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

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

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

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

Longitudinal association of e-cigarette use with important respiratory symptoms by combustible tobacco smoking status.

Longitudinal association of e-cigarette use with important respiratory symptoms by combustible tobacco smoking status.</p

Functionally important respiratory symptom index: Measures and calculation.

Functionally important respiratory symptom index: Measures and calculation.</p

Sample characteristics at Wave 4.

BackgroundWe assessed longitudinal effects of e-cigarette use on respiratory symptoms in a nationally representative sample of US adults by combustible tobacco smoking status.MethodsWe analyzed Waves 4–5 public-use data from the Population Assessment of Tobacco and Health Study. Study sample included adult respondents who reported no diagnosis of respiratory diseases at Wave 4, and completed Waves 4–5 surveys with no missing data on analytic variables (N = 15,291). Outcome was a validated index of functionally important respiratory symptoms based on 7 wheezing/cough questions (range 0–9). An index score of ≥2 was defined as having important respiratory symptoms. Weighted lagged logistic regression models were performed to examine the association between e-cigarette use status at Wave 4 (former/current vs. never use) and important respiratory symptoms at Wave 5 by combustible tobacco smoking status (i.e., never/former/current smokers), adjusting for Wave 4 respiratory symptom index, sociodemographic characteristics, secondhand smoke exposure, body mass index, and chronic disease.ResultsAmong current combustible tobacco smokers, e-cigarette use was associated with increased odds of reporting important respiratory symptoms (former e-cigarette use: adjusted odds ratio [AOR] = 1.39, 95% confidence interval [CI]: 1.07–1.81; current e-cigarette use: AOR = 1.55, 95% CI: 1.17–2.06). Among former combustible tobacco smokers, former e-cigarette use (AOR = 1.51, 95% CI: 1.06–2.15)—but not current e-cigarette use (AOR = 1.59, 95% CI: 0.91–2.78)—was associated with increased odds of important respiratory symptoms. Among never combustible tobacco smokers, no significant association was detected between e-cigarette use and important respiratory symptoms (former e-cigarette use: AOR = 1.62, 95% CI: 0.76–3.46; current e-cigarette use: AOR = 0.82, 95% CI: 0.27–2.56).ConclusionsThe association between e-cigarette use and respiratory symptoms varied by combustible tobacco smoking status. Current combustible tobacco smokers who use e-cigarettes have an elevated risk of respiratory impairments.</div

Number of days using e-cigarettes and smoking combustible cigarettes in the past 30 days at Wave 4.

Number of days using e-cigarettes and smoking combustible cigarettes in the past 30 days at Wave 4.</p

Study sample determination.

BackgroundWe assessed longitudinal effects of e-cigarette use on respiratory symptoms in a nationally representative sample of US adults by combustible tobacco smoking status.MethodsWe analyzed Waves 4–5 public-use data from the Population Assessment of Tobacco and Health Study. Study sample included adult respondents who reported no diagnosis of respiratory diseases at Wave 4, and completed Waves 4–5 surveys with no missing data on analytic variables (N = 15,291). Outcome was a validated index of functionally important respiratory symptoms based on 7 wheezing/cough questions (range 0–9). An index score of ≥2 was defined as having important respiratory symptoms. Weighted lagged logistic regression models were performed to examine the association between e-cigarette use status at Wave 4 (former/current vs. never use) and important respiratory symptoms at Wave 5 by combustible tobacco smoking status (i.e., never/former/current smokers), adjusting for Wave 4 respiratory symptom index, sociodemographic characteristics, secondhand smoke exposure, body mass index, and chronic disease.ResultsAmong current combustible tobacco smokers, e-cigarette use was associated with increased odds of reporting important respiratory symptoms (former e-cigarette use: adjusted odds ratio [AOR] = 1.39, 95% confidence interval [CI]: 1.07–1.81; current e-cigarette use: AOR = 1.55, 95% CI: 1.17–2.06). Among former combustible tobacco smokers, former e-cigarette use (AOR = 1.51, 95% CI: 1.06–2.15)—but not current e-cigarette use (AOR = 1.59, 95% CI: 0.91–2.78)—was associated with increased odds of important respiratory symptoms. Among never combustible tobacco smokers, no significant association was detected between e-cigarette use and important respiratory symptoms (former e-cigarette use: AOR = 1.62, 95% CI: 0.76–3.46; current e-cigarette use: AOR = 0.82, 95% CI: 0.27–2.56).ConclusionsThe association between e-cigarette use and respiratory symptoms varied by combustible tobacco smoking status. Current combustible tobacco smokers who use e-cigarettes have an elevated risk of respiratory impairments.</div