title: Exposure to DDT metabolite p,p'-DDE increases autoimmune type 1 diabetes incidence in NOD mouse model.
abstract: The incidence of autoimmune Type 1 diabetes (T1D) has been steadily rising in developed countries. Although the exact cause of T1D remains elusive, it is known that both genetics and environmental factors play a role in its immunopathogenesis. Whereas a positive association between p,p'-DDE, a DDT metabolite, and Type 2 diabetes (T2D) has been well established, its role in T1D development in an experimental animal model has never been elucidated. This study seeks to investigate the effects of DDE exposure on the development of T1D in a NOD mouse model. As T1D is a T-cell-mediated disease, the underlying mechanism of DDE action on T-cells was studied in vitro and, in the context of acute and chronic DDE exposure, in vivo by investigating lymphocytes' viability, proliferation, their subsets and cytokine profiles. Chronic high-dose DDE treatment, initiated in pre-diabetic 8-week-old NOD females administered twice weekly intraperitoneally with 50 mg/kg DDE, significantly increased diabetes incidence and augmented disease severity in treated animals. Whereas T-cell proliferation and cell viability in the spleens of treated mice were not affected, diabetogenic action of chronic DDE exposure was associated with a decrease in regulatory T-cells and a suppression of secretion of protective cytokines, such as IL-4 and IL-10. Interestingly, an acute high-dose in vivo treatment of 8-week-old NOD males with 100 mg DDE/kg, administered intraperitoneally every other day over a period of 10 days, increased T-cell proliferation and potentiated pro-inflammatory and TH1-type cytokine secretion, without affecting the splenocytes viability and the T-cell sub-populations. These results confirm that high-dose DDE treatments affect the immune system, in particularly T-cell function. In conclusion, this study shows for the first time that high-dose chronic DDE exposure exhibits a diabetogenic potential, with an underlying immunomodulatory mechanism of action, in the development of T1D in an experimental mouse NOD model.
authors.affiliation: a Department of Biological Sciences and.|b Laboratory for Immunology , St. Cloud State University , St. Cloud , MN , USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Cetkovic-Cvrlje
authors.affiliation: a Department of Biological Sciences and.|b Laboratory for Immunology , St. Cloud State University , St. Cloud , MN , USA.
authors.forename: Marin
authors.initials: M
authors.lastname: Olson
authors.affiliation: a Department of Biological Sciences and.
authors.forename: Broc
authors.initials: B
authors.lastname: Schindler
authors.affiliation: a Department of Biological Sciences and.
authors.forename: Hwee Kiat
authors.initials: HK
authors.lastname: Gong
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003634:DDT / Q000031:analogs & derivatives / Q000633:toxicity*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D003633:Dichlorodiphenyl Dichloroethylene / Q000633:toxicity*; D004195:Disease Models, Animal; D018450:Disease Progression; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects
chemical_list: D016207:Cytokines; D004785:Environmental Pollutants; D003633:Dichlorodiphenyl Dichloroethylene; D003634:DDT
keywords: DDE; NOD mice; T-cells; p,p′-DDE; persistent organic pollutants; type 1 diabetes