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Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line.

ABSTRACT: Inhalation exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with various adverse health effects, including chronic lung diseases and cancer. Using human bronchial epithelial cell line HBE1, we investigated the effects of structurally different PAHs on tissue homeostatic processes, namely gap junctional intercellular communication (GJIC) and MAPKs activity. Rapid (<1 h) and sustained (up to 24 h) inhibition of GJIC was induced by low/middle molecular weight (MW) PAHs, particularly by those with a bay- or bay-like region (1- and 9-methylanthracene, fluoranthene), but also by fluorene and pyrene. In contrast, linear low MW (anthracene, 2-methylanthracene) or higher MW (chrysene) PAHs did not affect GJIC. Fluoranthene, 1- and 9-methylanthracene induced strong and sustained activation of MAPK ERK1/2, whereas MAPK p38 was activated rather nonspecifically by all tested PAHs. Low/middle MW PAHs can disrupt tissue homeostasis in human airway epithelium via structure-dependent nongenotoxic mechanisms, which can contribute to their human health hazards.

SUBMITTER: Brozman O

PROVIDER: S-EPMC7486243 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line.

Brózman Ondřej O Novák Jiří J Bauer Alison K AK Babica Pavel P

Environmental toxicology and pharmacology 20200531

Inhalation exposures to polycyclic aromatic hydrocarbons (PAHs) have been associated with various adverse health effects, including chronic lung diseases and cancer. Using human bronchial epithelial cell line HBE1, we investigated the effects of structurally different PAHs on tissue homeostatic processes, namely gap junctional intercellular communication (GJIC) and MAPKs activity. Rapid (<1 h) and sustained (up to 24 h) inhibition of GJIC was induced by low/middle molecular weight (MW) PAHs, par ...[more]

PMID: 32492535

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Project description:Cisplatin is a very effective chemotherapeutic, but severe and permanent hearing loss remains a prevalent side effect. The processes underpinning cisplatin-induced ototoxicity are not well understood. Gap junction channels composed of connexin (Cx) subunits allow for the passage of small molecules and ions between contacting neighboring cells. These specialized channels have been postulated to enhance cisplatin-induced cell death by spreading "death signals" throughout the supporting cells of the organ of Corti. This study sought to investigate the role of Cx43 in cisplatin-induced ototoxicity using organotypic cochlear cultures from control and two Cx43-mutant mouse strains harboring either a moderate (Cx43I130T/+) or severe (Cx43G60S/+) reduction of Cx43 function. Cochlear cultures from Cx43-mutant mice with a severe reduction in Cx43-based gap junctional intercellular communication (GJIC) had an enhanced number of hair cells that were positive for cleaved caspase 3, a marker of active apoptosis, after cisplatin treatment. In cisplatin-treated organotypic cochlear cultures, there was a decrease in the co-localization of Cx26 and Cx30 compared with untreated cultures, suggesting that cisplatin causes reorganization of connexin composition in supporting cells. Both Cx26 and Cx30 protein expression as well as GJIC were decreased in organotypic cochlear cultures treated with the gap-junction blocker carbenoxolone. When cisplatin and carbenoxolone were co-administered, there were no differences in hair cell loss compared with cisplatin treatment alone. Using cisplatin-treated control and Cx43-ablated organ of Corti derived HEI-OC1 mouse cells, we found that greatly reducing GJIC led to preferential induction of an ER stress pathway. Taken together, this study strongly suggests that inhibition of GJIC in organ of Corti cells does not lead to differential susceptibility to cisplatin-induced ototoxicity. Although cisplatin causes the same degree of cell death in gap junction competent and incompetent cochlear cells, the engagement of the mitochondrial dysregulation and ER stress differs.

Project description:UNLABELLED:Gap junctional intercellular communication (GJIC) plays a critical role in the regulation of tissue homeostasis and carcinogenesis and is modulated by the levels, subcellular localization, and posttranslational modification of gap junction proteins, the connexins (Cx). Here, using oval cell-like rat liver epithelial cells, we demonstrate that the RNA-binding protein HuR promotes GJIC through two mechanisms. First, HuR silencing lowered the levels of Cx43 protein and Cx43 messenger RNA (mRNA), and decreased Cx43 mRNA half-life. This regulation was likely due to the direct stabilization of Cx43 mRNA by HuR, because HuR associated directly with Cx43 mRNA, a transcript that bears signature adenylate-uridylate-rich (AU-rich) and uridylate-rich (U-rich) sequences in its 3'-untranslated region. Second, HuR silencing reduced both half-life and the levels of beta-catenin mRNA, also a target of HuR; accordingly, HuR silencing lowered the levels of whole-cell and membrane-associated beta-catenin. Coimmunoprecipitation experiments showed a direct interaction between beta-catenin and Cx43. Small interfering RNA (siRNA)-mediated depletion of beta-catenin recapitulated the effects of decreasing HuR levels: it attenuated GJIC, decreased Cx43 levels, and redistributed Cx43 to the cytoplasm, suggesting that depletion of beta-catenin in HuR-silenced cells contributed to lowering Cx43 levels at the membrane. Finally, HuR was demonstrated to support GJIC after exposure to a genotoxic agent, doxorubicin, or an inducer of differentiation processes, retinoic acid, thus pointing to a crucial role of HuR in the cellular response to stress and in physiological processes modulated by GJIC. CONCLUSION:HuR promotes gap junctional intercellular communication in rat liver epithelial cells through two related regulatory processes, by enhancing the expression of Cx43 and by increasing the expression of beta-catenin, which, in turn, interacts with Cx43 and is required for proper positioning of Cx43 at the plasma membrane.

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Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line.

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Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line.

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