Exposure to DDT metabolitep,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 0 -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 T H 1-type cytokine secretion, without affecting the splenocytes viability and the T-cell subpopulations. 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.

Adverse effects of weight loss: Are persistent organic pollutants a potential culprit?

“…Furthermore, higher plasma levels of POPs and higher plasma inflammatory cytokine concentrations were found in First Nations individuals compared to Caucasians from Canada [102]. Moreover, acute exposure to DDE, increased T cell proliferation as well as Th1-dependent inflammatory cytokines and Cox2 while chronic exposure decreased suppressive regulatory T cells as well as protective suppressive cytokines [103,104].…”

Exposure to polychlorinated biphenyl-153 decreases incidence of autoimmune Type 1 diabetes in non-obese diabetic mice

“…Finally, a nested case-control study by Rignell-Hydbom et al (2010) investigated the role of PCB-153 and DDE in T1D; the authors concluded that these compounds did not exhibit negative effects on T1D development, even suggesting that they might impart a possible (although not significant) protection. Interestingly, Cetkovic-Cvrlje et al (2015) recently showed that DDE was able to accelerate T1D development in NOD mice treated chronically with the compound.…”

“…NOD mice were used following an experimental design previously used to study DDE effects on T1D development in the same model (Cetkovic-Cvrlje et al 2015). Initially, PCB-153 effects on development and severity of diabetes during subchronic exposures had been studied using NOD females, whereas the mechanism of action in the context of pollutant influence on the immune system, particularly T-cells, was evaluated using NOD males and females.…”

“…PCB-153 for intraperitoneal (IP) injections was prepared by suspending stock PCB-153 in corn oil (Sigma). The PCB/corn oil injection volume was adjusted to 6.7 ll/g BW as previously described in Cetkovic-Cvrlje et al (2015).…”

“…Concerning the relationship between POPs and T1D in NOD mice, recent studies reported aggravation of disease with exposure to diphenyldichlorodiphenylethylene (DDE) (Cetkovic-Cvrlje et al 2015), and bisphenol A (BPA) (Bodin et al 2013(Bodin et al , 2014. Considering PCBs, and specifically PCB-153, besides conflicting data provided by a few epidemiological studies (Longnecker & Daniels 2001;Langer et al 2002;Rignell-Hydbom et al 2010;Li et al 2013), there has been no study that directly investigated the association between PCB-153 exposure and development of T1D in an experimental animal model.…”