Interference of PAHs and their N-heterocyclic analogs with signaling of retinoids.
| Authors | |
|---|---|
| Year of publication | 2008 |
| Type | Article in Periodical |
| Magazine / Source | Toxicology in vitro |
| MU Faculty or unit | |
| Citation | |
| Field | Environment influence on health |
| Keywords | retinoids; PAHs; N-PAHs; quantitative structure-activity relationship |
| Description | Interference of PAHs and their N-heterocyclic analogs with signaling of retinoids. 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 6 h downregulated ATRA - mediated activity (most effective were two analogs of dibenz[a,h]anthracene with LOECs about 185 nM), while most compounds active after 24 h 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 that 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. |
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