Effects of perinatal DDT and adult HFD feeding on glucose homeostasis in adult female mice (n = 1 female/litter in 8 VEH + LFD, 8 DDT + LFD, 7 VEH + HFD and 8 DDT + HFD litters).

<p>(A) Glucose tolerance test and resulting AUC (DDT*HFD pi = 0.08), (B) fasting insulin (DDT*HFD pi = 0.08) and (C) HOMA-IR (DDT*HFD pi = 0.07) in 8 month old mice. (D) Hepatic IRβ total, AKT 473 phosphorylation, AKT 308 phosphorylation, AKT total, GSK 3 phosphorylation, GSK 3 total, ERK phosphorylation, and ERK total fold change (relative to LFD + VEH and adjusted by HSC 70) as assessed by Western blot analysis (n = 1 female/litter in 7 VEH and 8 DDT litters) in 9 month old mice fed HFD. *p<0.05, **p<0.01, ***p<0.001 significance between groups indicated by bars. Data are represented as LS means + SEM.</p

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

<div><p>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.</p></div

Effect of perinatal DDT on energy expenditure and cold tolerance in six month old female mice.

<p>(A) Oxygen consumption, (B) RER (period*DDT p_interaction<0.0001), (C) cumulative food intake, (D) energy expenditure, and (E) movement (over 5 day period and 4 female/treatment, 1 mouse/litter). (F) Core temperature (5 females/treatment, 1 female/litter). *p<0.05, **p<0.01, ***p<0.001 DDT vs. vehicle controls. Data are represented as LS means + SEM.</p

Effects of perinatal DDT and adult HFD feeding on body composition and energy balance in female mice (n = 1 female/litter in 7 VEH and 8 DDT litters).

<p>(A) Weekly body mass (HFD*age pi<0.0001). (B) Percent adiposity in 8 month old mice. (C) Cumulative caloric intake over 12 weeks of HFD or LFD feeding. (D) Core temperature in 8 month old mice (DDT*HFD pi = 0.01). *p<0.05, **p<0.01, ***p<0.0001 A–B) LFD vs. HFD only; D) significance between groups indicated by bars. Data are represented as LS means + SEM.</p

Effects of perinatal DDT and adult HFD feeding on RNA expression in BAT from 9 month old female mice (n = 1 female/litter in 8 VEH + LFD, 8 DDT + LFD, 7 VEH + HFD and 8 DDT + HFD litters).

<p>(A) <i>Ppargc1a</i>- (DDT*HFD pi<0.01), (B) <i>Dio2</i>- (DDT*HFD pi<0.01), (C) <i>Ucp1</i>-, (D) <i>Glut4</i>- (DDT*HFD pi<0.05), (E) <i>Lpl</i>- (DDT*HFD pi<0.05), (F) <i>Pnpla</i>- (DDT*HFD pi<0.05), (G) <i>Cpt2-</i> (DDT*HFD pi<0.05), and (H) <i>Twist1</i>- (DDT*HFD pi<0.1) fold change (relative to LFD + VEH and adjusted by <i>Tbp</i>). *p<0.05, **p<0.01 significance between groups indicated by bars. Data are represented as LS means + SEM.</p

Cognitive scores (Z scores) in groups of subjects defined by HbA1c at entry into the Diabetes Registry and trend over time in the registry^*.

<p>*Analysis of covariance to estimate and compare mean z-scores in the different cognitive domains among the trajectory groups, adjusting for sociodemographic, cardiovascular, diabetes-related covariates (years in the DR and anti-diabetic medications), and GDS score.</p

Study flow chart.

<p>Study flow chart.</p

Comparisons between cognitive scores in groups of subjects defined by HbA1c at entry into the Diabetes Registry and trend over time in the registry.

<p>Comparisons between cognitive scores in groups of subjects defined by HbA1c at entry into the Diabetes Registry and trend over time in the registry.</p

Trajectories in HbA1c levels.

<p>Groups: 1 = lower Stable, 2 = Higher Stable, 3 = Lower Increasing, 4 = Higher Increasing, 5 = Lower Decreasing, 6 = Higher Decreasing.</p

Overview of patient enrollment, clinical follow-up and personalized ctDNA analysis.

<p>Overview of patient enrollment, clinical follow-up and personalized ctDNA analysis.</p