Benzo(a)pyrene triggers desensitization of β2-adrenergic pathway

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.

Organic chemicals from diesel exhaust particles affects intracellular calcium, inflammation and β-adrenoceptors in endothelial cells

“…3). In line with our (Mayati et al, 2017), this indicates that lipophilic organic chemicals extracted by the two least polar solvents interacts with and desensitizes βARs. In contrast, the hydrophilic extracts had no significant effects.…”

“…Acknowledging that these lipophilic DEP-EOM affect multiple mechanisms, it is tempting to speculate that DCM-EOM activates ROCE via the GPCRs βAR and PAR-2. Studies indicating that certain PAHs may act as βAR agonists and that DEP increase [Ca 2+ ]i via PAR-2 in human bronchial cells, lend support to this suggestion (Li et al, 2011;Mayati et al, 2014;Mayati et al, 2012b;Mayati et al, 2017). However, as we have previously observed that DCM-EOM increased [Ca 2+ ]i via AhR-dependent mechanisms, the possibility that GPCRs could be trans-activated downstream of AhR activation also needs to be considered.…”

“…However, DCM-EOM-induced COX-2 expression was reduced by both carazolol and SKF96365, indicating that Ca 2+ -signalling is an upstream event at least partly involved in regulation of COX-2. This may be related to protein kinase C (PKC), which is involved in the regulation of COX-2 and is activated by Ca 2+ and di-acyl-glycerol (DAG) (Mochly-Rosen et al, 2012). Moreover, GPCRs may activate PLC, which is detrimental to [Ca 2+ ]i-regulation (Putney and Tomita, 2012).…”

G-protein coupled receptors (GPCR) and environmental exposure. Consequences for cell metabolism using the β-adrenoceptors as example

“…The β 2 AR is extensively expressed in M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT different system (respiratory, nervous, cardiovascular, inflammation and immune systems), and promote various physiological functions (bronchodilation, regulation of vasodilation and cardiac muscle contractility, regulation of activities of both T and B lymphocytes, homeostatic and neuroprotective functions, lipolysis regulation) [28,29,[34][35][36][37][38][39][40]. Hence, the observation that B[a]P at low concentrations can bind and stimulate β 2 AR signaling and attenuate effects from epinephrine [19,8,18] is potentially of considerable toxicological importance. As shown in Table 1, interference with GPCRs is not restricted to PAHs and β-adrenoceptors, but other GPCR-targets affected by other EDs are emerging.…”

“…Interference with Ca 2+ signaling could therefore lead to endothelial dysfunction [17]. Recent findings also indicate that B[a]P may promote β 2 ARdesensitization by stimulating receptor endocytosis, thus attenuating responses induced by epinephrine [18]. Furthermore, a study on adipocytes suggests that B[a]P disturbs epinephrine signaling through all the three β-adrenoceptors [19], underscoring that adrenoceptor disruption is not limited to interference of β 2 AR function.…”