PMID- 34607039 OWN - NLM STAT- MEDLINE DCOM- 20220107 LR - 20220531 IS - 1873-6750 (Electronic) IS - 0160-4120 (Linking) VI - 158 DP - 2022 Jan TI - A human relevant mixture of persistent organic pollutants induces reactive oxygen species formation in isolated human leucocytes: Involvement of the beta2-adrenergic receptor. PG - 106900 LID - S0160-4120(21)00525-0 [pii] LID - 10.1016/j.envint.2021.106900 [doi] AB - Exposure to chlorinated (Cl), brominated (Br) and perfluoroalkyl acid (PFAA) persistent organic pollutants (POPs) is associated with immunotoxicity and other adverse effects in humans and animals. Previous studies on POPs have mainly focused on single chemicals, while studies on complex mixtures are limited. Using DCF and luminol assays we examined effects on ROS generation in isolated human neutrophils, monocytes and lymphocytes, after in vitro exposure to a total mixture and sub-mixtures of 29 persistent compounds (Cl, Br, and PFAA). The mixtures were based on compounds prominent in blood, breast milk, and/or food. All mixture combinations induced ROS production in one or several of the cell models, and in some cases even at concentrations corresponding to human blood levels (compound range 1 pM - 16 nM). Whilst some interactions were detected (assessed using a mixed linear model), halogenated subgroups mainly acted additively. Mechanistic studies in neutrophils at 500x human levels (0.5 nM - 8 microM) indicated similar mechanisms of action for the Cl, PFAA, the combined PFAA + Cl and total (PFAA + Br + Cl) mixtures, and ROS responses appeared to involve beta2-adrenergic receptor (beta2AR) and Ca(2+) signalling, as well as activation of NADPH oxidases. In line with this, the total mixture also increased cyclic AMP at levels comparable with the non-selective betaAR agonist, isoproterenol. Although the detailed mechanisms involved in these responses remain to be elucidated, our data show that POP mixtures at concentrations found in human blood, may trigger stress responses in circulating immune cells. Mixtures of POPs, further seemed to interfere with adrenergic pathways, indicating a novel role of betaARs in POP-induced effects. CI - Copyright (c) 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Berntsen, Hanne Friis AU - Berntsen HF AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, NO-1432 As, Norway; National Institute of Occupational Health, P.O. Box 5330, Majorstuen, 0304 Oslo, Norway. Electronic address: Hanne.Berntsen@stami.no. FAU - Bodin, Johanna AU - Bodin J AD - Department of Methods Development and Analytics, Norwegian Institute of Public Health, N-0456 Oslo, Norway. Electronic address: JohannaEva.Bodin@fhi.no. FAU - Ovrevik, Johan AU - Ovrevik J AD - Department of Environmental Health, Norwegian Institute of Public Health, N-0456 Oslo, Norway; Department of Biosciences, University of Oslo, Norway. Electronic address: Johan.Ovrevik@fhi.no. FAU - Berntsen, Christopher Friis AU - Berntsen CF AD - Department of Internal Medicine, Sykehuset Innlandet Hospital Trust, Gjovik, Norway; Department of Internal Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway. Electronic address: christopherfriis.berntsen@lds.no. FAU - Ostby, Gunn C AU - Ostby GC AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, NO-1432 As, Norway. Electronic address: gunn.ostby@nmbu.no. FAU - Brinchmann, Bendik C AU - Brinchmann BC AD - National Institute of Occupational Health, P.O. Box 5330, Majorstuen, 0304 Oslo, Norway; Department of Environmental Health, Norwegian Institute of Public Health, N-0456 Oslo, Norway. Electronic address: Bendik.Brinchmann@stami.no. FAU - Ropstad, Erik AU - Ropstad E AD - Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, NO-1432 As, Norway. Electronic address: erik.ropstad@nmbu.no. FAU - Myhre, Oddvar AU - Myhre O AD - Department of Environmental Health, Norwegian Institute of Public Health, N-0456 Oslo, Norway. Electronic address: Oddvar.Myhre@fhi.no. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211001 PL - Netherlands TA - Environ Int JT - Environment international JID - 7807270 RN - 0 (Environmental Pollutants) RN - 0 (Reactive Oxygen Species) SB - IM MH - *Environmental Pollutants/toxicity MH - Female MH - Humans MH - Milk, Human MH - *Persistent Organic Pollutants MH - Reactive Oxygen Species MH - Signal Transduction OTO - NOTNLM OT - Human leucocytes OT - Immunotoxicity OT - Mixture toxicity OT - Persistent organic pollutants OT - Reactive oxygen species OT - beta2-adrenergic receptor EDAT- 2021/10/05 06:00 MHDA- 2022/01/08 06:00 CRDT- 2021/10/04 20:17 PHST- 2021/07/11 00:00 [received] PHST- 2021/09/17 00:00 [revised] PHST- 2021/09/22 00:00 [accepted] PHST- 2021/10/05 06:00 [pubmed] PHST- 2022/01/08 06:00 [medline] PHST- 2021/10/04 20:17 [entrez] AID - S0160-4120(21)00525-0 [pii] AID - 10.1016/j.envint.2021.106900 [doi] PST - ppublish SO - Environ Int. 2022 Jan;158:106900. doi: 10.1016/j.envint.2021.106900. Epub 2021 Oct 1.