A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells

Ajay Yadav; Mazia Amber; Denis Zosen; Nils Anders Labba; Eva Henriette Willemijn Huiberts; Johanna Samulin Erdem; Fred Haugen; Hanne Friis Berntsen; Shanbeh Zienolddiny; Ragnhild Elisabeth Paulsen; Erik Ropstad; Lisa Connolly; Steven Verhaegen

doi:10.1016/j.toxlet.2020.12.007

A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells

Ajay Yadav^*, Mazia Amber, Denis Zosen, Nils Anders Labba, Eva Henriette Willemijn Huiberts, Johanna Samulin Erdem, Fred Haugen, Hanne Friis Berntsen, Shanbeh Zienolddiny, Ragnhild Elisabeth Paulsen, Erik Ropstad, Lisa Connolly, Steven Verhaegen

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.

Original language	English
Pages (from-to)	85-96
Number of pages	12
Journal	Toxicology Letters
Volume	338
Early online date	24 Dec 2020
DOIs	https://doi.org/10.1016/j.toxlet.2020.12.007
Publication status	Published - 01 Mar 2021

Bibliographical note

Funding Information:
This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 722634 (http://protected.eu.com/). Support from the EU Erasmus+Programme to EHWH is gratefully acknowledged.

Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 722634 ( http://protected.eu.com/ ). Support from the EU Erasmus+Programme to EHWH is gratefully acknowledged.

Publisher Copyright:
© 2020 The Author(s)

Keywords

Glutathione
Live imaging
Mitochondrial mass
Mitochondrial membrane potential
Rat pheochromocytoma

ASJC Scopus subject areas

Toxicology

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10.1016/j.toxlet.2020.12.007Licence: CC BY

A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.76 MBLicence: CC BY

R6548GFS: PROTECTion against Endocrine Disruptors; Detection, mixtures, health effects, risk assessment and communication
Connolly, L. (PI), Dean, M. (CoI) & Elliott, C. (CoI)
03/10/2016 → …
Project: Research

Effects of endocrine disrupting chemicals and their human-relevant mixtures on cellular health and hormone receptor function
Amber, M. (Author), Connolly, L. (Supervisor), Verhaegen, S. (Supervisor), Ropstad, E. (Supervisor) & Green, B. (Supervisor), Jul 2023
Student thesis: Doctoral Thesis › Doctor of Philosophy

Cite this

Yadav, A., Amber, M., Zosen, D., Labba, N. A., Huiberts, E. H. W., Samulin Erdem, J., Haugen, F., Berntsen, H. F., Zienolddiny, S., Paulsen, R. E., Ropstad, E., Connolly, L., & Verhaegen, S. (2021). A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Toxicology Letters, 338, 85-96. https://doi.org/10.1016/j.toxlet.2020.12.007

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abstract = "Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.",

keywords = "Glutathione, Live imaging, Mitochondrial mass, Mitochondrial membrane potential, Rat pheochromocytoma",

author = "Ajay Yadav and Mazia Amber and Denis Zosen and Labba, {Nils Anders} and Huiberts, {Eva Henriette Willemijn} and {Samulin Erdem}, Johanna and Fred Haugen and Berntsen, {Hanne Friis} and Shanbeh Zienolddiny and Paulsen, {Ragnhild Elisabeth} and Erik Ropstad and Lisa Connolly and Steven Verhaegen",

note = "Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement No. 722634 (http://protected.eu.com/). Support from the EU Erasmus+Programme to EHWH is gratefully acknowledged. Funding Information: This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement No. 722634 ( http://protected.eu.com/ ). Support from the EU Erasmus+Programme to EHWH is gratefully acknowledged. Publisher Copyright: {\textcopyright} 2020 The Author(s)",

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Yadav, A, Amber, M, Zosen, D, Labba, NA, Huiberts, EHW, Samulin Erdem, J, Haugen, F, Berntsen, HF, Zienolddiny, S, Paulsen, RE, Ropstad, E, Connolly, L & Verhaegen, S 2021, 'A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells', Toxicology Letters, vol. 338, pp. 85-96. https://doi.org/10.1016/j.toxlet.2020.12.007

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AU - Yadav, Ajay

AU - Amber, Mazia

AU - Zosen, Denis

AU - Labba, Nils Anders

AU - Huiberts, Eva Henriette Willemijn

AU - Samulin Erdem, Johanna

AU - Haugen, Fred

AU - Berntsen, Hanne Friis

AU - Zienolddiny, Shanbeh

AU - Paulsen, Ragnhild Elisabeth

AU - Ropstad, Erik

AU - Connolly, Lisa

AU - Verhaegen, Steven

N1 - Funding Information: This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 722634 (http://protected.eu.com/). Support from the EU Erasmus+Programme to EHWH is gratefully acknowledged. Funding Information: This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 722634 ( http://protected.eu.com/ ). Support from the EU Erasmus+Programme to EHWH is gratefully acknowledged. Publisher Copyright: © 2020 The Author(s)

PY - 2021/3/1

Y1 - 2021/3/1

N2 - Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.

AB - Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.

KW - Glutathione

KW - Live imaging

KW - Mitochondrial mass

KW - Mitochondrial membrane potential

KW - Rat pheochromocytoma

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DO - 10.1016/j.toxlet.2020.12.007

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AN - SCOPUS:85099186861

SN - 0378-4274

VL - 338

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EP - 96

JO - Toxicology Letters

JF - Toxicology Letters

ER -

A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

R6548GFS: PROTECTion against Endocrine Disruptors; Detection, mixtures, health effects, risk assessment and communication

Student theses

Effects of endocrine disrupting chemicals and their human-relevant mixtures on cellular health and hormone receptor function

Cite this