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CHANGES IN MITOGEN-ACTIVATED PROTEIN KINASE IN CEREBELLAR GRANULE NEURONAL CULTURES BY POLYBROMINATED DIPHENYL ETHERS.
Citation:
FAN, C. Y. AND PRASADA RAO S. KODAVANTI. CHANGES IN MITOGEN-ACTIVATED PROTEIN KINASE IN CEREBELLAR GRANULE NEURONAL CULTURES BY POLYBROMINATED DIPHENYL ETHERS. Presented at Society of Toxicology, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
In the present study, we tested whether environmentally relevant PBDE mixtures and congeners affected mitogen-activated protein kinase (MAPK) pathways, which are down-stream events of calcium signaling in cerebellar granule neuronal cultures.
Description:
Polybrominated diphenyl ethers (PBDEs) are used as additive flame-retardants and have been detected in human blood, adipose tissue, and breast milk; clarifying the nature of the risks posed is important for clean-up and remediation. Both in vitro and in vivo studies have shown that the effects of PBDEs are similar to the known human developmental neurotoxicants such as polychlorinated biphenyls (PCBs) on a molar basis. Previously, we reported that both PBDE mixtures as well as congeners perturbed calcium (Ca) homeostasis that is critical for the development and function of the nervous system. In the present study, we tested whether environmentally relevant PBDE mixtures and congeners affected mitogen-activated protein kinase (MAPK) pathways, which are down-stream events of calcium signaling in cerebellar granule neuronal cultures. Phosphorylated extracellular signal-regulated kinase (ERK)1/2 levels were quantitated using western blot technique with phospo-specific antibodies. Glutamate (a positive control) increased phospho-ERK in a time and concentration-dependent manner reaching maximum activation at 15-30 min of exposure and at doses >10 uM. Both Aroclor 1254 (a commercial PCB mixture) and DE-71 (a commercial PBDE mixture) elevated phospho-ERK producing maximum stimulation at 30 min and at doses >10 ug/ml; Aroclor 1254 was more efficacious than DE-71. PBDE congeners 47, 77, and 153 also increased phospo-ERK at > 3 uM suggesting that PBDE congeners are more potent than the commercial mixtures. PCB 47 increased phospho-ERK as efficaciously as PBDE 47 suggesting a common mode of action for these chemicals. These results show that PBDE mixtures and congeners activate MAPK pathway at concentrations where no significant cytotoxicity was observed, suggesting that perturbed intracellular signaling might be involved in the initiation of adverse effects related to the persistent chemicals. (This abstract does not necessarily reflect USEPA policy).