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Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier
Despite the significant progress in both scientific understanding and regulations, the safety of agricultural pesticides continues to be called into question. The need for complementary analytics to identify dysregulation events associated with chemical exposure and leverage this information to pred...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431803/ https://www.ncbi.nlm.nih.gov/pubmed/34513802 http://dx.doi.org/10.3389/fbioe.2021.622175 |
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author | Miller, Dusty R. McClain, Ethan S. Dodds, James N. Balinski, Andrzej May, Jody C. McLean, John A. Cliffel, David E. |
author_facet | Miller, Dusty R. McClain, Ethan S. Dodds, James N. Balinski, Andrzej May, Jody C. McLean, John A. Cliffel, David E. |
author_sort | Miller, Dusty R. |
collection | PubMed |
description | Despite the significant progress in both scientific understanding and regulations, the safety of agricultural pesticides continues to be called into question. The need for complementary analytics to identify dysregulation events associated with chemical exposure and leverage this information to predict biological responses remains. Here, we present a platform that combines a model organ-on-chip neurovascular unit (NVU) with targeted mass spectrometry (MS) and electrochemical analysis to assess the impact of organophosphate (OP) exposure on blood-brain barrier (BBB) function. Using the NVU to simulate exposure, an escalating dose of the organophosphate chlorpyrifos (CPF) was administered. With up to 10 μM, neither CPF nor its metabolites were detected across the BBB (limit of quantitation 0.1 µM). At 30 µM CPF and above, targeted MS detected the main urinary metabolite, trichloropyridinol (TCP), across the BBB (0.025 µM) and no other metabolites. In the vascular chamber where CPF was directly applied, two primary metabolites of CPF, TCP and diethylthiophosphate (DETP), were both detected (0.1–5.7 µM). In a second experiment, a constant dose of 10 µM CPF was administered to the NVU, and though neither CPF nor its metabolites were detected across the BBB after 24 h, electrochemical analysis detected increases in acetylcholine levels on both sides of the BBB (up to 24.8 ± 3.4 µM) and these levels remained high over the course of treatment. In the vascular chamber where CPF was directly applied, only TCP was detected (ranging from 0.06 μM at 2 h to 0.19 μM at 24 h). These results provide chemical evidence of the substantial disruption induced by this widely used commercial pesticide. This work reinforces previously observed OP metabolism and mechanisms of impact, validates the use of the NVU for OP toxicology testing, and provides a model platform for analyzing these organotypic systems. |
format | Online Article Text |
id | pubmed-8431803 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84318032021-09-11 Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier Miller, Dusty R. McClain, Ethan S. Dodds, James N. Balinski, Andrzej May, Jody C. McLean, John A. Cliffel, David E. Front Bioeng Biotechnol Bioengineering and Biotechnology Despite the significant progress in both scientific understanding and regulations, the safety of agricultural pesticides continues to be called into question. The need for complementary analytics to identify dysregulation events associated with chemical exposure and leverage this information to predict biological responses remains. Here, we present a platform that combines a model organ-on-chip neurovascular unit (NVU) with targeted mass spectrometry (MS) and electrochemical analysis to assess the impact of organophosphate (OP) exposure on blood-brain barrier (BBB) function. Using the NVU to simulate exposure, an escalating dose of the organophosphate chlorpyrifos (CPF) was administered. With up to 10 μM, neither CPF nor its metabolites were detected across the BBB (limit of quantitation 0.1 µM). At 30 µM CPF and above, targeted MS detected the main urinary metabolite, trichloropyridinol (TCP), across the BBB (0.025 µM) and no other metabolites. In the vascular chamber where CPF was directly applied, two primary metabolites of CPF, TCP and diethylthiophosphate (DETP), were both detected (0.1–5.7 µM). In a second experiment, a constant dose of 10 µM CPF was administered to the NVU, and though neither CPF nor its metabolites were detected across the BBB after 24 h, electrochemical analysis detected increases in acetylcholine levels on both sides of the BBB (up to 24.8 ± 3.4 µM) and these levels remained high over the course of treatment. In the vascular chamber where CPF was directly applied, only TCP was detected (ranging from 0.06 μM at 2 h to 0.19 μM at 24 h). These results provide chemical evidence of the substantial disruption induced by this widely used commercial pesticide. This work reinforces previously observed OP metabolism and mechanisms of impact, validates the use of the NVU for OP toxicology testing, and provides a model platform for analyzing these organotypic systems. Frontiers Media S.A. 2021-08-27 /pmc/articles/PMC8431803/ /pubmed/34513802 http://dx.doi.org/10.3389/fbioe.2021.622175 Text en Copyright © 2021 Miller, McClain, Dodds, Balinski, May, McLean and Cliffel. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Bioengineering and Biotechnology Miller, Dusty R. McClain, Ethan S. Dodds, James N. Balinski, Andrzej May, Jody C. McLean, John A. Cliffel, David E. Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier |
title | Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier |
title_full | Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier |
title_fullStr | Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier |
title_full_unstemmed | Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier |
title_short | Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier |
title_sort | chlorpyrifos disrupts acetylcholine metabolism across model blood-brain barrier |
topic | Bioengineering and Biotechnology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431803/ https://www.ncbi.nlm.nih.gov/pubmed/34513802 http://dx.doi.org/10.3389/fbioe.2021.622175 |
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