scholarly journals A CRISPR/Cas9 Whole-Genome Screen Identifies Genes Required for Aryl Hydrocarbon Receptor-Dependent Induction of Functional CYP1A1

2019 ◽  
Vol 170 (2) ◽  
pp. 310-319 ◽  
Author(s):  
Christopher D Sundberg ◽  
Oliver Hankinson
Keyword(s):  
Cytochrome P450 ◽  
Aryl Hydrocarbon Receptor ◽  
Aromatic Hydrocarbons ◽  
Reverse Genetics ◽  
High Sensitivity ◽  
Prosthetic Group ◽  
Uroporphyrinogen Decarboxylase ◽  
Coproporphyrinogen Oxidase ◽  
Aryl Hydrocarbon ◽  
Genome Wide

Abstract Environmental pollutants including halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons, including benzo[a]pyrene, exert their deleterious effects through the activation of the aryl hydrocarbon receptor (AHR) and by the resulting transcription of genes not yet fully identified. Ligand-bound AHR translocates from cytoplasm to nucleus, where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT) protein. The AHR/ARNT dimer binds to enhancer regions of responsive genes to activate transcription. AHR also mediates carcinogenesis caused by PAHs, likely via CYP1A1, CYP1A2, and CYP1B1, which are massively induced by activated AHR in many tissues and generate carcinogenic electrophilic derivatives of PAHs. In the current study, we have used the mouse GeCKOv2 genome-wide CRISPR/Cas9 library to identify novel genes in the AHR pathway by taking advantage of a B[a]P selection assay that we previously used to identify core AHR pathway genes in Hepa-1c1c7 murine hepatoma cells. Besides Ahr, Arnt, and Cyp1a1, we report the identification of multiple additional putative AHR pathway genes including several that we validated. These include cytochrome P450 reductase (Por), which mediates redox regeneration of cytochromes P450, and 5 genes of the heme biosynthesis pathway: delta-aminolevulinate synthase 1 (Alas1), porphobilinogen deaminase (Hmbs), uroporphyrinogen decarboxylase (Urod), coproporphyrinogen oxidase (Cpox), and ferrochelatase (Fech): heme being an essential prosthetic group of cytochrome P450 proteins. Notably, several of these genes were identified by GeCKO screening, despite not being identifiable by reverse genetics approaches. This indicates the power of high-sensitivity genome-wide genetic screening for identifying genes in the AHR pathway.

Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells

1998 ◽  
Vol 56 (5) ◽  
pp. 599-612 ◽  
Author(s):  
Wei Li ◽  
Patricia A Harper ◽  
Bing-Kou Tang ◽  
Allan B Okey
Keyword(s):  
Cytochrome P450 ◽  
Aryl Hydrocarbon Receptor ◽  
Human Cells ◽  
Cytochrome P450 Enzymes ◽  
Aryl Hydrocarbon

scholarly journals Study and Determination of Aryl Hydrocarbon Receptor with Some Trace Elements in Fuel Filling Station Workers

2020 ◽  
Vol 10 (4) ◽  
pp. 233-251
Author(s):  
Bassem Abd Al-Raheem Twaij ◽  
Dr. Muthana Salam Mashkour ◽  
Dr.Hussein Kadhem Al-Hakeim
Keyword(s):  
Trace Elements ◽  
Serum Concentration ◽  
Aryl Hydrocarbon Receptor ◽  
Negative Correlation ◽  
Aromatic Hydrocarbons ◽  
Significant Negative Correlation ◽  
Correlation Study ◽  
Control Group ◽  
Aryl Hydrocarbon ◽  
Filling Station

