Exposure to a human relevant mixture of persistent organic pollutants or to perfluorooctane sulfonic acid alone dysregulates the developing cerebellum of chicken embryo

Ajay Yadav; Steven Verhaegen; Panagiotis Filis; Diana Domanska; Robert Lyle; Arvind Y M Sundaram; Magnus Leithaug; Gunn Charlotte Østby; Mona Aleksandersen; Hanne Friis Berntsen; Karin Elisabeth Zimmer; Paul A Fowler; Ragnhild Elisabeth Paulsen; Erik Ropstad

doi:10.1016/j.envint.2022.107379

Exposure to a human relevant mixture of persistent organic pollutants or to perfluorooctane sulfonic acid alone dysregulates the developing cerebellum of chicken embryo

Environ Int. 2022 Aug:166:107379. doi: 10.1016/j.envint.2022.107379. Epub 2022 Jun 27.

Authors

Affiliations

¹ Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, 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.
² Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, Norway. Electronic address: steven.verhaegen@nmbu.no.
³ Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. Electronic address: pfilis@abdn.ac.uk.
⁴ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway. Electronic address: diana.domanska@medisin.uio.no.
⁵ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway. Electronic address: robert.lyle@medisin.uio.no.
⁶ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. Electronic address: arvind.sundaram@medisin.uio.no.
⁷ Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. Electronic address: magnus.leithaug@vetinst.no.
⁸ Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, Norway. Electronic address: gunn.ostby@nmbu.no.
⁹ Department of Preclinical Sciences and Pathology, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, Norway. Electronic address: mona.aleksandersen@nmbu.no.
¹⁰ Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, Norway; National Institute of Occupational Health, P.O. Box 5330 Majorstuen, NO-0304, Oslo, Norway. Electronic address: Hanne.Berntsen@stami.no.
¹¹ Department of Preclinical Sciences and Pathology, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, Norway. Electronic address: karin.zimmer@nmbu.no.
¹² Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. Electronic address: p.a.fowler@abdn.ac.uk.
¹³ 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.h.paulsen@farmasi.uio.no.
¹⁴ Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, P.O. Box 5003, NO-1432 Ås, Norway. Electronic address: erik.ropstad@nmbu.no.

PMID: 35792514
DOI: 10.1016/j.envint.2022.107379

Abstract

Prenatal exposure to persistent organic pollutants (POPs) is associated with neurodevelopmental disorders. In the present study, we explored whether a human-relevant POP mixture affects the development of chicken embryo cerebellum. We used a defined mixture of 29 POPs, with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated exposure to a prominent compound in the mixture, perfluorooctane sulfonic acid (PFOS), alone. Embryos (n = 7-9 per exposure group) were exposed by injection directly into the allantois at embryonic day 13 (E13). Cerebella were isolated at E17 and subjected to morphological, RNA-seq and shot-gun proteomics analyses. There was a reduction in thickness of the molecular layer of cerebellar cortex in both exposure scenarios. Exposure to the POP mixture significantly affected expression of 65 of 13,800 transcripts, and 43 of 2,568 proteins, when compared to solvent control. PFOS alone affected expression of 80 of 13,859 transcripts, and 69 of 2,555 proteins. Twenty-five genes and 15 proteins were common for both exposure groups. These findings point to alterations in molecular events linked to retinoid X receptor (RXR) signalling, neuronal cell proliferation and migration, cellular stress responses including unfolded protein response, lipid metabolism, and myelination. Exposure to the POP mixture increased methionine oxidation, whereas PFOS decreased oxidation. Several of the altered genes and proteins are involved in a wide variety of neurological disorders. We conclude that POP exposure can interfere with fundamental aspects of neurodevelopment, altering molecular pathways that are associated with adverse neurocognitive and behavioural outcomes.

Keywords: Chicken embryo; Environmental toxicants; Neurodevelopment; Prenatal exposure; Proteomics; RNA-seq transcriptomics.