Maternal transfer of environmentally relevant polybrominated diphenyl ethers (PBDEs) produces a diabetic phenotype and disrupts glucoregulatory hormones and hepatic endocannabinoids in adult mouse female offspring

Abstract

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.

Persistent autism-relevant phenotype produced by in utero and lactational exposure of female mice to the commercial PBDE mixture, DE-71

“…1 ). Using this dosing paradigm, we have previously reported no differences in litter size at birth, secondary sex ratio, nor gestational maternal parameters 71 . Dams exposed to DE-71 did not build inferior nests and F1 litters at PND 46 had normal body mass relative to VEH/CON ( Supplementary Figure 1 ).…”

“…Offspring were exposed to DE-71 via maternal transfer using a 10-week dosing regimen as described previously ( Fig.1a ) 71 . Mice were randomly assigned to one of three exposure groups: corn oil vehicle control (VEH/CON), 0.1 mg/kg/d DE-71 (L-DE-71) or 0.4 mg/kg/d DE-71 (H-DE-71).…”

“…Offspring were exposed to DE-71 via maternal transfer using a 10-week dosing regimen as described previously (Fig. 1a) 71 . Mice were randomly assigned to one of three exposure groups: -71).…”

“…Using gas chromatography coupled with electron capture negative ion mass spectrometry (GC/ECNI-MS; Agilent 5975N MS), PBDE concentrations were measured in PND110 whole brain homogenate extracts by the Stapleton laboratory at Duke University as described previously 71 . Briefly, approximately 0.2-0.5 grams of tissue were first ground with clean sodium sulfate, spiked with two isotopically labeled standards (F-BDE-69 and 13C BDE-209) and then extracted using 50:50 DCM:hexane.…”

“…According to the female protective model, females may benefit from a higher threshold of genetic liability to manifest ASD phenotype 9, 10 but may be more susceptible to xenobiotic chemicals 11 that can potentially influence risk of neurodevelopmental disorders (NDDs). Indeed, we have found that female mice offspring exposed to PBDEs during prenatal and postnatal development exhibit endocrine and metabolic disruption, indicating that females may provide a more susceptible substrate for studying xenobiotic effects on neurodevelopment 12 .…”