Effect of subchronic 2,3,7,8-tetrachlorodibenzo- p -dioxin exposure on immune system and target gene responses in mice: calculation of benchmark doses for CYP1A1 and CYP1A2 related enzyme activities

Vogel, Christoph F.A.; Donat, Susanne; Döhr, Olaf; Kremer, Joachim; Esser, Charlotte; Roller, Markus; Abel, Josef

doi:10.1007/s002040050401

Cited by 40 publications

(27 citation statements)

References 38 publications

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“…The AhR has been shown to play important roles in regulating the expression of several cytokines. For example, exposure of rats to TCDD led to up-regulation of IL-1␤ and TNF-␣ in the liver (57,58). Interestingly, although TCDD suppressed the production of IFN-␥ by mediastinal lymph node cells, there was a 10-fold increase in the IFN-␥ level in the lungs of TCDD-treated mice (59).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance

Ishimaru

Takagi

Kohashi

et al. 2009

The Journal of Immunology

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Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to influence immune responses, the effects of low-dose TCDD on the development of autoimmunity are unclear. In this study, using NFS/sld mice as a model for human Sjögren’s syndrome, in which the lesions are induced by the thymectomy on day 3 after birth, the autoimmune lesions in the salivary glands, and in later phase, inflammatory cell infiltrations in the other organs were developed by neonatal exposure to nonapoptotic dosage of TCDD without thymectomy on day 3 after birth. We found disruption of thymic selection, but not thymic atrophy, in TCDD-administered mice. The endogenous expression of aryl hydrocarbon receptor in the neonatal thymus was significantly higher than that in the adult thymus, suggesting that the neonatal thymus may be much more sensitive to TCDD compared with the adult thymus. In addition, the production of TH1 cytokines such as IL-2 and IFN-γ from splenic CD4+ T cells and the autoantibodies relevant for Sjögren’s syndrome in the sera from TCDD-exposed mice were significantly increased compared with those in control mice. These results suggest that TCDD/aryl hydrocarbon receptor signaling in the neonatal thymus plays an important role in the early thymic differentiation related to autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance

Ishimaru

Takagi

Kohashi

et al. 2009

The Journal of Immunology

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“…Induction of the enzymatic activity of CYP1A1, frequently measured as ethoxyresoru® n-O-deethylase (EROD), or aryl hydrocarbon hydroxylas e (AHH), parallels that of the mRNA. Vogel et al (1997) observed signi® cant induction of EROD activity at a dose of~0.3ng/kg/ day. Kohn et al (1993) observed induction of CYP1A1 mRNA at 0.1 ng/kg/day in rats.…”

mentioning

confidence: 84%

“…Induction of CYP1A2 mRNA and protein occurs at similar doses to that of CYP1A1. Vogel et al (1997) demonstrat ed induction of CYP1A2 mRNA at a dose of~0.3 ng/kg/day, with a NOEL of~0.03 ng/kg/day. Measurements of the activity of this enzyme often involve the hydroxylation of acetanilide (ACOH) or the demethylation of methoxyreso ru® n (MROD).…”

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confidence: 95%

“…The mRNA levels for CYP1A1 were not signi® cantly above control levels at 0.1 ng/kg. More recently, Vogel et al (1997) detected signi® cant induction of CYP1A1 mRNA in the mouse at~0.3 ng/kg/day. In their study the NOEL was approximat ely 0.03 ng/kg/day.…”

mentioning

confidence: 98%

“…The mechanism of this clearly adverse response remains to be elucidated. It is interesting to note that daily doses of 0.3 ng/kg/day are associated with increased expression of the cytokine, IL-1 (Vogel et al 1997). This dose results in a similar body burden as acute exposure to 10 ng/kg.…”

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confidence: 99%

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Non-carcinogenic effects of TCDD in animals

Birnbaum

Tuomisto²

2000

Food Additives and Contaminants

263

151

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Exposure to TCDD and related chemicals leads to a plethora of effects in multiple species, tissues, and stages of development. Responses range from relatively simple biochemical alterations through overtly toxic responses, including lethality. The spectrum of effects shows some species variability, but many effects are seen in multiple wildlife, domestic, and laboratory species, ranging from fish through birds and mammals. The same responses can be generated regardless of the route of exposure, although the administered dose may vary. The body burden appears to be the most appropriate dosimetric. Many of the effects often attributed to TCDD are associated with relatively high doses: lethality, wasting, lymphoid and gonadal atrophy, chloracne, hepatotoxicity, adult neurotoxicity, and cardiotoxicity. Changes in multiple endocrine and growth factor systems have been reported in a manner which is tissue, sex, and age-dependent. The most sensitive adverse effects observed in multiple species appear to be developmental, including effects on the developing immune, nervous, and reproductive systems. Such effects have been observed at maternal body burdens in the range of 30-80 ng/kg in both non-human primates and rodents. Biochemical effects on cytokine expression and metabolizing enzymes occur at body burdens which are within a factor of ten of the clearly adverse developmental responses. Thus, effects on the immune system, learning, and the developing reproductive system of multiple animals occur at body burdens which are close to those present in the background human population.

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Risk assessments of polychlorinated dibenzo‐ p‐dioxins, polychlorinated dibenzofurans, and dioxin‐like polychlorinated biphenyls in food

Larsen

2006

Molecular Nutrition Food Res

101

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The polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and dioxin-like polychlorinated biphenyls (dioxin-like PCB) are ubiquitous in food of animal origin and accumulate in fatty tissues of animals and humans. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The toxic responses include dermal toxicity, immunotoxicity, carcinogenicity, and reproductive and developmental toxicity. Toxic equivalency factors have been established for the other PCDD, PCDF and dioxin-like PCB relative to TCDD, and the combined toxicity of a sample can be expressed as toxic equivalent (WHO-TEQ). The EC Scientific Committee for Food evaluated these compounds in 2001. The assessment used the most sensitive adverse toxicological end-points of TCDD in experimental animals. These were developmental and reproductive effects in the male offspring of rats administered TCDD during pregnancy. Because of the large difference between rats and humans in the biological half-life of TCDD, the assessment used a body burden approach to compare across species and derived a tolerable weekly intake of 14 pg TCDD/kg of body weight (bw), which was extended to include all the 2,3,7,8-substituted PCDD and PCDF, and the dioxin-like PCB, and expressed as a group tolerable weekly intake of 14 pg WHO-TEQ/kg bw. The FAO/WHO Joint Expert Committee on Food Additives (JECFA) performed a similar assessment whereas the US Environmental Protection Agency (US EPA) has paid more attention to human data on carcinogenicity.

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Effect of subchronic 2,3,7,8-tetrachlorodibenzo- p -dioxin exposure on immune system and target gene responses in mice: calculation of benchmark doses for CYP1A1 and CYP1A2 related enzyme activities

Cited by 40 publications

References 38 publications

Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance

Neonatal Exposure to Low-Dose 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Causes Autoimmunity Due to the Disruption of T Cell Tolerance

Non-carcinogenic effects of TCDD in animals

Risk assessments of polychlorinated dibenzo‐ p‐dioxins, polychlorinated dibenzofurans, and dioxin‐like polychlorinated biphenyls in food

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