Regular ArticleDisposition of Polycyclic Aromatic Hydrocarbons in the Respiratory Tract of the Beagle Dog: II. The Conducting Airways
Abstract
Physiological models have predicted that the lipophilicity of solutes such as polycyclic aromatic hydrocarbons (PAHs) will delay clearance from the respiratory tract. This clearance consists of a delayed penetration of the mucous lining layer (MLL), allowing mucociliary clearance, followed by a slow penetration of PAHs through walls of the conducting airways. To test this prediction, mucociliary clearance and retention in the mucosa of PAHs deposited in the conducting airways of the Beagle dog were measured. Mucociliary clearance of particles and dissolved PAHs was measured by instilling onto the MLL in a main stem bronchus or the distal trachea small volumes of saline containing either dissolved benzo[a]pyrene (BaP) or phenanthrene (Phe), or a suspension of particulate solvent green (SG) or macroaggregated albumin (MAA). Sequential lavage of the mucous-retained materials followed the instillations. Retention of BaP in the airway walls of the bronchial tree was studied by instilling the hydrocarbon in an ethanol/saline solution at precise locations of the upper bronchial tree, and measuring the concentration of BaP and its major metabolites in the tissues. Results indicated that mucociliary clearance of SG and MAA particles in the trachea of the Beagle dog occurred at average rates of 27-30 mm/min. Of the two solutes, only the highly lipophilic BaP was sufficiently retained within the MLL to be transported with the mucociliary escalator. In addition, a fraction of the lipophilic materials cleared at a very rapid rate, in excess of 90 mm/min. This may indicate that one monolayer of pulmonary surfactant at the air interface is spreading out of the lungs on top of the MLL at a faster rate than mucociliary clearance. However, despite the protective properties of the MLL, fractions of BaP penetrating to the bronchial epithelium had a clearance half-time in the range of 1.4 hr, a period during which considerable metabolism of the PAH occurred. This long retention indicates a diffusion-limited uptake of BaP by the airways, and underscores the potential for local toxicity of highly lipophilic toxicants in the bronchial epithelium.
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Insilico Insight into the Association between Polycyclic Aromatic Hydrocarbons and Human Toll like Receptor in Progression of Esophageal Carcinogenesis
2022, Polycyclic Aromatic CompoundsCancer creates enormous burden and is a leading cause of death in most of the countries. Esophageal cancer (EC) is one of the most common cancers in the world and has the worst survival of all cancers. Esophageal Squamous Cell Carcinoma (ESCC) and adenocarcinoma are the two main types of esophageal cancer. Exposure of polycyclic aromatic hydrocarbons (PAHs) can be cited as one of the reasons for development of Esophageal Squamous Cell Carcinoma. Toll Like Receptors (TLRs) present in human esophageal epithelial cells may pose a major role in pathogen recognition, activation of innate immunity and cancer. The study attempts to predict the role of carcinogenic PAHs in TLR4 signaling pathway and how it can ultimately result in immuno suppression and development of esophageal cancer by insilico docking evaluation. For the study we retrieved the structure of sixteen PAHs from the PubChem database and the protein model of TLR4 (PDB ID: 4G8A) from protein data bank (PDB). The binding affinity of PAHs to the TLR4 receptor was calculated using molecular docking software Auto Dock1.5. The results showed that Benzo[a]pyrene showed strong interaction toward TLR4 receptor with the highest number of polar contacts along with high binding affinity values. Considering the presence of Benzo[a] pyrene in different environmental, occupational and behavioral sources globally, there is a need for future research on the risk assessment of Benzo[a]pyrene on Esophageal Squamous Cell Carcinoma.
Polycyclic Aromatic Hydrocarbons: Part I. Exposure
2015, Advances in Clinical ChemistryCitation Excerpt :They are distributed to the tissues through the circulatory system of the body; hence, they reach the more perfused tissues rapidly and vice versa [72]. PAH cross the lungs through passive diffusion and partitioning into lipids and water layers of cells [73–75], while in the gastrointestinal tract, they are transported by lipoproteins to the blood through the thoracic duct lymph flow [70]. PAH are metabolized in the body in the presence of cytochrome P-450 and associated enzymes to several metabolites which include epoxide, dihydrodiols, phenols, quinones, and their various combinations.
