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Chlorpyrifos Disrupts Acetylcholine Metabolism Across Model Blood-Brain Barrier

Authors :
Dusty R. Miller
Ethan S. McClain
James N. Dodds
Andrzej Balinski
Jody C. May
John A. McLean
David E. Cliffel
Source :
Frontiers in Bioengineering and Biotechnology, Vol 9 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

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.

Details

Language :
English
ISSN :
22964185
Volume :
9
Database :
Directory of Open Access Journals
Journal :
Frontiers in Bioengineering and Biotechnology
Publication Type :
Academic Journal
Accession number :
edsdoj.004f0b9524ec4a3987f75b863dcd5caf
Document Type :
article
Full Text :
https://doi.org/10.3389/fbioe.2021.622175