Developmental Exposure to DDT or DDE Alters Sympathetic Innervation of Brown Adipose in Adult Female Mice

Abstract

Background: Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis. Methods: Pregnant C57BL/6J mice were exposed by oral gavage to environmentally relevant concentrations of DDT (1.7 mg/kg) or DDE (1.31 mg/kg) from gestational day 11.5 to postnatal day 5, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated.Results: We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDT or DDE. Perinatal DDT exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDT nor DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDT-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDT, but not DDE, and 48% and 43% fewer synapses in stellate ganglia of mice exposed to either DDT or DDE, respectively, compared to control. Conclusions: These data demonstrate that perinatal DDT and DDE exposure impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

Prenatal Exposures to Mixtures of Endocrine Disrupting Chemicals and Sex-Specific Associations with Children's BMI and Overweight at 5.5 Years of Age in the Selma Study

“…However, a follow-up study by Warner et al, found significant association between DDT and higher BMI zscores among boys at 12 years of age (Warner et al, 2017), and a metaanalysis of 33 epidemiological studies found that prenatal levels of DDE and HCB was associated with higher BMI z-score among children (Stratakis et al, 2022). Also, animal studies, suggest that prenatal exposure to DDE and HCB alters metabolic markers in mice and rat offspring (Al-Obaidi et al, 2022;La Merrill et al, 2014;vonderEmbse et al, 2021). Follow-up analysis in our study population would be informative to whether associations can be found later in childhood or puberty.…”