PollutiOn is the intrOduction Of contaminantsʹ intO the natural envirOnment that cause adverseʹ change. Gasoline is a toxic and highly flammable liquid consists of various types of aliphatic hydrocarbons, olefins, benzenes and aromatic hydrocarbons including toluene, xylene and a large number of volatile compounds in addition to tetraethyl lead. Gasoline consists of different types of aliphatic hydrocarbons, aryl compounds and some trace elements. Trace elements are several important roles in human bodies, some are essential for enzymes reactions where they attract and facilitate conversion of substrate molecules to specific end products. Aryl hydrocarbon receptor (AHR) is a receptor involved in the regulation of biological responses to planar aromatic hydrocarbons.       The aim of the present study is to compare the serum AHR level in the fuel station workers (FSW) with the non-workers as a control group. The other aim is to find out a possible correlation between AHR with trace elements.              Sixty male FSW and 30 controls, from ten fuel stations at Al-Najaf City-Iraq, were participated in the present study. The AHR level in serum was measured using ELISA technique. Determine the following metal ions Zn2+, Cu2+, Fe3+, Mg2+, Na+ and K+ level in filling station workers (FSW) and control group were measured spectrophotometrically by using ready for use kits. Serum Pb level was carried out using Atomic absorption spectroscopy.              The results serum concentration of AHR in FSW group revealed a significant increase (p<0.001) as compared with the control group. No significant difference was noticed in AHR as compered in exposure ≥12years with exposure <12years in FWS. Smoking has no significant correlation with other parameters. Correlation study indicated a correlation between AHR and Age. Serum concentration of Cu2+, Zn2+, K+ and Pb in FSW group revealed a significant increase (p<0.001) as compared with the control group. While Fe3+, Na+ and Mg2+ in FSW group revealed a significant decrease (p<0.001) as compared with the control group. Correlation study indicated a significant negative correlation between serum Pb and AHR while other trace elements showed no significant correlation with AHR in FSW group. There is a significant negative correlation between serum Cu2+ with age while there is significant increase correlation between Zn2+, Mg2+ and Pb with age in FWS group.                 Conclusion of study is The role of increase AHR on the health in FSW group, attention to use safety gloves and face mask is recommended for FSW and a long follow-up to the studied group is necessary to explore the    prognosis of increase AHR in FSW.  

Polycyclic Aromatic Hydrocarbons Can Trigger Hepatocyte Release of Extracellular Vesicles by Various Mechanisms of Action Depending on Their Affinity for the Aryl Hydrocarbon Receptor

2019 ◽  
Vol 171 (2) ◽  
pp. 443-462 ◽  
Author(s):  
Nettie van Meteren ◽  
Dominique Lagadic-Gossmann ◽  
Martine Chevanne ◽  
Isabelle Gallais ◽  
Dimitri Gobart ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Polycyclic Aromatic Hydrocarbons ◽  
Cell Membrane ◽  
Aryl Hydrocarbon Receptor ◽  
Extracellular Vesicles ◽  
Aromatic Hydrocarbons ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic ◽  
Cell Membrane Fluidity

Abstract Extracellular vesicles (EVs) are membrane-enclosed nanostructures released by cells into the extracellular environment. As major actors of physiological intercellular communication, they have been shown to be pathogenic mediators of several liver diseases. Extracellular vesicles also appear to be potential actors of drug-induced liver injury but nothing is known concerning environmental pollutants. We aimed to study the impact of polycyclic aromatic hydrocarbons (PAHs), major contaminants, on hepatocyte-derived EV production, with a special focus on hepatocyte death. Three PAHs were selected, based on their presence in food and their affinity for the aryl hydrocarbon receptor (AhR): benzo[a]pyrene (BP), dibenzo[a,h]anthracene (DBA), and pyrene (PYR). Treatment of primary rat and WIF-B9 hepatocytes by all 3 PAHs increased the release of EVs, mainly comprised of exosomes, in parallel with modifying exosome protein marker expression and inducing apoptosis. Moreover, PAH treatment of rodents for 3 months also led to increased EV levels in plasma. The EV release involved CYP metabolism and the activation of the transcription factor, the AhR, for BP and DBA and another transcription factor, the constitutive androstane receptor, for PYR. Furthermore, all PAHs increased cholesterol levels in EVs but only BP and DBA were able to reduce the cholesterol content of total cell membranes. All cholesterol changes very likely participated in the increase in EV release and cell death. Finally, we studied changes in cell membrane fluidity caused by BP and DBA due to cholesterol depletion. Our data showed increased cell membrane fluidity, which contributed to hepatocyte EV release and cell death.

scholarly journals Role of the Aryl Hydrocarbon Receptor/ARNT/Cytochrome P450 System in Pulmonary Vascular Diseases

2019 ◽  
Vol 125 (3) ◽  
pp. 356-366 ◽  
Author(s):  
Grazyna Kwapiszewska ◽  
Anne Katrine Z. Johansen ◽  
Jose Gomez-Arroyo ◽  
Norbert F. Voelkel
Keyword(s):  
Cytochrome P450 ◽  
Aryl Hydrocarbon Receptor ◽  
Vascular Diseases ◽  
Cytochrome P450 System ◽  
Aryl Hydrocarbon ◽  
Pulmonary Vascular Diseases

The role of functional human aryl hydrocarbon receptor in estrogenicity of polycyclic aromatic hydrocarbons

2017 ◽  
Vol 280 ◽  
pp. S85-S86
Author(s):  
Martina Hyzdalova ◽  
Jakub Pivnicka ◽  
Ondrej Zapletal ◽  
Gerardo Vazquez-Gomez ◽  
Jason Matthews ◽  
...  
Keyword(s):  
Polycyclic Aromatic Hydrocarbons ◽  
Aryl Hydrocarbon Receptor ◽  
Aromatic Hydrocarbons ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic
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