TY - JOUR

T1 - Xenobiotic Exposure and Migraine-Associated Signaling

T2 - A Multimethod Experimental Study Exploring Cellular Assays in Combination with Ex Vivo and In Vivo Mouse Models

AU - Rasmussen, Rikke H.

AU - Christensen, Sarah L.

AU - Calloe, Kirstine

AU - Nielsen, Brian Skriver

AU - Rehfeld, Anders

AU - Taylor-Clark, Thomas E.

AU - Haanes, Kristian A.

AU - Taboureau, Olivier

AU - Audouze, Karine

AU - Klaerke, Dan A.

AU - Olesen, Jes

AU - Kristensen, David M.

N1 - Funding Information: This work was supported by Svend Andersen Fonden, Candys Foundation, Brødrene Hartmanns Fond, Fonden til Lægevidenskabelig Fremme & Torben og Alice Frimodt Fond. Publisher Copyright: © 2023, Public Health Services, US Dept of Health and Human Services. All rights reserved.

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin generelated peptide (CGRP). OBJECTIVE: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain. METHODS: A calcium imaging–based screen of environmental chemicals was used to investigate activation of migraine pain–associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain. RESULTS: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100 lM. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipidbinding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response (Ntotal = 144). DISCUSSION: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. https://doi.org/10.1289/EHP12413.

AB - BACKGROUND: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin generelated peptide (CGRP). OBJECTIVE: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain. METHODS: A calcium imaging–based screen of environmental chemicals was used to investigate activation of migraine pain–associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain. RESULTS: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100 lM. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipidbinding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response (Ntotal = 144). DISCUSSION: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. https://doi.org/10.1289/EHP12413.

U2 - 10.1289/EHP12413

DO - 10.1289/EHP12413

M3 - Journal article

C2 - 37909725

AN - SCOPUS:85175878443

VL - 131

JO - Environmental Health Perspectives

JF - Environmental Health Perspectives

SN - 0091-6765

IS - 11

M1 - 117003

ER -