Role of glutamate receptors in tetrabrominated diphenyl ether (BDE-47) neurotoxicity in mouse cerebellar granule neurons.

The polybrominated diphenyl ether (PBDE) flame retardants are developmental neurotoxicants, as evidenced by numerous in vitro, animal and human studies. PBDEs can alter the homeostasis of thyroid hormone and directly interact with brain cells. Induction of oxidative stress, leading to DNA damage and apoptotic cell death is a prominent mechanism of PBDE neurotoxicity, though other mechanisms have also been suggested. In the present study we investigated the potential role played by glutamate receptors in the in vitro neurotoxicity of the tetrabromodiphenyl ether BDE-47, one of the most abundant PBDE congeners. Toxicity of BDE-47 in mouse cerebellar neurons was diminished by antagonists of glutamate ionotropic receptors, but not by antagonists of glutamate metabotropic receptors. Antagonists of NMDA and AMPA/Kainate receptors also inhibited BDE-47-induced oxidative stress and increases in intracellular calcium. The calcium chelator BAPTA-AM also inhibited BDE-47 cytotoxicity and oxidative stress. BDE-47 caused a rapid increase of extracellular glutamate levels, which was not antagonized by any of the compounds tested. The results suggest that BDE-47, by still unknown mechanisms, increases extracellular glutamate which in turn activates ionotropic glutamate receptors leading to increased calcium levels, oxidative stress, and ultimately cell death.

Troxerutin inhibits 2,2',4,4'-tetrabromodiphenyl ether (BDE-47)-induced hepatocyte apoptosis by restoring proteasome function.

Proteasome dysfunction has been associated with the pathogeneses of a variety of diseases and with the neurotoxicities of environmental chemicals; however, whether proteasome dysfunction plays a role in the cellular toxicity of polybrominated diphenyl ethers (PBDEs) has not been investigated to date. Emerging evidence suggests that antioxidants exhibit evident beneficial effects on the cellular toxicity associated with PBDEs. In the present study, we investigated whether troxerutin attenuates BDE-47-induced hepatocyte apoptosis by restoring proteasome function and explored the mechanisms underlying this effect. Our results revealed that proteasome dysfunction was involved in the BDE-47-induced hepatocyte apoptosis in the mouse liver. Furthermore, our results revealed that troxerutin effectively inhibited hepatocyte apoptosis by restoring oxidative stress-mediated proteasome dysfunction in BDE-47-treated mice. Consequently, troxerutin markedly suppressed endoplasmic reticulum (ER) stress in the livers of the BDE-47-treated mice. The inhibitory effects of troxerutin on ER stress and apoptotic pathways were markedly blunted by treatment with epoxomicin (a selective inhibitor of proteasome). Ultimately, troxerutin dramatically blocked TRAF2-ASK1-JNK signaling and CHOP-mediated apoptosis signaling in the BDE-47-treated mouse livers. This study provides novel mechanistic insights into the toxicity of BDE-47 and indicates that troxerutin might be a candidate for the prevention of and therapy for BDE-47-induced hepatotoxicity.

Mouse cerebellar astrocytes protect cerebellar granule neurons against toxicity of the polybrominated diphenyl ether (PBDE) mixture DE-71.

A large body of evidence indicates that polybrominated diphenyl ether (PBDE) flame retardants have become widespread environmental pollutants. Body burden is particularly high in infants and toddlers, due to exposure through maternal milk and house dust. Animal studies suggest that PBDEs may exert developmental neurotoxicity, via mechanisms that are still elusive. PBDEs have been reported to cause oxidative stress and apoptotic cell death in neurons in vitro, when tested in mono-cultures. Here we report the results of experiments in which mouse cerebellar granule neurons (CGNs) were co-cultured with cerebellar astrocytes. Astrocytes were found to protect neurons against the toxicity of the PBDE mixture DE-71. Astrocytes from Gclm (-/-) mice, which lack the modifier subunit of glutamate cysteine ligase and, as a consequence, have very low GSH levels, were much less effective at protecting CGNs from DE-71 toxicity. The protective effects were mostly due to the ability of Gclm (+/+) astrocytes to increase GSH levels in neurons. By increasing GSH, GSH ethylester provided a similar protective effect. In vivo, where both neurons and astrocytes would be either Gclm (+/+) or Gclm (-/-), the toxicity of DE-71 to CGNs is predicted to vary 16.8-fold, depending on genotype. Hence, in addition to being intrinsically more susceptible to DE-71 toxicity because of their low GSH content, CGNs in Gclm (-/-) mice would also lack the full protective effect provided by astrocytes. Since several polymorphisms, including some in the Gclm gene, cause very low levels of GSH, it may be speculated that such individuals might display a higher susceptibility to the neurotoxic effects of PBDEs.