PMID- 33497742 OWN - NLM STAT- MEDLINE DCOM- 20211028 LR - 20211028 IS - 1873-1708 (Electronic) IS - 0890-6238 (Linking) VI - 100 DP - 2021 Mar TI - A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) differentially affect glutamate induced excitotoxic responses in chicken cerebellum granule neurons (CGNs) in vitro. PG - 109-119 LID - S0890-6238(21)00022-8 [pii] LID - 10.1016/j.reprotox.2021.01.008 [doi] AB - Primary cultures of cerebellar granule neurons (CGNs) derived from chicken embryos were used to explore the effects on developmental neurotoxicity by a complex defined mixture of persistent organic pollutants (POPs). Its chemical composition and concentrations were based on blood levels in the Norwegian/Scandinavian population. Perfluorooctane sulfonic acid (PFOS) alone, its most abundant compound was also evaluated. Different stages of CGNs maturation, between day in vitro (DIV) 1, 3, and 5 were exposed to the POP mixture, or PFOS alone. Their combination with glutamate, an excitatory endogenous neurotransmitter important in neurodevelopment, also known to cause excitotoxicity was evaluated. Outcomes with the mixture at 500x blood levels were compared to PFOS at its corresponding concentration of 20 muM. The POP mixture reduced tetrazolium salt (MTT) conversion at earlier stages of maturation, compared to PFOS alone. Glutamate-induced excitotoxicity was enhanced above the level of that induced by glutamate alone, especially in mature CGNs at DIV5. Glutathione (GSH) concentrations seemed to set the level of sensitivity for the toxic insults from exposures to the pollutants. The role of N-methyl-D-aspartate receptor (NMDA-R) mediated calcium influx in pollutant exposures was investigated using the non-competitive and competitive receptor antagonists MK-801 and CGP 39551. Observations indicate a calcium-independent, but still NMDA-R dependent mechanism in the absence of glutamate, and a calcium- and NMDA-R dependent one in the presence of glutamate. The outcomes for the POP mixture cannot be explained by PFOS alone, indicating that other chemicals in the mixture contribute its overall effect. CI - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. 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 - 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. Electronic address: steven.verhaegen@nmbu.no. FAU - Verbruggen, Evelien AU - Verbruggen E AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. Electronic address: evelien.verbruggen@scarlet.be. FAU - Kerhoas, Marie AU - Kerhoas M AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. Electronic address: kerhoas.marie@gmail.com. FAU - Willemijn Huiberts, Eva Henriette AU - Willemijn Huiberts EH AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. Electronic address: eva.huiberts@hotmail.com. FAU - Hadera, Mussie Ghezu AU - Hadera MG AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, NO-0316, Oslo, Norway. Electronic address: mughezu@gmail.com. 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. Electronic address: Hanne.Berntsen@stami.no. FAU - Zimmer, Karin Elisabeth AU - Zimmer KE AD - Department of Preclinical Sciences and Pathology, Norwegian University of Life Sciences, P.O. Box 369 Sentrum, NO-0102, Oslo, Norway. Electronic address: karin.zimmer@nmbu.no. 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. Electronic address: erik.ropstad@nmbu.no. 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. Electronic address: r.e.paulsen@farmasi.uio.no. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210123 PL - United States TA - Reprod Toxicol JT - Reproductive toxicology (Elmsford, N.Y.) JID - 8803591 RN - 0 (Alkanesulfonic Acids) RN - 0 (Fluorocarbons) RN - 0 (Neurotoxins) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 3KX376GY7L (Glutamic Acid) RN - 9H2MAI21CL (perfluorooctane sulfonic acid) RN - GAN16C9B8O (Glutathione) RN - SY7Q814VUP (Calcium) SB - IM MH - Alkanesulfonic Acids/blood/*toxicity MH - Animals MH - Calcium/metabolism MH - Cerebellum/drug effects/*embryology MH - Chick Embryo MH - Chickens MH - Fluorocarbons/blood/*toxicity MH - Glutamic Acid/*pharmacology MH - Glutathione/analysis MH - Humans MH - Neurons/chemistry/*drug effects/metabolism MH - Neurotoxins/*toxicity MH - Persistent Organic Pollutants/blood/*toxicity MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Signal Transduction/drug effects OTO - NOTNLM OT - Developmental neurotoxicity OT - Glutathione OT - Intracellular calcium OT - NMDA-R OT - NMDA-R antagonists EDAT- 2021/01/27 06:00 MHDA- 2021/10/29 06:00 CRDT- 2021/01/26 20:09 PHST- 2020/05/12 00:00 [received] PHST- 2020/12/14 00:00 [revised] PHST- 2021/01/18 00:00 [accepted] PHST- 2021/01/27 06:00 [pubmed] PHST- 2021/10/29 06:00 [medline] PHST- 2021/01/26 20:09 [entrez] AID - S0890-6238(21)00022-8 [pii] AID - 10.1016/j.reprotox.2021.01.008 [doi] PST - ppublish SO - Reprod Toxicol. 2021 Mar;100:109-119. doi: 10.1016/j.reprotox.2021.01.008. Epub 2021 Jan 23.