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Published on: May 10, 2017
Mouse cerebellar astrocytes protect cerebellar granule neurons against toxicity of the polybrominated diphenyl ether
Gennaro Giordano1, Terrance J Kavanagh, Lucio G Costa
1Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA.
Insights
Polybrominated diphenyl ethers (PBDEs) are environmental pollutants that can harm developing brains. Astrocytes protect neurons from PBDE toxicity by boosting glutathione (GSH) levels, a protective mechanism that may be compromised in certain individuals.
Area of Science:
- Environmental Science
- Neuroscience
- Toxicology
Background:
- Polybrominated diphenyl ethers (PBDEs) are prevalent environmental contaminants.
- High body burdens of PBDEs are observed in infants and toddlers.
- PBDEs are suspected developmental neurotoxicants, with mechanisms requiring elucidation.
Purpose of the Study:
- To investigate the protective role of astrocytes against PBDE-induced neurotoxicity.
- To determine the involvement of glutathione (GSH) in astrocyte-mediated neuroprotection.
- To assess the impact of genetic variations affecting GSH levels on neurotoxicity susceptibility.
Main Methods:
- Co-culture of mouse cerebellar granule neurons (CGNs) with cerebellar astrocytes.
- Exposure to the PBDE mixture DE-71.
- Utilizing astrocytes and neurons from Gclm (-/-) mice with deficient GSH synthesis.
- Administration of GSH ethylester to assess its protective effects.
Main Results:
- Astrocytes protected CGNs from DE-71 toxicity.
- Astrocytes from Gclm (-/-) mice showed reduced neuroprotective capacity.
- The protective effect was primarily attributed to astrocytes increasing neuronal GSH levels.
- GSH ethylester mimicked the protective effects of astrocytes.
Conclusions:
- Astrocytes play a crucial role in mitigating PBDE neurotoxicity by enhancing GSH levels in neurons.
- Genetic deficiencies in GSH synthesis, such as in Gclm (-/-) mice, significantly increase susceptibility to PBDE neurotoxicity.
- Human genetic polymorphisms affecting GSH levels may confer increased vulnerability to PBDEs.
Abstract:
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.
