Relative effective potencies of dioxin-like compounds in rodent and human lung cell models

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F18%3AN0000066" target="_blank" >RIV/00027162:_____/18:N0000066 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68081707:_____/18:00502470

Výsledek na webu

<a href="https://linkinghub.elsevier.com/retrieve/pii/S0300483X18300659" target="_blank" >https://linkinghub.elsevier.com/retrieve/pii/S0300483X18300659</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.tox.2018.05.004" target="_blank" >10.1016/j.tox.2018.05.004</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Relative effective potencies of dioxin-like compounds in rodent and human lung cell models

Popis výsledku v původním jazyce

Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.

Název v anglickém jazyce

Relative effective potencies of dioxin-like compounds in rodent and human lung cell models

Popis výsledku anglicky

Toxicity of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls, is largely mediated via aryl hydrocarbon receptor (AhR) activation. AhR-mediated gene expression can be tissue-specific; however, the inducibility of AhR in the lungs, a major target of DLCs, remains poorly characterized. In this study, we developed relative effective potencies (REPs) for a series of DLCs in both rodent (MLE-12, RLE-6TN) and human (A549, BEAS-2B) lung and bronchial epithelial cell models, using expression of both canonical (CYP1A1, CYP1B1) and less well characterized (TIPARP, AHRR, ALDH3A1) AhR target genes. The use of rat, murine and human cell lines allowed us to determine both species-specific differences in sensitivity of responses to DLCs in lung cellular models and deviations from established WHO toxic equivalency factor values (TEF) values. Finally, expression of selected AhR target genes was determined in vivo, using lung tissues of female rats exposed to a single oral dose of DLCs and compared with the obtained in vitro data. All cell models were highly sensitive to DLCs, with murine MLE-12 cells being the most sensitive and human A549 cells being the least sensitive. Interestingly, we observed that four AhR target genes were more sensitive than CYP1A1 in lung cell models (CYP1B1, AHRR, TIPARP and/or ALDH3A1). We found some deviations, with strikingly low REPs for polychlorinated biphenyls PCBs 105, 167, 169 and 189 in rat RLE-6TN cells-derived REPs for a series of 20 DLCs evaluated in this study, as compared with WHO TEF values. For other DLCs, including PCBs 126, 118 and 156, REPs were generally in good accordance with WHO TEF values. This conclusion was supported by in vivo data obtained in rat lung tissue. However, we found that human lung REPs for 2,3,4,7,8-pentachlorodibenzofuran and PCB 126 were much lower than the respective rat lung REPs. Furthermore, PCBs 118 and 156 were almost inactive in these human cells. Our observations may have consequences for risk assessment. Given the differences observed between rat and human data sets, development of human-specific REP/TEFs, and the use of CYP1B1, AHRR, TIPARP and/or ALDH3A1 mRNA inducibility as sensitive endpoints, are recommended for assessment of relative effective potencies of DLCs.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30108 - Toxicology

Projekt

<a href="/cs/project/GA14-22016S" target="_blank" >GA14-22016S: Deregulace proliferačních, prozánětlivých a karcinogenních odpovědí v plicních epiteliálních modelech indukovaných chemickými kontaminanty z ovzduší</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Toxicology

ISSN

0300-483X

e-ISSN

—

Svazek periodika

404

Číslo periodika v rámci svazku

July

Stát vydavatele periodika

IE - Irsko

Počet stran výsledku

9

Strana od-do

33-41

Kód UT WoS článku

000438322800004

EID výsledku v databázi Scopus

—