Developmental Exposure to Indoor Flame Retardants Produces Diabetic Phenotype in Adult Female C57BL6 Mice

Abstract

Polybrominated diphenyl ethers are a group of flame‐retardant organohalogen pollutants that act as endocrine and neuroendocrine disrupting chemicals. In humans, exposure to brominated flame retardants or other environmentally persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) has been associated with increasing trends of diabetes and metabolic disease (Gray et al. 2013; Baker et al. 2013; Lim et al, 2008; Lee et al, 2006). POPs may disrupt metabolic homeostasis through chronic low‐level exposure and bio‐accumulation in liver, adipose tissue and brain (Zhang et al, 2016; Turyk et al, 2015). However, the effects of PBDEs on metabolic processes are poorly understood. In this study we examined the effects of gestational and lactational exposure to the industrial PBDE mixture DE‐71 on glucose tolerance test (GTT), insulin tolerance test (ITT), and liver lipid content in C57BL/6 female offspring in adulthood (128–147 days; 17.1–22 g). We also examined intestinal permeability since intestinal‐derived bacterial products entering the bloodstream may cause inflammation, liver disease that may contribute to obesity and diabetes (Turner, 2009). Mice were exposed to environmentally relevant doses of PBDEs for 10 weeks (pre‐conception: 4 weeks; gestation: 3 weeks; lactation: 3 weeks). Daily dosing consisted of low dose (0.1 mg/kg/d), high dose (0.4 mg/kg/d), or corn oil vehicle (control) via ingestion of infused corn flakes. GTT results revealed that blood glucose levels normalized to fasting levels were significantly elevated at 30 and 60 min post injection of glucose (2.0 g/kg) in LD mice relative to oil vehicle controls (p<0.0001, n=20). ITT results showed a significantly decreased sensitivity to insulin (0.5 U/kg) at post‐injection time points from 15–120 min for LD and 15–90 min for HD female offspring (p<0.05 to 0.0001, n=19). Mean levels of liver lipids were significantly elevated in LD female offspring compared to controls (p<0.05, n= 18). To determine if PBDE‐exposed offspring showed altered intestinal permeability, mice were orally gavaged with 60 mg/kg FITC‐dextran (mol. wt. 3,000–5,000; FD‐4, Sigma) and fluorescence measured in the blood 4 hr later by fluorimetry (excitation 490 nm, emission 530 nm). PBDE at HD had an apparent effect on elevated plasma FITC levels but the effects were not significant indicating that PBDEs may not produce their effects via changes in intestinal barrier integrity. These results indicate that mice perinatally exposed to PBDEs (0.1 mg/kg dose) display abnormal glucose and lipid metabolic parameters indicative of a diabetic phenotype.Support or Funding InformationSupported by University of California COR grant and UCMEXUS.