Sodium methyldithiocarbamate exerts broad inhibition of cellular signaling and expression of effector molecules of inflammation.

Abstract

Sodium methyldithiocarbamate (SMD) is one of the most abundantly used conventional pesticides in the United States. At dosages relevant to occupational exposure, it causes major effects on the immune system in mice, including a decreased resistance to sepsis. This lab has identified some of the mechanisms of action of this compound and some of the immunological parameters affected, but the global effects have not previously been assessed. The purpose of the present study was to conduct transcriptomic analysis of the effects of SMD on lipopolysaccharide-induced expression of mediators important in innate immunity and inflammation. The results revealed broad effects on expression of transcription factors in both branches of Toll-like receptor 4 (TLR4) signaling (MyD88 and TRIF). However, TLR3 and interferon signaling pathways were decreased to a greater extent, and assessment of the effects of SMD on polyinosinic polycytidylic acid-induced cytokine and chemokine production revealed that these responses mediated by TLR3 were indeed sensitive to the effects of SMD, with inhibition occurring at lower dosages than required to inhibit responses to other immunological stimuli tested in our previous studies. In the downstream signaling pathways of these TLRs, functional analysis also revealed that NF-κB activation was inhibited by SMD, as indicated by gene expression analysis and a reporter construct in mice. A previously unreported effect on luteinizing hormone and follicle-stimulating hormone pathways was also observed.

• Authors: Xiaomin Deng, Bindu Nanduri, Wei Tan, Bing Cheng, Ruping Fan, Stephen B Pruett
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 136 Issue 2 Pg. 430-42 (Dec 2013) ISSN: 1096-0929 [Electronic] United States
• PMID: 24056979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Inflammation Mediators
• Lipopolysaccharides
• Thiocarbamates
• methyldithiocarbamate

Topics

• Animals
• Cytokines (biosynthesis)
• Female
• Gene Expression Regulation (drug effects)
• Immunity, Innate (genetics)
• Inflammation (metabolism)
• Inflammation Mediators (metabolism)
• Lipopolysaccharides (administration & dosage)
• Macrophages, Peritoneal (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Signal Transduction (drug effects)
• Thiocarbamates (toxicity)