PMID- 30132043 OWN - NLM STAT- MEDLINE DCOM- 20191010 LR - 20230127 IS - 1432-0738 (Electronic) IS - 0340-5761 (Print) IS - 0340-5761 (Linking) VI - 92 IP - 10 DP - 2018 Oct TI - PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms. PG - 3163-3173 LID - 10.1007/s00204-018-2285-x [doi] AB - 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 microM), 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. FAU - Keil, Kimberly P AU - Keil KP AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. FAU - Miller, Galen W AU - Miller GW AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. AD - BioPlx Microbiomics, Boulder, CO, USA. FAU - Chen, Hao AU - Chen H AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. FAU - Sethi, Sunjay AU - Sethi S AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. FAU - Schmuck, Martin R AU - Schmuck MR AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. FAU - Dhakal, Kiran AU - Dhakal K AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. AD - Laboratory Corporation of America (LabCorp), Research Triangle Park, NC, USA. FAU - Kim, Ji Won AU - Kim JW AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. FAU - Lein, Pamela J AU - Lein PJ AUID- ORCID: 0000-0001-7665-7584 AD - Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA. pjlein@ucdavis.edu. LA - eng GR - P01 ES011269/ES/NIEHS NIH HHS/United States GR - R56 ES014901/ES/NIEHS NIH HHS/United States GR - U54 HD079125/HD/NICHD NIH HHS/United States GR - T32 ES007059/ES/NIEHS NIH HHS/United States GR - P30 ES023513/ES/NIEHS NIH HHS/United States GR - R833292/EPA/EPA/United States GR - R01 ES014901/ES/NIEHS NIH HHS/United States GR - S10 RR029304/RR/NCRR NIH HHS/United States GR - P30 ES005605/ES/NIEHS NIH HHS/United States GR - F32 HD088016/HD/NICHD NIH HHS/United States GR - F32 ES024070/ES/NIEHS NIH HHS/United States PT - Journal Article DEP - 20180821 PL - Germany TA - Arch Toxicol JT - Archives of toxicology JID - 0417615 RN - 0 (RyR2 protein, rat) RN - 0 (Ryanodine Receptor Calcium Release Channel) RN - 0YO8J06WCR (2,2',3,5',6-pentachlorobiphenyl) RN - DFC2HB4I0K (Polychlorinated Biphenyls) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 5.2.1.- (Tacrolimus Binding Protein 1A) SB - IM MH - Animals MH - Animals, Newborn MH - Cells, Cultured MH - Coculture Techniques MH - Dendrites/*drug effects/physiology MH - Female MH - Hippocampus/*cytology MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Mechanistic Target of Rapamycin Complex 2/metabolism MH - Neuroglia/cytology MH - Neurons/*drug effects/metabolism MH - Polychlorinated Biphenyls/*toxicity MH - Rats, Sprague-Dawley MH - Ryanodine Receptor Calcium Release Channel/metabolism MH - TOR Serine-Threonine Kinases/*metabolism MH - Tacrolimus Binding Protein 1A/metabolism PMC - PMC6162988 MID - NIHMS989962 OTO - NOTNLM OT - Developmental neurotoxicity OT - Neurodevelopmental disorders OT - Persistent organic pollutants OT - Sholl analysis COIS- Conflict of interest: The authors declare that they have no conflict of interest. EDAT- 2018/08/23 06:00 MHDA- 2019/10/11 06:00 PMCR- 2019/10/01 CRDT- 2018/08/23 06:00 PHST- 2018/06/06 00:00 [received] PHST- 2018/08/06 00:00 [accepted] PHST- 2018/08/23 06:00 [pubmed] PHST- 2019/10/11 06:00 [medline] PHST- 2018/08/23 06:00 [entrez] PHST- 2019/10/01 00:00 [pmc-release] AID - 10.1007/s00204-018-2285-x [pii] AID - 10.1007/s00204-018-2285-x [doi] PST - ppublish SO - Arch Toxicol. 2018 Oct;92(10):3163-3173. doi: 10.1007/s00204-018-2285-x. Epub 2018 Aug 21.