In vitro exposure to ambient fine and ultrafine particles alters dopamine uptake and release, and D2 receptor affinity and signaling
Introduction
Environmental air pollution is a persistent problem with serious negative impact on human health. Fine particles (FP; aerodynamic diameter ≤ 2.5 μm) and ultrafine particles (UFP; aerodynamic diameter ≤ 0.1 μm) are atmospheric pollutants that elicit, in a size-dependent manner, oxidative stress and inflammatory responses in the respiratory, cardiovascular and central nervous systems (Gillespie et al., 2013; Guerra et al., 2013; Aztatzi-Aguilar et al., 2015). The toxic effects of particulate matter (PM) in the brain are related to damage to the blood-brain barrier and translocation of particles, and to cytokines produced in peripheral systems (Oberdörster et al., 2002; Peters et al., 2006; Genc et al., 2012; Liu et al., 2015). In addition, minerals, metals, and carbonaceous and organic components contained in PM are involved in the cellular toxicity and neurotoxic effects (Guerra-Garcia et al., 2013; Haghani et al., 2020).
The striatum, a neuronal nucleus critical for the control of motor behavior, is a target of PM toxicity (Guerra et al., 2013; Andrade-Oliva et al., 2018). PM induces damage to the dopaminergic nigro-striatal neurons in a size-dependent manner, and alters striatal dopamine turnover as well as glutamate and serotonin levels (Block et al., 2004; Allen et al., 2014; Liu et al., 2015). We recently reported that both acute and chronic exposures of rats to FP induce glial activation in the striatum, and that whereas the acute exposure reduced the density of dopamine D2-like receptors, the sub-chronic exposure had no effect on receptor density, but decreased agonist-induced G protein activation as evaluated by [35S]-GTPγS binding to striatal membranes (Andrade-Oliva et al., 2018).
PM exposure has been associated to increased risk for developing neurological diseases involving mood and the control of motor behavior, such as Parkinson’s disease, depression, autism and anxiety, in which dopaminergic transmission is affected (Lim et al., 2011; Oudin et al., 2016; Pun et al., 2017). In the brain, dopaminergic transmission is controlled by processes that regulate transmitter release from axon terminals, clearance from the extracellular space by the dopamine transporter (DAT), dopamine synthesis and catabolism, and receptor signaling (Elsworth and Roth, 1997). Among the dopamine receptor subtypes (D1 to D5), D2 receptors (D2Rs) are major regulators of motor activity and have been widely studied because antipsychotic drugs act as antagonists at these receptors (Agid et al., 2007; Seeman et al., 2005). D2Rs are expressed pre- and post-synaptically, couple to Gαi/o proteins, and serve as autoreceptors in dopaminergic neurons (Beaulieu et al., 2015; Sulzer et al., 2016).
In this study, we have assessed the in vitro effects of PM on dopaminergic transmission evaluating dopamine uptake and release by striatal nerve terminals (synaptosomes), as well as the affinity and signaling of native and cloned D2Rs.
Section snippets
Chemicals
The following chemicals were purchased from Sigma Aldrich (St. Louis, MO): adenosine 3′,5′-cyclic monophosphate (cAMP), l-ascorbic acid, (±)-butaclamol hydrochloride, 1,4-dithio-DL-threitol (DL-DTT), 5,5′-dithiobis-2-nitrobenzoic acid (DTNB), dopamine hydrochloride, GBR-12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), 3-isobutyl-1-methylxanthine (IBMX), pargyline hydrochloride, Percoll® and (±)-quinpirole dihydrochloride. [3H]-dopamine (48 Ci/mmol), [
PM physicochemical characterization
PM chemical characterization (Table 1) showed that total constituents, inorganic substances and organic compounds were higher in FP (36-, 45- and 17-fold of UFP values, respectively). Elemental components represented the main fraction for both types of particles, but the relative contribution of metals and organic substances was different (84/16 % for FP, and 67/33 % for UFP, respectively). Elements found were Ca, S, Fe, Cl, Cu, Zn, K, Ti, Mn and V, whereas organic compounds were phthalates,
Discussion
This study sought to determine whether the in vitro exposure to PM altered dopaminergic transmission by analyzing some of its components, namely dopamine uptake, neurotransmitter release, D2R affinity for dopamine and D2R signaling. We found that both FP and UFP reduced [3H]-dopamine uptake and enhanced depolarization-evoked release in rat striatal synaptosomes, and increased the affinity and potency of dopamine at native and cloned D2Rs.
