Abstract
Exposure to environmental polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene (B(a)P), has been linked to several health-threatening risks. PAHs were also shown to hinder adrenergic receptor (ADR) responses. As we previously demonstrated that B(a)P can directly interact with the β2ADR, we investigated here whether B(a)P could decrease β2ADR responsiveness by triggering receptor desensitization phenomena. We firstly showed that exposure to B(a)P reduced β2ADR-mediated epinephrine-induced induction of NR4A gene mRNAs and of intracellular cAMP. Analysis of β2ADR protein expression demonstrated that B(a)P rapidly decreased membrane expression of β2ADR with a subsequent degradation of receptor protein. B(a)P exposure concomitantly rapidly increased the β2ADR mRNA levels. The use of the β-blockers, propranolol and ICI 118.551, demonstrated the involvement of β2ADR itself in this increase. However, sustained exposure to B(a)P induced a diminution of β2ADR mRNA steady-state as a result of the acceleration of its degradation. Together, these results show that, beside the well-known activation of the aryl hydrocarbon receptor, PAH deleterious effects may involve the dysfunction of adrenergic responses through, in part, the desensitization of β2ADR. This may be taken in consideration when β2-agonists/antagonists are administered in patients exposed to important concentrations of PAHs, e.g. in cigarette smokers.
Highlights
Polycyclic aromatic hydrocarbons (PAHs), such as the prototypical molecule benzo(a)pyrene (B(a)P), constitute an ubiquitous family of environmental contaminants, that are notably found in cigarette smoke, exhaust particles, grilled foods and industrial waste by-products[1, 2]
nuclear receptor 4A (NR4A) subfamily is a group of orphan nuclear receptors, including Nur[77] (NR4A1), Nurr[1] (NR4A2), and NOR1 (NR4A3), whose expressions are rapidly induced by EN through the activation of β2-adrenergic receptor (β2ADR) pathway[18]
Our results indicate that the referent polycyclic aromatic hydrocarbons (PAHs) is able to markedly reduce HMEC-1 cells’ responsiveness to β2ADR activation by β2-agonists (e.g. EN), as a consequence of receptor desensitization, i.e. receptor internalization followed by receptor mRNA and protein degradation
Summary
Polycyclic aromatic hydrocarbons (PAHs), such as the prototypical molecule benzo(a)pyrene (B(a)P), constitute an ubiquitous family of environmental contaminants, that are notably found in cigarette smoke, exhaust particles, grilled foods and industrial waste by-products[1, 2] Exposure to these pollutants has been correlated to various pathological situations, including inflammation, cancer development, cardiovascular and pulmonary diseases[3, 4]. Our attempts to explain these AhR-independent effects have recently revealed an important role of β2-adrenergic receptor (β2ADR) signaling pathway[10, 11] This role seems to involve a direct activation of β2ADR by PAHs, adding these pollutants to the list of β2ADR-interacting agents[10]. In parallel to the activation of these signaling pathways, exposure to β2-agonists leads to receptor desensitization; i.e. agonist-induced time-dependent loss of β2ADR responsiveness. Our results revealed that B(a)P decreased the receptor responsiveness to β2-agonists with a concomitant β2ADR internalization and, for more sustained exposures, receptor degradation at both protein and mRNA levels
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