PMID- 33186814 OWN - NLM STAT- MEDLINE DCOM- 20210421 LR - 20210421 IS - 1873-6750 (Electronic) IS - 0160-4120 (Linking) VI - 146 DP - 2021 Jan TI - Effects of a human-based mixture of persistent organic pollutants on the in vivo exposed cerebellum and cerebellar neuronal cultures exposed in vitro. PG - 106240 LID - S0160-4120(20)32195-4 [pii] LID - 10.1016/j.envint.2020.106240 [doi] AB - Exposure to persistent organic pollutants (POPs), encompassing chlorinated (Cl), brominated (Br) and perfluoroalkyl acid (PFAA) compounds is associated with adverse neurobehaviour in humans and animals, and is observed to cause adverse effects in nerve cell cultures. Most studies focus on single POPs, whereas studies on effects of complex mixtures are limited. We examined the effects of a mixture of 29 persistent compounds (Cl + Br + PFAA, named Total mixture), as well as 6 sub-mixtures on in vitro exposed rat cerebellar granule neurons (CGNs). Protein expression studies of cerebella from in vivo exposed mice offspring were also conducted. The selection of chemicals for the POP mixture was based on compounds being prominent in food, breast milk or blood from the Scandinavian human population. The Total mixture and sub-mixtures containing PFAAs caused greater toxicity in rat CGNs than the single or combined Cl/Br sub-mixtures, with significant impact on viability from 500x human blood levels. The potencies for these mixtures based on LC(50) values were Br + PFAA mixture > Total mixture > Cl + PFAA mixture > PFAA mixture. These mixtures also accelerated induced lipid peroxidation. Protection by the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 3-((R)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) indicated involvement of the NMDA receptor in PFAA and Total mixture-, but not Cl mixture-induced toxicity. Gene-expression studies in rat CGNs using a sub-toxic and marginally toxic concentration ((0.4 nM-5.5 microM) 333x and (1 nM-8.2 microM) 500x human blood levels) of the mixtures, revealed differential expression of genes involved in apoptosis, oxidative stress, neurotransmission and cerebellar development, with more genes affected at the marginally toxic concentration. The two important neurodevelopmental markers Pax6 and Grin2b were downregulated at 500x human blood levels, accompanied by decreases in PAX6 and GluN2B protein levels, in cerebellum of offspring mice from mothers exposed to the Total mixture throughout pregnancy and lactation. In rat CGNs, the glutathione peroxidase gene Prdx6 and the regulatory transmembrane glycoprotein gene Sirpa were highly upregulated at both concentrations. In conclusion, our results support that early-life exposure to mixtures of POPs can cause adverse neurodevelopmental effects. CI - Copyright (c) 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Berntsen, Hanne Friis AU - Berntsen HF AD - Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway; National Institute of Occupational Health, P.O. Box 5330 Majorstuen, 0304 Oslo, Norway. Electronic address: hanne.friis.berntsen@nmbu.no. FAU - Duale, Nur AU - Duale N AD - Section of Molecular Toxicology, Norwegian Institute of Public Health, N-0403 Oslo, Norway. Electronic address: Nur.Duale@fhi.no. FAU - Bjorklund, Cesilie Granum AU - Bjorklund CG AD - Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway. Electronic address: cesilie@permakem.no. FAU - Rangel-Huerta, Oscar Daniel AU - Rangel-Huerta OD AD - Section of Chemistry and Toxinology, Norwegian Veterinary Institute, N-0454 Oslo, Norway. Electronic address: Oscar.Daniel.Rangel.Huerta@vetinst.no. FAU - Dyrberg, Kine AU - Dyrberg K AD - Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway. Electronic address: kine.dyrberg@tine.no. FAU - Hofer, Tim AU - Hofer T AD - Section of Toxicology and Risk Assessment, Norwegian Institute of Public Health, N-0403, Oslo, Norway. Electronic address: Tim.Hofer@fhi.no. FAU - Rakkestad, Kirsten Eline AU - Rakkestad KE AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1072, Blindern, NO-0316 Oslo, Norway. Electronic address: KirstenEline.Rakkestad@vkm.no. FAU - Ostby, Gunn AU - Ostby G AD - Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway. Electronic address: gunn.ostby@nmbu.no. FAU - Halsne, Ruth AU - Halsne R AD - Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway. Electronic address: ruhals@ous-hf.no. FAU - Boge, Gudrun AU - Boge G AD - Department of Companion Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway. Electronic address: Gudrun.Boge@legemiddelverket.no. FAU - Paulsen, Ragnhild Elisabeth AU - Paulsen RE AD - Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1072, Blindern, NO-0316 Oslo, Norway. Electronic address: r.e.paulsen@farmasi.uio.no. FAU - Myhre, Oddvar AU - Myhre O AD - Section of Toxicology and Risk Assessment, Norwegian Institute of Public Health, N-0403, Oslo, Norway. Electronic address: Oddvar.Myhre@fhi.no. FAU - Ropstad, Erik AU - Ropstad E AD - Department of Production Animal Clinical Sciences, NMBU-School of Veterinary Science, P.O. Box 369 sentrum, N-0102 Oslo, Norway. Electronic address: erik.ropstad@nmbu.no. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201111 PL - Netherlands TA - Environ Int JT - Environment international JID - 7807270 RN - 0 (Environmental Pollutants) SB - IM MH - Animals MH - Cerebellum MH - *Environmental Pollutants/toxicity MH - Female MH - Humans MH - Mice MH - Neurons MH - Oxidative Stress MH - *Persistent Organic Pollutants MH - Rats OTO - NOTNLM OT - Cerebellum OT - Gene expression OT - Human relevant mixtures OT - Neurodevelopment OT - Persistent organic pollutants OT - Redox signalling EDAT- 2020/11/14 06:00 MHDA- 2021/04/22 06:00 CRDT- 2020/11/13 20:11 PHST- 2020/06/04 00:00 [received] PHST- 2020/09/25 00:00 [revised] PHST- 2020/10/22 00:00 [accepted] PHST- 2020/11/14 06:00 [pubmed] PHST- 2021/04/22 06:00 [medline] PHST- 2020/11/13 20:11 [entrez] AID - S0160-4120(20)32195-4 [pii] AID - 10.1016/j.envint.2020.106240 [doi] PST - ppublish SO - Environ Int. 2021 Jan;146:106240. doi: 10.1016/j.envint.2020.106240. Epub 2020 Nov 11.