Journal Article

Developmental exposure to DDT or DDE alters sympathetic innervation of brown adipose in adult female mice

Pennell, Kurt D., Lein, Pamela J., Habecker, Beth A., La Merrill, Michele A., vonderEmbse, Annalise N., Jackson, Kyle B., Manz, Katherine E., Elmore, Sarah E.

2021

Overview

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/6 J mice were administered environmentally relevant concentrations of DDTs (p,p’-DDT and o,p’-DDT) or DDE (p,p’-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, 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 DDTs or p,p’-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p’-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p’-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p’-DDE, respectively, compared to control. Conclusions These data demonstrate that perinatal exposure to DDTs or p,p’-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT. Graphical abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adipose tissue / Adipose tissue (brown) / Adipose Tissue, Brown - drug effects / Adipose Tissue, Brown - innervation / Adipose Tissue, Brown - metabolism / Adrenergic receptors / Animals / Axons / Bioaccumulation / Body mass index / Body temperature / Body Temperature - drug effects / Brown adipose tissue / Calorimetry / DDE / DDT / DDT (Insecticide) / DDT - pharmacokinetics / DDT - toxicity / Dichlorodiphenyl Dichloroethylene - pharmacokinetics / Dichlorodiphenyl Dichloroethylene - toxicity / Earth and Environmental Science / Environment / Environmental aspects / Environmental Health / Exposure / Female / Females / Ganglia / Global Environment / Health aspects / Heat measurement / Immunohistochemistry / Innervation / Insulin / Insulin resistance / Laboratory animals / Male / Males / Maternal-Fetal Exchange / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / Morphology / Nervous system / Neural networks / Neurotoxicity / Nitrous oxide / Norepinephrine / Obesity / Obesogen / Occupational Medicine/Industrial Medicine / Offspring / P,p’-DDE / Perinatal exposure / Persistent organic pollutants / Pesticides / Pesticides - toxicity / Physiological aspects / Pregnancy / Prenatal Exposure Delayed Effects / Prenatal influences / Public Health / Receptors (physiology) / Regulation / Stellate ganglion / Stellate Ganglion - drug effects / Sympathetic innervation / Sympathetic nerves / Sympathetic nervous system / Synapses / Synaptic connectivity / Thermogenesis / Tissue Distribution