Gene Expression Alterations in Immune System Pathways following Exposure to Immunosuppressive Chemicals

Abstract

Exposure to environmental agents can affect a number of adverse immunological outcomes, including changes in the incidence of infectious disease. Diethylstilbestrol (DES), dexamethasone (DEX), cyclophosphamide, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that can induce similar pathophysiological end points in the thymus; however, the mechanism of toxicity is different for each compound. We examined differential gene expression in the spleen and thymus following chemical exposure and correlated these changes with alterations in functional immune end points and our knowledge of the known mechanisms of action. RNA from the spleen and thymus has been analyzed using Illumina Sentrix arrays and BeadStudio software. Preliminary data suggest that DES induced the greatest number of gene changes in the spleen, while DEX induced the most changes in the thymus. In both spleen and thymus, genomic analysis revealed gene expression changes that were common to multiple chemicals and that may be associated with xenobiotic-induced immune system perturbations, including alterations in genes associated with apoptosis, antigen processing and presentation, and response to biotic stimulus. This was particularly evident in the thymus, where there were many similarities in the expression profiles, as well as gene alterations unique to a single compound. In contrast, expression profiles in spleen were more distinct. The category of genes most profoundly affected by all four chemicals was response to biotic stimulus: there were both clusters of genes modulated by multiple chemicals and genes altered by a single chemical. The distinct gene profiles may specifically relate to cellular targets and mechanism of action.

Gene Expression Alterations in Immune System Pathways in the Thymus after Exposure to Immunosuppressive Chemicals

“…Initial analyses of this data set were described by Patterson and Germolec (2006). That report included an enumeration of alterations in gene expression, clustering of expression profiles, and a limited, low-stringency survey of gene ontology.…”

Review article. Predicting disease onset in clinically healthy people

“…OS does not directly cause infectious diseases, but does so indirectly by undermining the functioning of the immune system via immuno-suppression (Hughes, 1999 ; Akaike, 2001 ; Xu et al ., 2015 ; Splettstoesser & Schuff-Werner, 2002 ). It is to be noted that all the chemicals listed in Table 1 are immuno-suppressants (Veraldi et al ., 2006 ; Patterson & Gerrmolec, 2006 ). These include: polynuclear aromatic hydrocarbons (Jeng et al ., 2011 ), dioxins (Schneider et al ., 2008 ), tobacco smoke (Arcavi & Benowitz, 2004 ), pesticides (Banerjee et al ., 1999 ) and heavy metals (Liu et al ., 2009 ).…”

Does Cyclophosphamide Play a Protective Role Against Neuronal Loss in Chronic T. cruzi Infection?

“…Another hypothesis is that since CY is an inactive cyclic phosphamide ester of mechlorethamine, it is transformed via hepatic and intracellular enzymes to active alkylating metabolites that cause prevention of cell division primarily by cross-linking with DNA strands. Its action is similar to those played by glucocorticoids, in which the effects are mediated by binding to glucocorticoid receptors [27]. When stimulated, these receptors alter the transcription of various target genes.…”

“…A possible role of CY in protecting against neuronal loss is probably based on several facts. According to Patterson and Germolec [27], distinct immunosuppressive drugs such as CY could trigger alterations in functional immune end points, in which the greatest number of gene changes occurred in different organs. The author describes that the genomic analysis revealed gene expression changes that were common to multiple chemicals and may be associated with xenobiotic-induced immune system perturbations, including alterations in genes associated with apoptosis, antigen processing, presentation, and response to biotic stimulus.…”