The contribution of hepatic steroid metabolism to serum estradiol and estriol concentrations in nonylphenol treated MMTVneu mice and its potential effects on breast cancer incidence and latency.
The two major pathways for the metabolism of estradiol-17beta (E2) are the 2- and 16-hydroxylase pathways. Research has suggested that the increased production of the estrogenically active 16-hydroxy products such as estriol (E3) may be involved in increased susceptibility to breast cancer. 4-Nonylphenol (4-NP) is an environmental estrogen that also can activate the pregnane-X receptor (PXR) and induce P-450 enzymes responsible for the production of E3. It is hypothesized that 4-NP may act in part as an environmental estrogen by increasing E3 production. Based on its affinity for the estrogen receptor (ER) alone, 4-NP may be more potent than predicted at increasing mammary cancer incidence in the MMTVneu mouse. Female mice were treated per os for 7 days at 0, 25, 50 or 75 mg kg(-1) day(-1) 4-NP to investigate the effects of 4-NP on hepatic estrogen metabolism after an acute treatment. 4-Nonylphenol increased the hepatic formation of E3 in a dose-dependent manner. However, serum E3 concentrations were only increased at 25 mg kg(-1) day(-1) presumably due to direct inhibition of E3 formation by 4-NP. MMTVneu mice were then treated for 32 weeks at 0, 30 or 45 mg kg(-1) day(-1) 4-NP to determine its effects on mammary cancer formation and estrogen metabolism. 4-Nonylphenol increased mammary cancer formation in the MMTVneu mice at 45 mg kg(-1) day(-1) but not at 30 mg kg(-1) day(-1). Mice treated with an equipotent dose of E2, 10 microg kg(-1) day(-1), based on the relative binding affinities of nonylphenol and estradiol for ER alpha, did not develop mammary cancer. This suggests that nonylphenol is more potent than predicted based on its affinity for the estrogen receptor. However, no changes in serum E3 concentrations or hepatic E3 production were measured after the chronic treatment. Changes in E3 formation were correlated with increased CYP2B levels after the 7 day 4-NP treatment, and repression of CYP2B and CYP3A after 32 weeks of 4-NP treatment. Microarray analysis and Q-PCR of liver mRNA from the mice treated for 32 weeks demonstrated a decrease in RXR alpha, the heterodimeric partner of the PXR, which may in part explain the repressed transcription of the P450s measured. In conclusion, 4-NP treatment for 32 weeks increased mammary cancer formation at a dose of 45 mg kg(-1) day(-1). However, chronic treatment with 4-NP did not increase hepatic E3 formation or serum E3 concentrations. The transient induction by 4-NP of hepatic E3 formation and serum concentrations is most likely not involved in the increased incidence of mammary cancer in MMTVneu mice since E3 serum concentrations were only increased at 25 mg kg(-1) day(-1), a dose that was not sufficient to induce mammary tumor formation. Nevertheless, the induced hepatic E3 production in the acute exposures to 4-NP was indicative of an increase in mammary cancer incidence after the chronic exposure.
Acevedo
Ricardo
R
University of Texas at El Paso, Biological Sciences, El Paso, TX 79968, USA.
Parnell
Pamela G
PG
Villanueva
Hugo
H
Chapman
Laura M
LM
Gimenez
Tomas
T
Gray
Sandra L
SL
Baldwin
William S
WS
D000818:Animals; D015153:Blotting, Western; D004958:Estradiol / Q000097:blood / Q000378:metabolism*; D004964:Estriol / Q000097:blood / Q000378:metabolism*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000453:epidemiology* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010636:Phenols / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
D004968:Estrogens, Non-Steroidal; D010636:Phenols; D013256:Steroids; D013739:Testosterone; D004958:Estradiol; C025256:nonylphenol; D004964:Estriol