Xenobiotic Exposure and Migraine-Associated Signaling: A Multimethod Experimental Study Exploring Cellular Assays in Combination with Ex Vivo and In Vivo Mouse Models.,Environmental Health Perspectives

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Xenobiotic Exposure and Migraine-Associated Signaling: A Multimethod Experimental Study Exploring Cellular Assays in Combination with Ex Vivo and In Vivo Mouse Models.
Environmental Health Perspectives ( IF 10.4 ) Pub Date : 2023-11-01 , DOI: 10.1289/ehp12413
Rikke H Rasmussen ₁ , Sarah L Christensen ₁ , Kirstine Calloe ₂ , Brian Skriver Nielsen ₃ , Anders Rehfeld ₃ , Thomas E Taylor-Clark ₄ , Kristian A Haanes _{5,

6} , Olivier Taboureau ₇ , Karine Audouze ₈ , Dan A Klaerke ₂ , Jes Olesen ₁ , David M Kristensen _{3,

9,

10}

Affiliation

Department of Neurology, Danish Headache Center, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark.
Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, USA.
Department of Clinical Experimental Research, Rigshospitalet Glostrup, Glostrup, Denmark.
Department of Biology, Section of Cell Biology and Physiology, University of Copenhagen, Denmark.
Unité de Biologie Fonctionnelle, Université Paris Cité, Centre national de la recherche scientifique (CNRS, French National Centre for Scientific Research), Institut national de la santé et de la recherche médicale (Inserm, National Institute of Health & Medical Research), Paris, France.
Université Paris Cité, T3S, Inserm U1124, Paris, France.
Institut de recherche en santé, environnement et travail (Irset) - UMR_S 1085, Université de Rennes, Inserm, École des hautes études en santé publique (EHESP), Rennes, France.
Department of Science and Environment, Roskilde University, Roskilde, Denmark.

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 gene-related 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 100μM. 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 lipid-binding 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.

更新日期：2023-11-01

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