A human relevant mixture of persistent organic pollutants induces reactive oxygen species formation in isolated human leucocytes: Involvement of the β2-adrenergic receptor

Hanne Friis Berntsen; Johanna Bodin; Johan Øvrevik; Christopher Friis Berntsen; Gunn C Østby; Bendik C Brinchmann; Erik Ropstad; Oddvar Myhre

doi:10.1016/j.envint.2021.106900

A human relevant mixture of persistent organic pollutants induces reactive oxygen species formation in isolated human leucocytes: Involvement of the β2-adrenergic receptor

Environ Int. 2022 Jan:158:106900. doi: 10.1016/j.envint.2021.106900. Epub 2021 Oct 1.

Authors

Hanne Friis Berntsen¹, Johanna Bodin², Johan Øvrevik³, Christopher Friis Berntsen⁴, Gunn C Østby⁵, Bendik C Brinchmann⁶, Erik Ropstad⁷, Oddvar Myhre⁸

Affiliations

¹ Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, NO-1432 Ås, Norway; National Institute of Occupational Health, P.O. Box 5330, Majorstuen, 0304 Oslo, Norway. Electronic address: Hanne.Berntsen@stami.no.
² Department of Methods Development and Analytics, Norwegian Institute of Public Health, N-0456 Oslo, Norway. Electronic address: JohannaEva.Bodin@fhi.no.
³ 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.
⁴ Department of Internal Medicine, Sykehuset Innlandet Hospital Trust, Gjøvik, Norway; Department of Internal Medicine, Lovisenberg Diaconal Hospital, Oslo, Norway. Electronic address: christopherfriis.berntsen@lds.no.
⁵ Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, NO-1432 Ås, Norway. Electronic address: gunn.ostby@nmbu.no.
⁶ 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.
⁷ Department of Production Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, P.O. Box 5003 NMBU, NO-1432 Ås, Norway. Electronic address: erik.ropstad@nmbu.no.
⁸ Department of Environmental Health, Norwegian Institute of Public Health, N-0456 Oslo, Norway. Electronic address: Oddvar.Myhre@fhi.no.

PMID: 34607039
DOI: 10.1016/j.envint.2021.106900

Abstract

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 500× human levels (0.5 nM - 8 µM) 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 β2-adrenergic receptor (β2AR) and Ca²⁺ 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 βAR 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 βARs in POP-induced effects.

Keywords: Human leucocytes; Immunotoxicity; Mixture toxicity; Persistent organic pollutants; Reactive oxygen species; β2-adrenergic receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Environmental Pollutants* / toxicity
Female
Humans
Milk, Human
Persistent Organic Pollutants*
Reactive Oxygen Species
Signal Transduction

Substances

Environmental Pollutants
Reactive Oxygen Species