Sodium methyldithiocarbamate exerts broad inhibition of cellular signaling and expression of effector molecules of inflammation.
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.
* Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762.
Xiaomin
X
Deng
Bindu
B
Nanduri
Wei
W
Tan
Bing
B
Cheng
Ruping
R
Fan
Stephen B
SB
Pruett
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects*; D013859:Thiocarbamates / Q000633:toxicity*
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D013859:Thiocarbamates; C008435:methyldithiocarbamate
chemokines; cytokine; microarray.; pesticides; signal transduction; signaling; transcription factors