The brominated flame retardant BDE-47 causes oxidative stress and apoptotic cell death in vitro and in vivo in mice

Abstract

Polybrominated diphenyl ethers (PBDEs), used for decades as flame retardants, have become widespread environmental contaminants. Exposure is believed to occur primarily through diet and dust, and infants and toddlers have the highest body burden, raising concern for potential developmental neurotoxicity. The exact mechanisms of PBDE neurotoxicity have not been elucidated, but two relevant modes of action relate to impairment of thyroid hormone homeostasis and to direct effects on brain cells causing alterations in signal transduction, oxidative stress and apoptotic cell death. The present study shows that BDE-47 (2,2′,4,4′-tetrabromodiphenyl ether) induces oxidative stress and ensuing apoptotic cell death in mouse cerebellar granule neurons in vitro. Similarly, in vivo administration of BDE-47, according to an exposure protocol shown to induce behavioral and biochemical alterations (10 mg/kg, per os on post-natal day 10), induces oxidative stress and apoptosis, without altering serum levels of thyroid hormones. The effects of BDE-47 both in vitro and in vivo were more pronounced in a mouse model lacking the modifier subunit of glutamate cysteine ligase (GCLM) which results in reduced anti-oxidant capability due to low levels of GSH. Concentrations of BDE-47 in brain were in the mid-nanomolar range. These findings indicate that effects observed with BDE-47 in vitro are also present after in vivo administration, suggesting that in addition to potential endocrine effects, which were not seen here, direct interactions with brain cells should be considered as a potential mechanism of BDE-47 neurotoxicity.

MS-Based Metabolomics for the Investigation of Neuro-Metabolic Changes Associated with BDE-47 Exposure in C57BL/6 Mice

“…The increased formation of GSH was reported under conditions of oxidative stress by upregulating the rate-limiting GSH biosynthetic enzyme, γ-glutamatecysteine ligase [33]. In our study, GSH and glutathione disulfide (GSSG) were both upregulated, suggesting that BDE-47 exposure could induce oxidative stress in striatum, which is in accordance with the findings in the BDE-47 exposed cell and earthworm models [10,34]. Oxidative stress is not only believed linked to heart disease and cancer, and to contribute to the pathogenesis of PD, but also has impact on DNA methylation.…”

An autophagic process is activated in HepG2 cells to mediate BDE-100-induced toxicity

“…Some articles show that in vivo exposure to PBDEs cause oxidative stress and cell death by apoptosis in mouse cerebellar granule neurons in vitro (5µM) and in vivo after a single exposure of 10 mg/kg in mice (Costa et al, 2015).…”

Developmental neurotoxicity of polybrominated diphenyl ethers mixture de71 in Sprague-Dawley rats

“…However the mechanisms underlying such developmental effects remain to be determined (Costa et al, 2015). Changes were observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release.…”

“…The U.S. EPA has recently reported that exposure in children (average PBDE intake, 47.2 ng/kg/d) is greater than in adults (average PBDE intake, 7.1 ng/ kg/d) (Costa et al, 2015;U.S. EPA, 2010).…”