Recent advances in understanding the mechanisms of TCDD immunotoxicity

Kerkvliet, Nancy I.

doi:10.1016/s1567-5769(01)00179-5

Cited by 195 publications

(146 citation statements)

References 80 publications

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“…The effects of TCDD generally include carcinogenicity, hepatotoxicity, immune suppression and developmental toxicity as ED effects [2,11,14]. In addition to these effects, a decreased male/female sex ratio among children born to males who were exposed to TCDD at a relatively young age compared with unexposed males has also been reported [15,16,20].…”

Section: Discussionmentioning

confidence: 99%

Dose Paternal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) affect the Sex Ratio of Offspring?

Ishihara

Warita

Tanida

et al. 2007

The Journal of Veterinary Medical Science

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ABSTRACT. In 1976, men who were exposed to the highest concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after an explosion at a chemical plant near Seveso, Italy, produced more girls than boys. However, few studies have examined the possibility that the exposure of laboratory animals to TCDD, especially that of males, could lead to a lower male/female sex ratio. The aim of this study was to investigate whether direct paternal exposure to TCDD affects the sex ratio of offspring using a relatively large-scale experimental design. Male ICR mice (n=120) were randomly assigned to three, one of which served as a vehicle control, the other two were administered TCDD orally with an initial loading dose of 2 or 2,000 ng TCDD/kg, followed by a weekly maintenance dose of 0.4 (T2/0.4 group) or 400 (T2000/400 group) ng/kg prior to mating. The major organs of each mouse were weighed and histopathologically and immunohistologically investigated, and the sex ratio of offspring [males/(males + females) × 100] was calculated in each dam. There were no significant effects on organ weights, or on the structure of the testis and epididymis between the control and TCDD-exposed males, but TCDD administration produced a significantly lower proportion of male offspring from T2000/400-exposed sires despite no alteration in litter size (Control: 53.1 ± 1.7; T2/0.4: 48.8 ± 2.5; T2000/400: 46.2 ± 2.1). In addition, we further divided the T2000/400 group into 3 subgroups based on the proportion of CYP1A1-immunoreactive areas in the liver; there was a significant correlation between sex ratio and CYP1A1 immunoreactivity. Thus, the present study confirms that direct paternal exposure to TCDD might be associated with an alteration in the sex ratio of offspring. Possible mechanisms through which TCDD might decrease the fertility potential of Ybearing gametes before conception are discussed. KEY WORDS: CYP1A1, paternal exposure, Seveso data, sex ratio of offspring, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

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Section: Discussionmentioning

confidence: 99%

Dose Paternal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) affect the Sex Ratio of Offspring?

Ishihara

Warita

Tanida

et al. 2007

The Journal of Veterinary Medical Science

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“…The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) is used as a model AhR agonist because of all the AhR agonists identified to date, it has the highest binding affinity, and has been used for the majority of studies characterizing the consequences of AhR activation (6,(11)(12)(13)(14). 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.…”

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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“…Even at doses with no obvious signs of toxicity, TCDD alters the immune functions in virtually every species studied so far (Holsapple et al, 1991;Kerkvliet, 2002). TCDD acts via the activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that belongs to the basic helix-loop-helix superfamily whose members play key roles in gene expression networks underlying many essential physiological and developmental processes.…”

Section: Introductionmentioning

confidence: 99%

“…A large body of data demonstrates the effects of AhR activation on the differentiation of the T-cell subsets (Nguyen et al, 2013), including a number of genome-wide expression studies on T-cells (Li et al, 2013;Stubbington et al, 2015). While the roles of AhR in B cell differentiation are demonstrated (De Abrew et al, 2011;Zhang et al, 2013), there is a dearth of data that allows a better mechanistic understanding of the long-term consequence of the chronic TCDD exposure on humoral immunity (e.g., B cells) that underlie referenced above adverse outcomes of TCDD exposure (Kerkvliet, 2002). With the application of transcriptome analysis, we could gain a full view of the effects of TCDD on B lymphocytes at the transcriptional level.…”

Section: Introductionmentioning

confidence: 99%

Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

Tian

Krylova

et al. 2016

Journal of Environmental Sciences

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Recent advances in understanding the mechanisms of TCDD immunotoxicity

Cited by 195 publications

References 80 publications

Dose Paternal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) affect the Sex Ratio of Offspring?

Dose Paternal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) affect the Sex Ratio of Offspring?

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

Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

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