Interference of PAHs and their N-heterocyclic analogs with signaling of retinoids in vitro.
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.
Research Centre for Environmental Chemistry and Ecotoxicology (RECETOX), Faculty of Science, Masaryk University, Kamenice 126/3, 625 00 Brno, Czech Republic.
Martin
M
Benísek
Ludek
L
Bláha
Klára
K
Hilscherová
D000818:Animals; D018236:Carcinoma, Embryonal / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D017930:Genes, Reporter; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism*
D004785:Environmental Pollutants; D011084:Polycyclic Aromatic Hydrocarbons; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D008156:Luciferases