Immune modulation by sodium methyldithiocarbamate, a fumigant-type pesticide

Sodium methyldithiocarbamate (SMD) is a fumigant-type pesticide that is immunotoxic in mice. Previously, SMD was reported to cause thymic atrophy in mice. In the current study, SMD caused an increase in serum corticosterone that, when blocked by adrenalectomy or chemical inhibition of synthesis, was directly associated with the thymic atrophy. Further, SMD caused suppression of both cytokine mRNA and serum protein after stimulation by anti-CD3ϵ, LPS, and poly I:C. Of the cytokines studied, interleukin-2 (IL-2), IL-4, IL-12, and interferon-γ were suppressed by SMD. Serum IL-10, on the other hand, was upregulated when SMD was administered with LPS or poly I:C. This upregulation was nonetheless unassociated with the downregulation of the other cytokines. Cytokine suppression was dose dependent and lasted for several hours. Western blot analysis and DNA binding assays implicated NFκB in the cytokine alterations. Cytokine-mediated immune endpoints were also measured after SMD exposure. First, antibody production of IgG1 to KLH antigen was not altered with SMD, whereas IgG2a was upregulated by SMD. Cytokine production after KLH administration during SMD intoxication was varied with both suppression and enhancement. Further, analysis of cellular proliferation in draining lymph nodes dermal exposure to immune sensitizers during SMD intoxication indicated that SMD enhanced cellular proliferation. SMD also caused limited alterations of cytokine mRNA during co-administration of immune sensitizers. Lastly, GeneChip ® analysis of splenic mRNA transcripts modified during SMD intoxication identified several candidate genes for further study. Overall, SMD alters cytokine production while enhancing some immune endpoints after exposure.; Hypothesis. SMD depletes thymocytes via an adrenal-mediated mechanism by increasing production of serum corticosterone. SMD also alters NFκB signaling and subsequently alters antibody and cytokine production in response to antigen or other stimuli.; Specific aim 1. SMD alters the normal thymic cellularity and profile of thymocyte subpopulations by an indirect adrenal-mediated mechanism.; Specific aim 2. SMD alters NFκB signaling and subsequently alters the cytokine profile induced by immunological stimuli (including antigen) and antibody production in response to antigen.; Specific aim 3. SMD alters cytokine production after stimulation by an antigen or by chemical sensitizers.