The xenoestrogen 4-nonylphenol modulates hepatic gene expression of pregnane X receptor, aryl hydrocarbon receptor, CYP3A and CYP1A1 in juvenile Atlantic salmon (Salmo salar).
Nonylphenol is a degradation product of alkylphenol polyethoxylates (APEs). APEs represent an important class of non-ionic surfactants widely used in many detergent formulations and plastic products for industrial and domestic use. Nonylphenol interacts with xenobiotic- and drug-metabolizing CYP forms, including members of the CYP3A and CYP1A1 subfamilies in fish. The pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) are known regulators of the induction of CYP3A and CYP1A1, respectively. Previously in our laboratory, we have shown that nonylphenol, in addition to inducing plasma egg-yolk and eggshell proteins, also modulates hepatic CYP3A- and CYP1A1-mediated enzyme activities in juvenile Atlantic salmon. Given the potential for indirect actions of nonylphenol on xenobiotic and steroid metabolism, studies were carried out to determine the effects of nonylphenol on the expression of two critical enzyme systems using juvenile salmon and waterborne nonylphenol at environmentally relevant concentrations (5, 15 and 50 microg/L) and ethanol solvent control and sampled at different time intervals (days 0 (control), 3 and 7) post-exposure. Our data show that nonylphenol-induced CYP3A and CYP1A1 mRNA levels correlate with PXR and AhR at day 7 post-exposure to 5 and 15 microg NP/L. For CYP1A1 and AhR, nonylphenol caused a temporal decrease at day 3 post-exposure, thereafter CYP1A1 and AhR mRNA levels were significantly induced at day 7. 50 microg NP/L caused a more pronounced effect on CYP1A1 by decreasing the mRNA levels at days 3 and 7, compared to control. Despite the decreased CYP1A1 mRNA levels at day 7, 50 microg NP/L caused a significant induction of AhR mRNA at the same time period. This study suggests a possible regulation by xenoestrogens of fish hepatic CYP3A and CYP1A1 enzymes via PXR and AhR, respectively, and may have impact on the metabolism of endogenous and exogenous substrates. This is the first study that simultaneously examined CYP3A, CYP1A1, PXR and AhR transcripts following nonylphenol treatment in any aquatic species or earlier diverging vertebrates.
Meucci
Valentina
V
Department of Veterinary Clinics, Section of Pharmacology and Toxicology, University of Pisa, Italy.
Arukwe
Augustine
A
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D011987:Receptors, Steroid / Q000096:biosynthesis*; D020317:Salmo salar; D014874:Water Pollutants, Chemical / Q000494:pharmacology
D004968:Estrogens, Non-Steroidal; D010636:Phenols; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014874:Water Pollutants, Chemical; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C041594:4-nonylphenol