1: Toxicol Appl Pharmacol. 2006 Dec 15;217(3):308-21. Epub 2006 Oct 7. 

Developmental toxicity of 4-ring polycyclic aromatic hydrocarbons in zebrafish
is differentially dependent on AH receptor isoforms and hepatic cytochrome
P4501A metabolism.

Incardona JP, Day HL, Collier TK, Scholz NL.

Ecotoxicology and Environmental Fish Health Program, Environmental Conservation
Division, Northwest Fisheries Science Center, 2725 Montlake Blvd E, Seattle, WA
98112, USA. john.incardona@noaa.gov

Polycyclic aromatic hydrocarbons (PAHs) derived from fossil fuels are ubiquitous
contaminants and occur in aquatic habitats as highly variable and complex
mixtures of compounds containing 2 to 6 rings. For aquatic species, PAHs are
generally accepted as acting through either of two modes of action: (1)
"dioxin-like" toxicity mediated by activation of the aryl hydrocarbon receptor
(AHR), which controls a battery of genes involved in PAH metabolism, such as
cytochrome P4501A (CYP1A) and (2) "nonpolar narcosis", in which tissue uptake is
dependent solely on hydrophobicity and toxicity is mediated through non-specific
partitioning into lipid bilayers. As part of a systematic analysis of mechanisms
of PAH developmental toxicity in zebrafish, we show here that three tetracyclic
PAHs (pyrene, chrysene, and benz[a]anthracene) activate the AHR pathway
tissue-specifically to induce distinct patterns of CYP1A expression. Using
morpholino knockdown of ahr1a, ahr2, and cyp1a, we show that distinct
embryolarval syndromes induced by exposure to two of these compounds are
differentially dependent on tissue-specific activation of AHR isoforms or
metabolism by CYP1A. Exposure of embryos with and without circulation (silent
heart morphants) resulted in dramatically different patterns of CYP1A induction,
with circulation required to deliver some compounds to internal tissues.
Therefore, biological effects of PAHs cannot be predicted simply by quantitative
measures of AHR activity or a compound's hydrophobicity. These results indicate
that current models of PAH toxicity in fish are greatly oversimplified and that
individual PAHs are pharmacologically active compounds with distinct and
specific cellular targets.

Publication Types:
    Comparative Study
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, Non-P.H.S.

PMID: 17112560 [PubMed - indexed for MEDLINE]