Induction of Intracellular Calcium Concentration by Environmental Benzo(a)pyrene Involves a β2-Adrenergic Receptor/Adenylyl Cyclase/Epac-1/Inositol 1,4,5-Trisphosphate Pathway in Endothelial Cells

Mayati, Abdullah; Levoin, Nicolas; Paris, Hervé; N’Diaye, Monique; Courtois, Arnaud; Uriac, Philippe; Lagadic‐Gossmann, Dominique; Fardel, Olivier; Ferrec, Eric Le

doi:10.1074/jbc.m111.319970

Cited by 60 publications

(77 citation statements)

References 58 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BaP induces a Ca 2+ increases in endothelial cells, which is independent of the AHR but required for CYP1B1 induction (Mayati et al , 2012). Common mechanisms that do not require AHR signaling have also been observed with CYP1B1 and TGFB -related genes in AHR-null vascular smooth muscle cells exposed to BaP and TCDD (Karyala et al , 2004).…”

Section: Resultsmentioning

confidence: 99%

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

Goodale

Tilton

Corvi

et al. 2013

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the Aryl Hydrocarbon Receptor (AHR) in a structurally dependent manner, and induce toxicity via both AHR-dependent and-independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at concentrations that induced developmental malformations by 120 hours post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burdens were analyzed at both time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the least number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure, and may provide a path for unraveling the toxicity of complex PAH mixtures.

show abstract

Section: Resultsmentioning

confidence: 99%

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

Goodale

Tilton

Corvi

et al. 2013

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…This may be indicative of rapid Ca 2+ release from the internal stores followed by a slower and sustained Ca 2+ influx. A recent study of cultured human microvascular endothelial (HMEC‐1) cells showed that β 2 ‐adrenoceptor‐mediated activation of Epac induced IP 3 accumulation and an increase in intracellular Ca 2+ , suggesting that Epac may target IP 3 ‐sensitive stores as a primary mode of action in the endothelium (Mayati et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca²⁺‐sensitive K⁺ channels in rat mesenteric artery

Roberts

Kamishima

Barrett‐Jolley

et al. 2013

The Journal of Physiology

View full text Add to dashboard Cite

Key points• Relaxation of vascular smooth muscle, which increases blood vessel diameter, is often mediated through vasodilator-induced elevations of intracellular 3 -5 -cyclic adenosine monophosphate (cAMP), although the mechanisms are incompletely understood.• In this study we investigate the role of the novel cAMP effector exchange protein directly activated by cAMP (Epac) in mediating vasorelaxation in rat mesenteric arteries.• We show that Epac mediates vasorelaxation in mesenteric arteries by facilitating the opening of several subtypes of Ca 2+ -sensitive K + channel within the endothelium and on vascular smooth muscle.• Epac-mediated hyperpolarization of the smooth muscle membrane brought about by opening of these channels acts to limit Ca 2+ entry via voltage-gated Ca 2+ channels leading to vasorelaxation.• This represents a potentially important, previously uncharacterised mechanism through which vasodilator-induced elevation of cAMP can regulate vascular tone and thus blood flow.Abstract Vasodilator-induced elevation of intracellular cyclic AMP (cAMP) is a central mechanism governing arterial relaxation but is incompletely understood due to the diversity of cAMP effectors. Here we investigate the role of the novel cAMP effector exchange protein directly activated by cAMP (Epac) in mediating vasorelaxation in rat mesenteric arteries.In myography experiments, the Epac-selective cAMP analogue 8-pCPT-2 -O-Me-cAMP-AM (5 μM, subsequently referred to as 8-pCPT-AM) elicited a 77.6 ± 7.1% relaxation of phenylephrine-contracted arteries over a 5 min period (mean ± SEM; n = 6). 8-pCPT-AM induced only a 16.7 ± 2.4% relaxation in arteries pre-contracted with high extracellular K + over the same time period (n = 10), suggesting that some of Epac's relaxant effect relies upon vascular cell hyperpolarization. This involves Ca 2+ -sensitive, large-conductance K + (BK Ca ) channel opening as iberiotoxin (100 nM) significantly reduced the ability of 8-pCPT-AM to reverse phenylephrine-induced contraction (arteries relaxed by only 35.0 ± 8.5% over a 5 min exposure to 8-pCPT-AM, n = 5; P < 0.05). 8-pCPT-AM increased Ca 2+ spark frequency in Fluo-4-AM-loaded mesenteric myocytes from 0.045 ± 0.008 to 0.103 ± 0.022 sparks s −1 μm −1 (P < 0.05) and reversibly increased both the frequency (0.94 ± 0.25 to 2.30 ± 0.72 s −1 ) and amplitude (23.9 ± 3.3 to 35.8 ± 7.7 pA) of spontaneous transient outward currents (STOCs) recorded in isolated mesenteric myocytes (n = 7; P < 0.05). 8-pCPT-AM-activated STOCs were sensitive to iberiotoxin (100 nM) and to ryanodine (30 μM). Current clamp recordings of isolated myocytes showed a 7.9 ± 1.0 mV (n = 10) hyperpolarization in response to 8-pCPT-AM that was sensitive to iberiotoxin (n = 5). Endothelial disruption suppressed 8-pCPT-AM-mediated relaxation in phenylephrine-contracted arteries (24.8 ± 4.9% relaxation after 5 min of exposure, n = 5; P < 0.05), as did apamin and TRAM-34, blockers of Ca 2+ -sensitive, small-and intermediate-conductance K + (SK Ca and IK Ca ) channels, respectively, and ...

show abstract

“…These pathways included TGF-beta signaling, p38 mitogen-activated protein kinase (MAPK) signaling, VEGF signaling, and apoptosis signaling in all three tissues and data points (Table 8). Altered intracellular signaling may result from BaP binding to the human β2-adrenergic receptor and increasing intracellular calcium levels to activate multiple signaling pathways, including protein kinase C (Mayati et al, 2012). …”

Section: Genomics Approaches (Ra2 and Ra3)mentioning

confidence: 99%

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Moffat

Chepelev

Labib

et al. 2015

Critical Reviews in Toxicology

134

100

View full text Add to dashboard Cite

Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying toxicogenomics has never been done. We conducted a case study to evaluate the utility of toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lung 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work.

show abstract

Induction of Intracellular Calcium Concentration by Environmental Benzo(a)pyrene Involves a β2-Adrenergic Receptor/Adenylyl Cyclase/Epac-1/Inositol 1,4,5-Trisphosphate Pathway in Endothelial Cells

Cited by 60 publications

References 58 publications

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca²⁺‐sensitive K⁺ channels in rat mesenteric artery

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Contact Info

Product

Resources

About

Induction of Intracellular Calcium Concentration by Environmental Benzo(a)pyrene Involves a β2-Adrenergic Receptor/Adenylyl Cyclase/Epac-1/Inositol 1,4,5-Trisphosphate Pathway in Endothelial Cells

Cited by 60 publications

References 58 publications

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish

Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca2+‐sensitive K+ channels in rat mesenteric artery

Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Contact Info

Product

Resources

About

Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca²⁺‐sensitive K⁺ channels in rat mesenteric artery