Perinatal Exposure of Mice to the Pesticide DDT Impairs Energy Expenditure and Metabolism in Adult Female Offspring

Abstract

Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring.

Perinatal triphenyl phosphate exposure accelerates type 2 diabetes onset and increases adipose accumulation in UCD-type 2 diabetes mellitus rats

“…Every 2 weeks body temperature was assessed in rats from the obesity and diabetes studies by inserting a thermocouple probe into the rectum (BAT-10, Physitemp, Clifton, NJ). Cumulative energy intake (kcal) was calculated as the difference in food weight divided by the number of rats that had access to it and the number of days they had access, and transformed to kcal [31]. …”

Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice

“…o ., n = 14 dams) daily to primigravid C57BL/6J dams from 11.5 days post coitus (DPC) to postnatal day (PND) 5 to span a developmental exposure window important for rodent kidney and heart function (Aragon et al 2008; Couture et al 1990; Lin et al 2001; Thackaberry et al 2005; Xu et al 2011). We previously reported mean (± SEM) maternal serum levels (in nanograms/milliliter serum) of 2.2 (± 0.1) p , p ´-DDE, 51.1 (± 10.2) p , p ´-DDT, and no detectable o , p ´-DDT on PND 6, 24 hr after an identical daily dosing protocol of 1.7 mg/kg from 11.5 DPC to PND5 (La Merrill et al 2014). These exposures are within the range of past and contemporary human serum levels of both p , p ´-DDT and p , p ´-DDE (Bouwman et al 1992; Cox et al 2007; Gauthier et al 2014; Herrera-Portugal et al 2005; La Merrill et al 2013; Rylander et al 2009; Vafeiadi et al 2015).…”

Metabolism disrupting chemicals and metabolic disorders

“…Prenatal exposure to HCB has been associated with rapid growth in the first 6 months of life and obesity in infancy and childhood [383, 392]. Similarly, prenatal exposure to specific PCB congeners resulted in increased BMI at 14 months [387], at 1 and 3 yrs. of age [390], and age 5 and 7 [393].…”

“…In addition, it remains uncertain to what extent the effects of these chemicals on long-term growth may be due to indirect effects, dependent on the mismatch between a prenatal environment that can program offspring to survive in an environment that inhibits growth and the energy-dense diets available in the postnatal environment. Many POPs for which prenatal exposure is associated with obesity are also associated with smaller size at birth [385], and thus associations with obesity may be, at least in part, related to rapid postnatal growth in these children, similar to that observed in offspring of smokers and malnourished infants [316, 387, 388, 395]. In contrast to the human data, there is a paucity of animal data on the role of POPs on obesity; this area requires future study.…”