Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

• Published in: The Journal of biological chemistry 2020-05, Vol.295 (18), p.6120-6137
• Main Authors: Poston, Robert G., Murphy, Lillian, Rejepova, Ayna, Ghaninejad-Esfahani, Mina, Segales, Joshua, Mulligan, Kimberly, Saha, Ramendra N.
• Format: Article
• Language: English
• Subjects: 6-OH–BDE-47; Animals; axon; Developmental Biology; Drosophila; Drosophila melanogaster; environmental toxins; Ethers - chemistry; Ethers - pharmacology; Halogenation; Hydroxylation; Intracellular Space - drug effects; Intracellular Space - metabolism; MEK–ERK; Nervous System - cytology; Nervous System - drug effects; Nervous System - growth & development; neurodevelopmental toxicity; Neurons - cytology; Neurons - drug effects; PBDE; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; signal transduction; Signal Transduction - drug effects; toxicology; toxin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA119.011138

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.