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/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

Chronic DDE Exposure Modifies Mitochondrial Respiration during Differentiation of Human Adipose-Derived Mesenchymal Stem Cells into Mature Adipocytes

“…The negative effects of DDT/DDE on thermogenic proteins expression and substrate transport/utilization in adipocytes were also documented, which could lead to an increased ATP need to compensate for compromised fuel transport or heat dissipation [37]. A recent study suggests that impaired thermogenesis in DDT-affected adipocytes could be caused by targeting mechanisms upstream of adipose tissue without the necessity to compromise the expression of uncoupling proteins [38]. In this study, the leak respiration needed to compensate for proton leak, electron slip, and cation cycling increased in the course of adipocyte differentiation in all groups to a similar extent, without reaching any significant difference between DDE-treated and control groups on day 21.…”

Cross-species metabolomic analysis of tau- and DDT-related toxicity

“…Worm tissue concentrations of p, p’-DDT, p, p’-DDE, p, p’-DDD, o, p’-DDT, o, p’-DDE, and o, p’-DDD were measured using methods previously described ( 39 ). Prior to extraction, each sample was spiked with labeled isotope internal standards to assess analyte recovery.…”

Obesogens: How They Are Identified and Molecular Mechanisms Underlying Their Action

“…DDT has been shown in mouse models to affect the sympathetic nervous system that innervates both BAT and WAT. The sympathetic nervous system controls thermogenesis in brown fat and is needed for the beiging of WAT ( 77 , 135 ). Dual administration of DDT and DDE or single treatment with DDE induced a loss of thermogenic abilities in BAT in adult female mice by reducing their BAT sympathetic innervation and regulation ( 77 ).…”