• Publikační typ
• abstrakt z konference MeSH

Polycyclic aromatic hydrocarbons (PAHs) and their N-heterocyclic analogs (N-PAHs) are important environmental contaminants with negative effects in living organisms, including teratogenicity and embryotoxicity. Though most studies linked their embryotoxicity with aryl hydrocarbon receptor (AhR) and cytochrome P450 activation, the exact mechanism is not known. Other mechanisms such as disruption of retinoid signaling were recently suggested to be of importance. This study investigated PAHs and N-PAHs interference with retinoid signaling in vitro by modulating all-trans retinoic acid (ATRA) mediated response in a reporter gene assay using P19/A15 cell line. Further, effects on pluripotency and differentiation processes were evaluated by measuring octamer-4 (Oct-4), an important pluripotency marker and master differentiation factor. Two of the studied compounds, benz[a]anthracene and benz[c]acridine significantly up-regulated ATRA-mediated response in the co-exposure with a range of ATRA concentrations. Another structural N-PAH variant, 1,7-phenanthroline, downregulated ATRA-mediated response at most of tested ATRA concentrations and exposure times. Interesting concentration-dependent biphasic effects (i.e. downregulation with subsequent up-regulation to control levels) were observed at co-exposures of ATRA and parent PAH phenanthrene. Non significant Oct-4 modulation in co-exposure with ATRA was observed at compounds, which potentiated ATRA-mediated effects in the reporter gene assay. On the other hand, 1,7-phenanthroline and phenanthrene significantly suppressed Oct-4 levels in higher tested concentrations. Our results further extend the knowledge of PAH and N-PAH in vitro effects and indicate that these environmental toxicants may have influence on differentiation process and embryonic development by interfering with ATRA signaling and by modulating levels of Oct-4.

• MeSH
• down regulace účinky léků   MeSH
• exprese genu účinky léků   MeSH
• heterocyklické sloučeniny toxicita   MeSH
• látky znečišťující životní prostředí toxicita   MeSH
• luciferasy genetika   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• oktamerní transkripční faktor 3 biosyntéza   genetika   MeSH
• polycyklické aromatické uhlovodíky toxicita   MeSH
• reportérové geny genetika   MeSH
• retinoidy fyziologie   MeSH
• tretinoin farmakologie   MeSH
• upregulace MeSH
• viabilita buněk účinky léků   MeSH
• western blotting MeSH
• xenobiotika toxicita   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Retinoids are dietary hormones acting through nuclear receptors for retinoic acid, important especially during embryonic development. This study focuses on the disruption of signaling pathways of retinoids by polycyclic aromatic hydrocarbons (PAHs) and their N-heterocyclic analogs (N-PAHs), important environmental contaminants with numerous biological effects. In vitro test with P19/A15 cell line stably transfected with luciferase reporter gene under control of retinoic acid-responsive elements was used to investigate both direct activation of retinoic acid receptors and modulation of response induced by natural ligand all-trans retinoic acid (ATRA) by 26 PAHs and N-PAHs. While none of individual compounds alone activated retinoic acid receptors, many of them modulated ATRA-mediated activity both after 6 h and 24 h exposure. Majority of compounds active after 6h downregulated ATRA-mediated activity (most effective were two analogs of dibenz[a,h]anthracene with LOECs about 185 nM), while most compounds active after 24h upregulated the effects of ATRA (most effective benz[a]acridine and dibenz[a,i]acridine caused 400% induction of ATRA response). Quantitative structure-activity relationship analysis identified molecular volume and dipole moment as the most important descriptors of inhibitory effects after 6h, while length, total molecular energy, gap-HOMO/LUMO and Van der Waals energy are important descriptors for stimulatory effects of PAHs and N-PAHs. This study demonstrates those abundant pollutants such as PAHs and their analogs interfere in vitro with retinoid signaling, which could play role in some in vivo effects of these organic contaminants such as teratogenicity.

• MeSH
• časové faktory MeSH
• down regulace účinky léků   MeSH
• embryonální karcinom patologie   MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• látky znečišťující životní prostředí chemie   toxicita   MeSH
• luciferasy metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• polycyklické aromatické uhlovodíky chemie   toxicita   MeSH
• receptory kyseliny retinové metabolismus   MeSH
• reportérové geny MeSH
• responzivní elementy MeSH
• signální transdukce účinky léků   MeSH
• tretinoin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Retinoids are known to regulate important processes such as differentiation, development, and embryogenesis. Some effects, such as malformations in frogs or changes in metabolism of birds, could be related to disruption of the retinoid signaling pathway by exposure to organic contaminants. A new reporter gene assay has been established for evaluation of the modulation of retinoid signaling by individual chemicals or environmental samples. The bioassay is based on the pluripotent embryonic carcinoma cell line P19 stably transfected with the firefly luciferase gene under the control of a retinoic acid-responsive element (clone P19/ A15). The cell line was used to characterize the effects of individual chemicals and sediments extracts on retinoid signaling pathways. The extracts of sediments from the River Kymi, Finland, which contained polychlorinated dioxins and furans and polycyclic aromatic hydrocarbons (PAHs), significantly increased the potency of all-trans retinoic acid (ATRA), while no effect was observed with the extract of the sediment from reference locality. Considerable part of the effect was caused by the labile fraction of the sediment extracts. Also, several individual PAHs potentiated the effect of ATRA; on the other hand, 2,3,7,8-tetrachlorodibenzo-p-dioxin and several phthalates showed slightly inhibiting effect. These results suggest that PAHs could be able to modulate the retinoid signaling pathway and that they could be responsible for a part of the proretinoid activity observed in the sediment extracts. However, the effects of PAHs on the retinoic acid signaling pathways do not seem to be mediated directly by crosstalk with aryl hydrocarbon receptor.

• MeSH
• biotest metody   MeSH
• dioxiny analýza   toxicita   MeSH
• embryonální karcinom patologie   MeSH
• financování organizované MeSH
• furany analýza   toxicita   MeSH
• geologické sedimenty chemie   MeSH
• hodnocení rizik MeSH
• kyseliny ftalové analýza   toxicita   MeSH
• látky znečišťující životní prostředí analýza   toxicita   MeSH
• luciferasy světlušek genetika   MeSH
• nádorové buněčné linie MeSH
• polycyklické aromatické uhlovodíky analýza   toxicita   MeSH
• reportérové geny MeSH
• retinoidy genetika   metabolismus   MeSH
• signální transdukce MeSH
• tretinoin analýza   toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Geografické názvy
• Finsko MeSH