach, the risk-based benchmark dose (BMD₀₁) represents the dose with an estimated excess risk of 1% of the animals in the abnormal range rather than an arbitrary change in the value of the measured endpoint. Values for the relative and risk-based benchmark doses are computed from published data for a variety of non-cancer health effects associated with exposure to TCDD. For the 30 cases investigated, the BMD₀₁ tended to vary around the lowest experimental dose tested, whereas the relative ED₀₁ tended to be about a factor of three below the lowest dose, and the BMD₀₁ was more precisely estimated than the ED₀₁ as reflected by narrower confidence intervals. The BMDL₀₁ values were on average more than fivefold higher than the corresponding LED₀₁ values. However, these values still provide a conservative assessment for POD assessment, because the BMDL₀₁ tends to be about an order of magnitude lower (more conservative) than the no-observed-adverse-effect level. This analysis demonstrates the potential impact of alternative choices in benchmark dose methodology. In combination with selection of appropriate adverse health effect endpoint(s) and studies, use of the risk-based BMD results in identification of more valid and meaningful POD estimates for non-cancer effects compared to the use of the relative ED approach.
Ah receptor and NF-κB interactions: Mechanisms and physiological implications
2002, Chemico-Biological Interactions
Citation Excerpt :
The Ah receptor clearly plays a key role in TCDD-induced immune suppression [17,82–84]. In earlier studies, the role of the Ah receptor in the toxicity induced by halogenated aromatic hydrocarbons was demonstrated by structure–activity relationship studies [85–87]. Using Ahr−/− mice, Staples et al. demonstrated that the Ah receptor plays a pivotal role in thymic atrophy induced by TCDD.
The aryl hydrocarbon (Ah) receptor mediates most of the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, which are ubiquitous environmental contaminants causing toxic responses in human and wildlife. Nuclear factor kappa B (NF-κB) is a pleiotropic transcription factor that plays a pivotal role in a wide array of physiological and pathological responses including immune modulation, inflammatory responses and apoptosis. Many physiological functions adversely affected by TCDD are also known to be regulated by NF-κB, such as immune activation, maintenance of skin differentiation, control of cell proliferation and survival, as well as induction of xenobiotic metabolizing enzymes. In the past few years, evidence has emerged to show that the Ah receptor and NF-κB interact and transcriptionally modulate each other. This review discusses Ah receptor–NF-κB interactions and examines potential mechanistic explanations for toxic responses as a result of TCDD exposure and the suppression of cytochrome P450 1A1/1A2 by stress stimuli such as inflammation and infection.
Aryl hydrocarbon receptor-dependent inhibition of AP-1 activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in activated B cells
2002, Toxicology and Applied Pharmacology
B cells have been identified as sensitive cellular targets responsible for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated suppression of humoral immunity. In previous studies, TCDD was shown to produce a significant inhibition of IgM secretion and mu gene expression in LPS-activated CH12.LX B cells (AhR expressing) but not in BCL-1 B cells (AhR deficient). The present studies extend these previous findings by investigating the effect of TCDD on AP-1 and nuclear factor (NF)-κB, both of which play an important role in B-cell activation, differentiation, and immunoglobulin (Ig) gene expression. Electrophoretic mobility shift assays and chloramphenicol acetyl transferase reporter gene experiments demonstrated that lipopolysaccharide (LPS)-induced DNA binding and transcriptional activity of AP-1 was markedly inhibited by TCDD at 24, 48, and 72 h after cellular activation of CH12.LX cells. Conversely, TCDD treatment produced no significant change on the activity of NF-κB. Two AhR antagonists, α-naphthoflavone and 2,2′,5,5′-tetrachlorobiphenyl, attenuated TCDD-induced inhibition of AP-1 binding in CH12.LX cells. Concordant with this result, TCDD did not inhibit LPS-induced AP-1 activity in BCL-1 B cells. Moreover, supershift analysis revealed the major component of the AP-1 complex in LPS-activated CH12.LX cells was c-Jun. Additional studies revealed that the nuclear c-jun and c-jun steady-state mRNA expression was inhibited by TCDD treatment. Collectively, these results suggest that TCDD-induced inhibition of IgM expression by B cells may be mediated, at least in part, through a down-regulation of AP-1 activity in an AhR-dependent manner.
Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression
2001, Toxicology and Applied Pharmacology
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates many of the toxic effects induced by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high-affinity AhR ligand and a potent immunotoxicant. AhR-deficient mice have been constructed, and there are reports that the animals display altered splenic architecture and cellularity with an apparent increased incidence of infection. These observations have led to speculation that the immune system of these animals might be compromised, however, their functional immune response has not been directly tested. In the studies presented here, we examined the immune response of two strains of 8- to 10-week-old AhR-deficient mice. Mice were challenged with model antigens, allogeneic P815 tumor cells, or sheep red blood cells, and their ability to generate cell-mediated and humoral immune responses was examined. In addition, to address the obligatory role of the AhR in TCDD-induced immune suppression, we examined the immune response of the AhR-null animals following exposure to an immunosuppressive dose of TCDD. Results from these studies showed that AhR-deficient mice were able to mount normal productive immune responses to both model antigens and that neither the cellular nor the humoral response was suppressed by exposure to TCDD. Interestingly, however, we found that the immune response of heterozygous AhR^+/− mice was less sensitive to TCDD than homozygous AhR^+/+ mice. The results of these studies suggest that the absence of the AhR does not impact the function of the immune system, but confirm the findings of previous studies that have indicated the AhR plays an obligatory role in TCDD-induced immune suppression.
2,3,7,8-Tetrachlorodibenzo-p-dioxin affects the number and function of murine splenic dendritic cells and their expression of accessory molecules
2001, Toxicology and Applied Pharmacology
Primary T cell-mediated immune responses are highly susceptible to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, yet direct effects of TCDD on T cells have been difficult to demonstrate. Since the activation of naive T cells has been shown to be initiated primarily by dendritic cells (DC), these cells represent a potential target for TCDD immunotoxicity. In this report, we have examined the influence of TCDD exposure on splenic DC phenotype and function in the absence of antigenic stimulation. Results showed that DC from TCDD-treated mice expressed higher levels of several accessory molecules including ICAM-1, CD24, B7–2, and CD40, whereas the expression of LFA-1 was significantly reduced. These effects were dose-dependent and persisted for at least 14 days after exposure. The effects were also dependent upon the aryl hydrocarbon receptor (AhR), as similar effects were observed in AhR^+/+ C57Bl/6 and Balb/c mice but not in AhR⁻^/− mice. When DC from TCDD-treated mice were cultured with allogeneic T cells, the proliferative response and production of IL-2 and IFN-γ by the T cells were increased. Production of IL-12 by the DC was likewise enhanced in comparison to cells from vehicle-treated mice. Interestingly, however, the number of DC recovered from TCDD-treated mice was significantly decreased. Taken together, these results suggest that, in the absence of antigen, TCDD provides an activation stimulus to DC that may lead to their premature deletion. Since the survival of DC has been shown to influence the strength and duration of the immune response, these results suggest a possible novel mechanism for TCDD-induced immune suppression.

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²: Biostastics Unit, Istituto Mario Negri.

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Immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in strains of mice with different susceptibility to induction of aryl hydrocarbon hydroxylase

Abstract

Toxicol. Appl. Pharmacol.

Anal. Biochem.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Biochimie

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Advan. Cancer Res.