PMID- 33309997 OWN - NLM STAT- MEDLINE DCOM- 20210118 LR - 20210118 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 338 DP - 2021 Mar 1 TI - A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. PG - 85-96 LID - S0378-4274(20)30500-2 [pii] LID - 10.1016/j.toxlet.2020.12.007 [doi] AB - Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth. CI - Copyright (c) 2020 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Yadav, Ajay AU - Yadav A AD - Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 369 Sentrum, NO-0102, Oslo, Norway; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. Electronic address: ajay.yadav@nmbu.no. FAU - Amber, Mazia AU - Amber M AD - Institute for Global Food Security, Queen's University Belfast, 19 Chlorine Gardens, Belfast, BT9 5DL, Northern Ireland, United Kingdom. FAU - Zosen, Denis AU - Zosen D AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. FAU - Labba, Nils Anders AU - Labba NA AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. FAU - Huiberts, Eva Henriette Willemijn AU - Huiberts EHW AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. FAU - Samulin Erdem, Johanna AU - Samulin Erdem J AD - National Institute of Occupational Health, P.O. Box 5330 Majorstuen, NO-0304, Oslo, Norway. FAU - Haugen, Fred AU - Haugen F AD - National Institute of Occupational Health, P.O. Box 5330 Majorstuen, NO-0304, Oslo, Norway. FAU - Berntsen, Hanne Friis AU - Berntsen HF AD - Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 369 Sentrum, NO-0102, Oslo, Norway; National Institute of Occupational Health, P.O. Box 5330 Majorstuen, NO-0304, Oslo, Norway. FAU - Zienolddiny, Shanbeh AU - Zienolddiny S AD - National Institute of Occupational Health, P.O. Box 5330 Majorstuen, NO-0304, Oslo, Norway. FAU - Paulsen, Ragnhild Elisabeth AU - Paulsen RE AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. FAU - Ropstad, Erik AU - Ropstad E AD - Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 369 Sentrum, NO-0102, Oslo, Norway. FAU - Connolly, Lisa AU - Connolly L AD - Institute for Global Food Security, Queen's University Belfast, 19 Chlorine Gardens, Belfast, BT9 5DL, Northern Ireland, United Kingdom. FAU - Verhaegen, Steven AU - Verhaegen S AD - Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 369 Sentrum, NO-0102, Oslo, Norway. LA - eng PT - Journal Article DEP - 20201209 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Alkanesulfonic Acids) RN - 0 (Environmental Pollutants) RN - 0 (Fluorocarbons) RN - 9061-61-4 (Nerve Growth Factor) RN - 9H2MAI21CL (perfluorooctane sulfonic acid) RN - EC 6.3.2.2 (Glutamate-Cysteine Ligase) RN - GAN16C9B8O (Glutathione) SB - IM MH - Alkanesulfonic Acids/*toxicity MH - Animals MH - Cell Survival/drug effects MH - Environmental Pollutants/*toxicity MH - Fluorocarbons/*toxicity MH - Glutamate-Cysteine Ligase/genetics/metabolism MH - Glutathione/metabolism MH - Nerve Growth Factor/*pharmacology MH - Neurites/*drug effects/metabolism/pathology MH - Neuronal Outgrowth/*drug effects MH - Neurotoxicity Syndromes/*etiology/metabolism/pathology MH - PC12 Cells MH - Rats MH - Time Factors OTO - NOTNLM OT - Glutathione OT - Live imaging OT - Mitochondrial mass OT - Mitochondrial membrane potential OT - Rat pheochromocytoma COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/12/15 06:00 MHDA- 2021/01/20 06:00 CRDT- 2020/12/14 10:19 PHST- 2020/10/23 00:00 [received] PHST- 2020/12/01 00:00 [revised] PHST- 2020/12/06 00:00 [accepted] PHST- 2020/12/15 06:00 [pubmed] PHST- 2021/01/20 06:00 [medline] PHST- 2020/12/14 10:19 [entrez] AID - S0378-4274(20)30500-2 [pii] AID - 10.1016/j.toxlet.2020.12.007 [doi] PST - ppublish SO - Toxicol Lett. 2021 Mar 1;338:85-96. doi: 10.1016/j.toxlet.2020.12.007. Epub 2020 Dec 9.