Effect of chronic p,p′-dichlorodiphenyldichloroethylene (DDE) exposure on high fat diet-induced alterations in glucose and lipid metabolism in male C57BL/6H mice

Abstract

Diabetes mellitus is a highly prevalent metabolic disease affecting 29.1 million people or 9.3% of the population of the United States. The most prevalent form of diabetes is type 2 diabetes (T2D) which comprises 90-95% of all reported cases of diabetes. While the exact cause of T2D remains an enigma, known risk factors include age, weight, sedentary lifestyle, poor dietary habits, and genetic predisposition. However, these risk factors can not sufficiently explain the increasing prevalence of T2D. Recently, environmental exposures have been explored as potential risk factors. Indeed, epidemiological and limited empirical studies have revealed elevated serum concentrations of certain persistent organic pollutants (POPs), including the bioaccumulative metabolite of p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethylene (DDE), are positively correlated with increased T2D prevalence. The goal of the present study is to determine if chronic exposure to DDE promotes T2D in a widely used in vivo model, the high saturated fat-fed mouse. Male C57BL/6H mice were exposed to DDE (2.0mg/kg) or vehicle (corn oil; 1ml/kg) via gavage for 5 consecutive days, then every 7 days for the duration of the study. One week following the 5 day consecutive DDE dosing, animals were placed on either a low fat (10%kcal from lard) or high fat (45%kcal from lard) diet (HFD) for 13 weeks. Chronic exposure to DDE promoted fasting hyperglycemia after 4 and 8 weeks on the HFD diet and normalized fasting blood glucose levels at week 13. This DDE-mediated decrease in fasting hyperglycemia was preceded by improved glucose tolerance at week 12. In addition to normalizing fasting hyperglycemia at the end of high fat feeding, DDE exposure decreased HFD-induced fasting hyperinsulinemia, homeostasis model assessment of insulin resistance (HOMA-IR) values, and hepatic steatosis. Therefore, based on the current data, chronic DDE exposure appears to have a biphasic effect on HFD-induced hyperglycemia in the male C57BL/6H mouse characterized by elevated fasting blood glucose at weeks 4 and 8 of HFD intake followed by normoglycemia upon sacrifice. In addition, chronic DDE exposure reduced HFD-induced hepatic steatosis upon sacrifice. These results indicate chronic exposure to DDE can directly affect systemic glucose and hepatic lipid metabolism and that these effects can be diet dependent.

Potential contribution of insecticide exposure and development of obesity and type 2 diabetes

“…Exposures to organochlorine insecticides (DDE, HCB, and ɣ-HCH) have led to increased body weight gain in rodents (Table 4) (Chadwick et al, 1988; Howell et al, 2014; Howell et al, 2015; Villeneuve et al, 1977), including a study of parental trans-generational exposure to DDT linked to increased obesity rate in the offspring (Skinner et al, 2013). Similarly, others reported that perinatal exposure to DDT was linked to significant weight gain, but only in female offspring (La Merrill et al, 2014) or reduced weight was reported after dieldrin exposure (Shakoori et al, 1984).…”

Combined effects of DDE and hyperlipidic diet on metallothionein expression and synthesis in rat tissues

“…The 1,1′‐(2,2,2‐trichloroethane‐1,1‐diyl)bis(4‐chlorobenzene) (known as dichloro–diphenyl–trichloroethane, DDT) is a synthetic organochlorine, low‐cost pesticide widely used in the past years against malaria . It exerts its toxicity on the central nervous system altering the functionality of ion channels; many in vivo and in vitro studies have demonstrated adverse effects also on vertebrates including humans, affecting lipid and glucose metabolism and inducing cellular oxidative stress . Though having been banned in rich industrialized countries from ‘70s, it is still used in developing areas of Africa and Asia, where malaria, dengue and other diseases transmitted by mosquitoes are endemic .…”

Adulthood dietary exposure to a common pesticide leads to an obese-like phenotype and a diabetic profile in apoE3 mice

“…In the light of this trend, the risk factors commonly studied fail to explain by themselves the global boom of both diseases. Hence, "non-traditional" risk factors have been reconsidered (Arrebola et al, 2015;Howell et al, 2015). Some epidemiological evidence links general pesticide exposure (Arrebola et al, 2013(Arrebola et al, , 2015Suarez-Lopez et al, 2015) and more specifically OP exposure (Montgomery et al, 2008;Saldana et al, 2007) to a higher incidence of type 2 diabetes and related metabolic dysfunctions.…”