Funding
This work was supported by Cinvestav (Proyecto 166 SEP-Cinvestav to J.-A.A.M.) and Conacyt (grants 220448 to J.-A.A.M. and 167778 and 286773 to A.D.V.R.). The funding sources were not involved at all in the study design, collection, analysis and interpretation of data, writing of the manuscript or the decision to submit this report.
CRediT authorship contribution statement
María-de-los-Angeles Andrade-Oliva: Conceptualization, Writing - original draft. Juan Escamilla-Sánchez: Investigation, Formal analysis, Investigation. Yazmín Debray-García: Investigation. Russell A. Morales-Rubio: Investigation. Raúl González-Pantoja: Investigation. Marisela Uribe-Ramírez: Investigation. Omar Amador-Muñoz: Investigation, Formal analysis. Raúl V. Díaz-Godoy: Investigation, Formal analysis. Andrea De Vizcaya-Ruiz: Conceptualization, Formal analysis, Funding acquisition, Writing
Declaration of Competing Interest
The authors disclose no conflict of interest.
Acknowledgements
We are thankful to Alejandro Vilchis-Núñez and Josefina Poblano-Bata for assistance in PM chemical characterization. The authors acknowledge the support from Laboratorio Nacional de Nanoscopía Electrónica (LANE), Cinvestav-IPN. M.A.A.O. held a Conacyt graduate scholarship (281111).
References (91)
- et al.
Consequences of developmental exposure to concentrated ambient ultrafine particle air pollution combined with the adult paraquat and maneb model of the Parkinson’s disease phenotype in male mice
Neurotoxicology
(2014) - et al.
Organic compounds of PM2.5in Mexico Valley: spatial and temporal patterns, behavior and sources
Sci. Total Environ.
(2011) - et al.
Current situation of polycyclic aromatic hydrocarbons (PAH) in PM2.5 in a receptor site in Mexico city and estimation of carcinogenic PAH by combining non-real-time and real-time measurement techniques
Sci. Total Environ.
(2020) The dopamine uptake inhibitor GBR 12909: selectivity and molecular mechanism of action
Eur. J. Pharmacol.
(1989)- et al.
Effect of in vivo exposure to ambient fine particles (PM2. 5) on the density of dopamine D2-like receptors and dopamine-induced [35S]-GTPγS binding in rat prefrontal cortex and striatum membranes
Environ. Toxicol. Pharmacol.
(2018) - et al.
Histamine H3 receptor activation reduces the impairment in prepulse inhibition (PPI) of the acoustic startle response and Akt phosphorylation induced by MK-801 (dizocilpine), antagonist at N-Methyl-d-Aspartate (NMDA) receptors
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2019) - et al.
Allosteric modulation of 5-HT1A receptors by zinc: binding studies
Neuropharmacology
(2009) - et al.
An innovative ultrasound assisted extraction micro-scale cell combined with gas chromatography/mass spectrometry in negative chemical ionization to determine persistent organic pollutants in air particulate matter
J. Chromatogr. A
(2016) - et al.
The effects of organic and inorganic lead and mercury on neurotransmitter high-affinity transport and release mechanisms
Environ. Res.
(1979) - et al.
Status and characteristics of ambient PM2.5 pollution in global megacities
Environ. Int.
(2016)
Mesostriatal and mesolimbic dopamine uptake binding sites are reduced in Parkinson’s disease and progressive supranuclear palsy: a quantitative autoradiographic study using [3H] mazindol
Neuroscience
Redox activity of airborne particulate matter (PM) at different sites in the Los Angeles Basin
Environ. Res.
