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
