Genomic analysis of DES induced immunotoxic effects in the thymus

Gene expression alterations in immune system pathways in the thymus after exposure to immunosuppressive chemicals

2010 Study Abstract

BACKGROUND
Dysregulation of positive and negative selection, antigen presentation, or apoptosis in the thymus can lead to immunosuppression or autoimmunity. Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide (CPS), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that induce similar immunotoxic effects in the thymus, however, the mechanism of toxicity is purported to be different for each compound.

OBJECTIVES
We hypothesized that genomic analysis of thymus after chemical-induced atrophy would yield transcriptional profiles that suggest pathways of toxicity associated with reduced function.

METHODS
Female B6C3F1 mice were exposed to these immunosuppressive agents and changes in gene expression and immune cell subpopulations were evaluated.

RESULTS
All four chemicals induced thymic atrophy and changes in both the relative proportion and absolute number of CD3(+), CD4(+)/CD8(-), CD4(-)/CD8(+), and CD4(+)/CD8(+) thymocytes. The most significant impact of exposure to DEX, DES, and CPS was modulation of gene expression in the T-cell receptor (TCR) complex and TCR and CD28 signaling pathways; this could represent a common mechanism of action and play a pivotal role in lineage commitment and development of T cells. Up-regulation of genes associated with the antigen presentation and dendritic cell maturation pathways was the most distinctive effect of TCDD exposure. These elements, which were also up-regulated by DEX and DES, contribute to positive and negative selection.

Seventeen genes (Ccnd3↓, Tcf7↓, Cdk2↓, Gfi1↓, Lat↓, Ifngr1↓, Capn2↑, Ifi16↑, Pbef1↑, Gpx3↑, Tyrobp↑, Klf2↑, Casp1↑, Fcer1g↑, Fcgr3↑, Apoe↑, Ly6a↑) associated with T-cell development and differentiation, cellular homeostasis, and apoptosis, proliferation, and cell cycle regulation were differentially expressed (Illumina DIFF score, |≥ 20|; concordance and detection scores ≥ 0.95) by the high dose of all four chemicals.

  • Conversely, exposure to DEX and DES resulted in genes altered at the low dose only (DEX, 21 genes; DES, 21 genes),
  • genes altered at both low and high doses (DEX, 149 genes; DES, 99 genes),
  • and genes altered at the high dose only (DEX, 64 genes; DES, 46 genes).

CONCLUSIONS
Genomic analysis revealed gene expression changes in several pathways that are commonly associated with xenobiotic-induced immune system perturbations, particularly those that contribute to the development and maturation of thymic T cells.

Sources and more information
  • Full study (free access) : Gene Expression Alterations in Immune System Pathways in the Thymus after Exposure to Immunosuppressive Chemicals, Environmental Health Perspectives, NCBI PubMed PMC3060001, 2010 Nov 1.
  • Three indicators of toxicity, body weight, thymus weight, and thymus cell number, measured to evaluate acute toxicity and thymic atrophy after low dose (A) or high dose (B) of immunosuppressive agents (percent control; mean ± SE, n = 8).
    *p ≤ 0.05; **p ≤ 0.01 versus matched control
    featured image credit PMC3060001/figure/f1-ehp-119-371.
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