Ambient PM 2.5 caused depressive-like responses through Nrf2/NLRP3 signaling pathway modulating inflammation
J. Hazard. Mater.
Evaluation of the effect of an environmental management program on exposure to manganese in a mining zone in Mexico
Neurotoxicology
Effects of air pollution on the nervous system and its possible role in neurodevelopmental and neurodegenerative disorders
Pharmacol. Ther.
Manganese distribution across the blood–brain barrier: I. Evidence for carrier-mediated influx of manganese citrate as well as manganese and manganese transferrin
Neurotoxicology.
Characterization and in vitro biological effects of concentrated particulate matter from Mexico city
Atmos. Environ.
Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson’s disease
Exp. Neurol.
Anxiety is associated with striatal dopamine transporter availability in newly diagnosed untreated Parkinson’s disease patients
Parkinson. Relat. Disord.
The role of medial prefrontal cortex in memory and decision making
Neuron
Adenosine receptor–dopamine receptor interactions in the basal ganglia and their relevance for brain function
Physiol. Behav.
Particulate matter neurotoxicity in culture is size-dependent
Neurotoxicology
Exposure to inhaled particulate matter activates early markers of oxidative stress, inflammation and unfolded protein response in rat striatum
Toxicol. Lett.
Extracellular calcium modulates actions of orthosteric and allosteric ligands on metabotropic glutamate receptor 1α
J. Biol. Chem.
Size, source and chemical composition as determinants of toxicity attributable to ambient particulate matter
Atmos. Environ.
Probing dopamine transporter structure and function by Zn2+−site engineering
Eur. J. Pharmacol.
Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes
Toxicol. Appl. Pharmacol.
Enhancement of agonist binding to 5-HT1A receptors in rat brain membranes by millimolar Mn 2+
Neurosci. Lett.
Millimolar Mn2+ influences agonist binding to 5-HT1A receptors by inhibiting guanosine nucleotide binding to receptor-coupled G-proteins
Neurotoxicology
Striatal dopamine neurotransmission: regulation of release and uptake
Basal Ganglia
Identification of an allosteric binding site for Zn2+ on the β2 adrenergic receptor
J. Biol. Chem.
Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3
Neuropharmacology
Zinc oxide nanoparticle disruption of store-operated calcium entry in a muscarinic receptor signaling pathway
Toxicol. In Vitro
Effect of long-term particulate matter exposure on Parkinson’s risk
Environ. Geochem. Health
Nanoceria restrains PM2.5-induced metabolic disorder and hypothalamus inflammation by inhibition of astrocytes activation related NF-κB pathway in Nrf2 deficient mice
Free Radic. Biol. Med.
Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response a double-blind PET study in schizophrenia
Neuropsychopharmacology
The concise guide to pharmacology 2019/20: g protein-coupled receptors
Br. J. Pharmacol. ogy
Acute and subchronic exposure to air particulate matter induces expression of angiotensin and bradykinin-related genes in the lungs and heart: Angiotensin-II type-I receptor as a molecular target of particulate matter exposure
Part. Fibre Toxicol.
The physiology, signaling, and pharmacology of dopamine receptors
Pharmacol. Rev.
Dopamine receptors–IUPHAR review 13
Br. J. Pharmacol.
Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase
FASEB J.
Synaptic organisation of the basal ganglia
J. Anat.
Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities
Hum. Exp. Tox.
Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid β-42 and α-synuclein in children and young adults
Toxicol. Pathol.
Cerebrospinal fluid biomarkers in highly exposed PM 2.5 urbanites: the risk of Alzheimer’s and Parkinson’s diseases in young Mexico city residents
J. Alzheimers D.
Cited by (3)
Adverse effects of exposure to fine particles and ultrafine particles in the environment on different organs of organisms
2024, Journal of Environmental Sciences (China)
- 1
These authors contributed equally to this work.