PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms

• Published in: Archives of toxicology Vol. 92; no. 10; pp. 3163 - 3173
• Main Authors: Keil, Kimberly P., Miller, Galen W., Chen, Hao, Sethi, Sunjay, Schmuck, Martin R., Dhakal, Kiran, Kim, Ji Won, Lein, Pamela J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2018; Springer Nature B.V
• Subjects: Animals; Animals, Newborn; Biomedical and Life Sciences; Biomedicine; Calcium; Cells, Cultured; Chemosphere; Coculture Techniques; Congeners; Dendrites - drug effects; Dendrites - physiology; Dendritic branching; Dendritic structure; Dioxins; Environmental Health; Female; Hippocampus; Hippocampus - cytology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - metabolism; Mutation; Nervous system; Neurodevelopmental disorders; Neuroglia - cytology; Neuronal-glial interactions; Neurons; Neurons - drug effects; Neurons - metabolism; Occupational Medicine/Industrial Medicine; Organ Toxicity and Mechanisms; PCB; PCB compounds; Pharmacology; Pharmacology/Toxicology; Phosphorylation; Polychlorinated biphenyls; Polychlorinated Biphenyls - toxicity; Proteins; Rapamycin; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel - metabolism; Signaling; siRNA; Tacrolimus; Tacrolimus Binding Protein 1A - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription; Developmental neurotoxicity; Neurodevelopmental disorders; Persistent organic pollutants; Sholl analysis
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-018-2285-x

Polychlorinated biphenyls (PCBs), and in particular non-dioxin-like (NDL) congeners, continue to pose a significant risk to the developing nervous system. PCB 95, a prevalent NDL congener in the human chemosphere, promotes dendritic growth in rodent primary neurons by activating calcium-dependent transcriptional mechanisms that normally function to link activity to dendritic growth. Activity-dependent dendritic growth is also mediated by calcium-dependent translational mechanisms involving mechanistic target of rapamycin (mTOR), suggesting that the dendrite-promoting activity of PCB 95 may also involve mTOR signaling. Here, we test this hypothesis using primary neuron-glia co-cultures derived from the hippocampi of postnatal day 0 Sprague Dawley rats. PCB 95 (1 nM) activated mTOR in hippocampal cultures as evidenced by increased phosphorylation of mTOR at ser2448. Pharmacologic inhibition of mTOR signaling using rapamycin (20 nM), FK506 (5 nM), or 4EGI-1 (1 µM), and siRNA knockdown of mTOR, or the mTOR complex binding proteins, raptor or rictor, blocked PCB 95-induced dendritic growth. These data identify mTOR activation as a novel molecular mechanism contributing to the effects of PCB 95 on dendritic arborization. In light of clinical data linking gain-of-function mutations in mTOR signaling to neurodevelopmental disorders, our findings suggest that mTOR signaling may represent a convergence point for gene by environment interactions that confer risk for adverse neurodevelopmental outcomes.