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 glucose regulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses showed that DE-71 produced fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, 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 occur more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity, decreased thermogenic brown adipose tissue mass 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.

Glucoregulatory Reprogramming in Male Mice Offspring Induced by Maternal Transfer of Indoor Flame Retardant Endocrine Disruptors

“…Metrics studied were chosen based on in vivo and ex vivo biomarkers of diabetes in adulthood that are used to validate diabetic animals models (46). The reprogrammed metabolic profile observed in DE-71 exposed males does not exactly overlap with that reported for exposed female offspring (23).…”

“…Dosing solutions were prepared as described previously (23), (24). In brief, technical pentabromodiphenyl ether (DE-71; Lot no.…”

“…Perinatal PBDE exposure via the dam was accomplished as described previously (23). In brief, female mice (PND 30-60) were introduced to cornflakes daily for 1 week.…”

“…The PBDE congeners that have been associated with T2D are found in DE-71, a commercial mixture of PBDEs. Our past work shows that DE-71 congeners at the doses used here can be transferred perinatally via the dam and accumulate in offspring liver (23) and brain (24) at environmentally relevant levels. DE-71 may lead to metabolic reprogramming in offspring especially if exposure is administered during a period of high biological plasticity such as gestation and lactation.…”

“…However, in T2D there is a lack of inhibitory tone of insulin on glucagon secretion leading to elevated glucagon levels (26). We have previously shown the differential effect of PBDEs on insulin and glucagon in female offspring and GLP-1 in dams exposed in adulthood (23). While few studies have examined sex-differences in T2D patients (27) and less is known about sex differences in hormonal pathophysiology of T2D, several hormones regulating glucose control have been found to vary by sex and body type (28).…”