Polycyclic aromatic hydrocarbons (PAH) comprise the largest class of cancer-causing chemicals and are ranked ninth among chemical compounds threatening to humans. Although interest in PAH has been mainly due to their carcinogenic property, many of these compounds are genotoxic, mutagenic, teratogenic, and carcinogenic. They tend to bioaccumulate in the soft tissues of living organisms. Interestingly, many are not directly carcinogenic, but act like synergists. PAH carcinogenicity is related to their ability to bind DNA thereby causing a series of disruptive effects that can result in tumor initiation. Thus, any structural attribute or modification of a PAH molecule that enhances DNA cross linking can cause carcinogenicity. In part I, we review exposure to these dangerous chemicals across a spectrum of use in the community and industry.
The detection and evaluation of aneugenic chemicals
1996, Mutation Research - Fundamental and Molecular Mechanisms of MutagenesisAlthough aneuploidy makes a significant contribution to both somatic and inherited disease the mechanisms by which environmental chemicals may induce numerical chromosome aberrations are only poorly defined. The European Union Project was aimed to further our understanding of those chemical interactions with the components of the mitotic and meiotic cell division cycle which may lead to aneuploidy and to characterise the parameters such as cellular metabolism which may influence the activity of aneugenic chemicals. C-mitosis can be induced by the highly lipophilic polychlorinated biphenyl and the completion of mitosis and cleavage can be modified by agents which deplete cellular levels of reduced glutathione. Modifications of the fidelity of chromosome segregation were produced by inhibiting the functioning of topoisomerase II during chromatid separation. In contrast, the modification of centromere integrity resulted in chromosome breakage as opposed to disturbance of segregation. Modifiers of tubulin assembly and centriolar functioning in somatic cells such as acrylamide, vinblastine and diazepam reproduced their activity in rodent bone marrow and male germ cells. The analysis of chromosome malsegregation in Aspergillus nidulans by a structurally related series of halogenated hydrocarbons was used to develop a QSAR model which had high predictive value for the results of fungal tests for previously untested related chemicals. Metabolic studies of potential aneugens in genetically engineered human lymphoblastoid cells demonstrated the detoxification of the aneugenic activity of chloral hydrate and the activation of 2,3-dichlorobutane, 1,1,2-trichloroethane and trichloroethylene by Phase I biotransforming enzymes. Cell transformation studies in Syrian hamster dermal cultures using a panel of 22 reference and or potential aneugens indicated that 15 of the 22 produced positive results following single exposures. Five of the aneugens which were negative following single exposures produced positive results where cultures were continuously exposed for up to 6 weeks to low concentrations following a single non-transforming exposure to the mutagen dimethyl sulphate. The transformation studies indicate that a significant proportion of chemical aneugens are potential complete carcinogens and/or co-carcinogens. To optimise the enumeration of chromosomes following exposure to potential chemical aneugens whole chromosome paints and centromere specific probes suitable for use in fluorescence in situ hybridisation (FISH) were developed for the rat, mouse and Chinese hamster and selected human probes evaluated for their suitability for routine use. Molecular chromosome probes were used to develop protocols for enumerating chromosomes in metaphase cells and centromeres and micronuclei in interphase cells. The analysis of segregation of specific centromeres in binucleate cells following cytochalasin B treatment was shown to be a potentially valuable system for characterising non-disjunction following chemical exposure. Whole chromosome paints and centromere specific probes were used to demonstrate the presence of dose-response thresholds following treatment with a reference panel of spindle inhibiting chemicals. These data indicate that the FISH technology is suitable for evaluating the relative hazards of low-dose exposures to aneugenic chemicals.
Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. ii. the conducting airways
1993, Toxicology and Applied PharmacologyPhysiological models have predicted that the lipophilicity of solutes such as polycyclic aromatic hydrocarbons (PAHs) will delay clearance from the respiratory tract. This clearance consists of a delayed penetration of the mucous lining layer (MLL), allowing mucociliary clearance, followed by a slow penetration of PAHs through walls of the conducting airways. To test this prediction, mucociliary clearance and retention in the mucosa of PAHs deposited in the conducting airways of the Beagle dog were measured. Mucociliary clearance of particles and dissolved PAHs was measured by instilling onto the MLL in a main stem bronchus or the distal trachea small volumes of saline containing either dissolved benzo[a]pyrene (BaP) or phenanthrene (Phe), or a suspension of particulate solvent green (SG) or macroaggregated albumin (MAA). Sequential lavage of the mucous-retained materials followed the instillations. Retention of BaP in the airway walls of the bronchial tree was studied by instilling the hydrocarbon in an ethanol/saline solution at precise locations of the upper bronchial tree, and measuring the concentration of BaP and its major metabolites in the tissues. Results indicated that mucociliary clearance of SG and MAA particles in the trachea of the Beagle dog occurred at average rates of 27-30 mm/min. Of the two solutes, only the highly lipophilic BaP was sufficiently retained within the MLL to be transported with the mucociliary escalator. In addition, a fraction of the lipophilic materials cleared at a very rapid rate, in excess of 90 mm/min. This may indicate that one monolayer of pulmonary surfactant at the air interface is spreading out of the lungs on top of the MLL at a faster rate than mucociliary clearance. However, despite the protective properties of the MLL, fractions of BaP penetrating to the bronchial epithelium had a clearance half-time in the range of 1.4 hr, a period during which considerable metabolism of the PAH occurred. This long retention indicates a diffusion-limited uptake of BaP by the airways, and underscores the potential for local toxicity of highly lipophilic toxicants in the bronchial epithelium.
Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. i. the alveolar region
1993, Toxicology and Applied PharmacologyClearance of polycyclic aromatic hydrocarbons (PAHs) from the respiratory tract follows a biphasic pattern, with a rapid clearance of most of the PAH followed by a slow clearance of a small fraction. In previously published models, it was predicted that the rapid phase represents clearance through the thin epithelial barriers in the alveoli, the slow clearance is through the thicker epithelium of the airways, and the rate of clearance from either region will be slowed if the PAH has a high degree of lipophilicity. The objective of this first study in a series of three was to validate model predictions for rates of alveolar clearance of PAHs of different lipophilicities. A new method was developed to expose dogs to a bolus of aerosolized crystals of either benzo[a]pyrene (BaP) or phenanthrene (Phe) in a single breath. A bolus of PAH crystals was formed by condensation from a heated vapor and was injected into the pulmonary region. The bloodborne clearance of the PAHs was monitored by repeatedly sampling blood through catheters in the ascending aorta and the right atrium of the dog. Half of the Phe and the BaP cleared within 1 min and 2.4 min, respectively. The data indicated that the clearance of the highly lipophilic BaP was limited by diffusion of the PAH through the alveolar septa, while clearance of the moderately lipophilic Phe was limited mostly by the rate of perfusion of the blood. The results indicate that inhaled PAHs of sufficient lipophilicity to limit diffusion through cells have a greater potential for toxicity to the lung than less lipophilic PAHs. Because of thicker epithelia, bronchi should be at greater risk than the alveoli for PAH-induced toxicity exerted at the portal of entry.
Disposition of polycyclic aromatic hydrocarbons in the respiratory tract of the beagle dog. iii. mechanisms of the dosimetry
1993, Toxicology and Applied PharmacologyThe disposition of polycyclic aromatic hydrocarbons (PAHs) in the respiratory tract of the Beagle dog was measured and presented in two previous papers. In this paper, the data were used to demonstrate that highly lipophilic toxicants, such as PAHs, were diffusion-limited during clearance from the respiratory tract. Organic toxicants are usually regarded as perfusion-limited during clearance from the lungs. Within minutes after inhalation, the perfusion-limited substance is thought to be cleared from all regions of the respiratory tract to the circulating blood. However, the length of time required for appearance of highly lipophilic PAHs in blood exiting the lungs following transient exposures of the alveolar region suggested that alveolar clearance of highly lipophilic PAHs was diffusion-limited. But even though this transport was diffusion-limited, clearance of the highly lipophilic PAH benzo[a]pyrene (BaP) from the thin alveolar epithelium of the dog took only minutes, whereas clearance through the thicker epithelium of the conducting airways took hours. This phenomenon of slow airway clearance results from slower diffusion of highly lipophilic substances through the thicker air/blood barrier of the conducting airways compared to the thinner alveolar epithelium. A direct result of slowed clearance is a high concentration of BaP in the bronchial walls and an increased opportunity for metabolism to reactive forms. For this reason, the bronchial epitheliuni may become a preferential target of inhaled highly lipophilic toxicants. While the elevated dose during diffusion-limited clearance involves only a few cell layers, the importance of this microdosimetry in contributing to local toxicity should not be overlooked. The findings suggest that bronchial cancer following inhalation exposures is more likely to be induced by highly lipophilic carcinogens such as PAHs than by less lipophilic carcinogens.