PMID- 18511136
OWN - NLM
STAT- MEDLINE
DCOM- 20081014
LR  - 20121115
IS  - 0166-445X (Print)
IS  - 0166-445X (Linking)
VI  - 88
IP  - 3
DP  - 2008 Jul 7
TI  - Evidence for multiple mechanisms of toxicity in larval rainbow trout 
      (Oncorhynchus mykiss) co-treated with retene and alpha-naphthoflavone.
PG  - 200-6
LID - 10.1016/j.aquatox.2008.04.007 [doi]
AB  - Alkylated polycyclic aromatic hydrocarbons, such as retene 
      (7-isopropyl-1-methylphenanthrene), induce cytochrome P450 1A (CYP1A) enzymes and 
      produce dioxin-like toxicity in the embryo-larval stages of fish characterized by 
      the signs of blue sac disease (BSD). The signs of toxicity are well 
      characterized; however, the mechanism is not well understood. To elucidate the 
      role of CYP1A in retene toxicity, larval rainbow trout (Oncorhynchus mykiss) were 
      co-treated with a range of concentrations of alpha-naphthoflavone (ANF), a known 
      CYP1A inhibitor. The co-treatment produced synergistic toxicity at 3.2-100 
      microg/L ANF, after which toxicity at 180 microg/L ANF dropped to levels typical 
      of retene-only. At 320 microg/L ANF, toxicity increased with or without retene, 
      indicating that ANF alone was capable of inducing BSD. In addition, the additive 
      toxicity of retene-only and 320 microg/L ANF-only approximately equalled that of 
      the co-exposed larvae (100 microg/L retene+320 microg/L ANF), indicating response 
      addition. Thus, two mechanisms of action occurred in co-exposed larvae at 
      different concentrations of ANF. In trout larvae, there was a correlation between 
      toxicity and CYP1A protein concentrations, and in juvenile trout, ANF produced a 
      concentration-dependent inhibition of ethoxyresorufin-O-deethylase (EROD) 
      activity without a measurable drop in CYP1A protein. Taken together, the 
      mechanism underlying the synergistic toxicity is EROD-independent and may be 
      AhR-dependent. This study demonstrated that multiple, exposure-dependent 
      mechanisms can occur in mixture toxicity, suggesting that current risk assessment 
      models may drastically underestimate toxicity, particularly of mixtures 
      containing both CYP1A inducers and inhibitors.
FAU - Scott, Jason A
AU  - Scott JA
AD  - Department of Biology, Queen's University, Kingston, ON, Canada.
FAU - Hodson, Peter V
AU  - Hodson PV
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080422
PL  - Netherlands
TA  - Aquat Toxicol
JT  - Aquatic toxicology (Amsterdam, Netherlands)
JID - 8500246
RN  - 0 (Benzoflavones)
RN  - 0 (Phenanthrenes)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0W2D2E1P9Q (retene)
RN  - 604-59-1 (alpha-naphthoflavone)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
SB  - IM
MH  - Animals
MH  - Benzoflavones/*toxicity
MH  - Blotting, Western
MH  - Cytochrome P-450 CYP1A1/analysis/antagonists & inhibitors/metabolism
MH  - Fish Diseases/*chemically induced/enzymology
MH  - Liver/enzymology/metabolism
MH  - *Oncorhynchus mykiss
MH  - Phenanthrenes/*toxicity
MH  - Receptors, Aryl Hydrocarbon/metabolism
MH  - Statistics, Nonparametric
MH  - Survival Analysis
MH  - Toxicity Tests
EDAT- 2008/05/31 09:00
MHDA- 2008/10/15 09:00
CRDT- 2008/05/31 09:00
PHST- 2008/03/06 00:00 [received]
PHST- 2008/04/09 00:00 [revised]
PHST- 2008/04/11 00:00 [accepted]
PHST- 2008/05/31 09:00 [pubmed]
PHST- 2008/10/15 09:00 [medline]
PHST- 2008/05/31 09:00 [entrez]
AID - S0166-445X(08)00131-8 [pii]
AID - 10.1016/j.aquatox.2008.04.007 [doi]
PST - ppublish
SO  - Aquat Toxicol. 2008 Jul 7;88(3):200-6. doi: 10.1016/j.aquatox.2008.04.007. Epub 
      2008 Apr 22.