Department of Environmental and Molecular Toxicology and the Linus Pauling Institute, 571 Weniger Hall, Oregon State University, Corvallis, Oregon 97331-6512
Received January 18, 2001; accepted August 27, 2001
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ABSTRACT |
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Key Words: indole-3-carbinol; CYP1A1; CYP1B1; sex-dependent; transplacental.
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INTRODUCTION |
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Other mechanisms of chemoprevention by I3C not associated with induction of detoxication enzymes have also been observed. Several researchers have reported I3C-mediated electron scavenging, intervention in free radical hepatotoxicity and lipid peroxidation (Fong et al., 1990; Shertzer et al., 1988
), and effects on control of the cell cycle and programmed cell death (Chang et al., 1999
; Cover et al., 1998
; 1999; Ge et al., 1996
, 1999
; Katdare et al., 1998
).
Chemoprevention is not always observed with dietary I3C administration. Several studies indicate I3C can act as a promoter of carcinogenesis, especially when administered after a carcinogen (Dashwood et al., 1991; Oganesian et al., 1999
). Our laboratory reported dietary administration of I3C and the dimer of I3C, 3,3`-diindolylmethane, dramatically down-regulated both the expression and activity of flavin-containing monooxygenase (FMO), form 1 (Katchamart et al., 2000
; Larsen-Su and Williams, 1996
). This down-regulation is associated with the concomitant induction of CYP, with the predicted result of altered metabolism of drugs that are substrates for both monooxygenases, including nicotine and tamoxifen (Katchamart et al., 2000
).
The parent compound I3C may not be responsible for any of the above-mentioned effects. Indole-3-carbinol is a light-sensitive, unstable compound, especially under acid conditions. On exposure to the acid environment of the stomach, I3C undergoes hydrolysis, yielding a variety of dimers, linear and cyclic trimers (Fig. 1), as well as a host of other as yet unidentified high-molecular-weight oligomers (Stresser et al., 1995
). A number of acid condensation products of I3C (notably 3,3`-diindolylmethane [I33`] and indolocarbazole [ICZ]) have been shown to be potent Ah receptor agonists (Bjeldanes et al., 1991
; Chen et al., 1996
), which provides a partial explanation for the relative potency I3C exhibits in the induction of CYP1A1 and CYP1A2. In contrast to the adults (Katchamart et al., 2000
; Larsen-Su and Williams, 1996
) in the present study, we find that fetal transplacental exposure to I3C does not affect hepatic levels of FMO1 (data not shown).
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This study demonstrates that some I3C oligomers have the ability to traverse the maternal placenta in the rat and can alter the overall metabolic profile of the neonate. The observed differential induction of xenobiotic-metabolizing enzymes in the exposed neonates could have profound effects on the metabolism of endogenous substrates, as well as the potential for selective activation of xenobiotics. Previous studies have shown I3C acid condensation products capable of eliciting both pro- and antiestrogenic effects (Chang et al., 1999; Chen et al., 1998
; Liu et al., 1994; Riby et al., 2000
; Shilling et al., 2001
). Such biological effects may be critical in the developing fetus. These results indicate the possible involvement of sex-specific modulators in the early developmental expression of Ah receptor-mediated responses, and underscores the need for caution in the use of I3C in ongoing chemoprevention trials.
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MATERIALS AND METHODS |
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Animals.
Eight timed-pregnant Fischer 344 rats were purchased from Simonsens (Gilroy, CA) at day 10 of gestation. Animals were randomly divided into two groups and fed either AIN93G powdered semisynthetic control diet, or control diet containing 2000 ppm I3C for the next 11 days until parturition. Both water and diet were available ad libitum throughout the study. Animals nearing parturition were monitored closely, and at birth, neonates were immediately separated from the mother before they could nurse to avoid any possible lactational exposure. One female assigned to the I3C-fed group was found to not be pregnant after 21 days, did not give birth, and was removed from the study, resulting in a total of four controls and three I3C-fed dams. The four control-fed dams gave birth to a total of 40 pups, 19 males and 21 females. The three I3C-fed dams gave birth to a total of 26 pups, 11 males and 15 females. Immediately after parturition all pups were separated by sex (as determined by measurement of anogenital distance). Animals were then killed by CO2 asphyxiation (pups were sacrificed by CO2 asphyxiation plus decapitation), and their livers removed. These protocols were approved by the Oregon State University Institutional Animal Care and Use Committee and are in accordance with the Guiding Principles in the Use of Animals in Toxicology. A portion of the maternal liver was removed for extraction of I3C acid condensation products. Pup livers from each experimental group were also randomly selected and set aside for extraction of I3C acid condensation products. All liver samples were quick-frozen in liquid nitrogen and stored at 80°C until analysis. (Note: one rat pup was excluded from the study. The pup, from control dam no.2, was delivered normally, but was incompletely formed, born dead, and of indeterminate sex.).
Microsome preparation.
Maternal livers were individually homogenized by hand in glass homogenizers kept on ice, using four volumes of homogenization buffer (0.1 M potassium phosphate [pH 7.25] containing 0.15 M potassium chloride, 1.0 mM EDTA, 0.1 mM phenyl-methylsulfonylfluoride, 1.0 mM dithiothreitol, and 20 µM butylated hydroxytoluene (BHT). Liver microsomes were then prepared by ultracentrifugation (Guengerich, 1989). Protein levels were determined by the method of Lowry et al. (1951). Ten neonatal livers of each sex were randomly selected from the four control litters and also from the three litters from I3C-fed mothers, combined into five pools of two livers each, and microsomes prepared as described above.
Tissue extraction.
Maternal and neonatal livers were initially homogenized as described above. Homogenates were then extracted three times each with three volumes of ice-cold ethyl acetate (containing 0.001% BHT). The extract was kept on ice, shielded from light, and evaporated to near dryness under a gentle stream of nitrogen. The final residue was redissolved in THF (to a total volume of 30 µl) and stored at 80°C until analysis.
HPLC analysis.
A standard I3C acid reaction mixture was prepared as previously described (Bjeldanes et al., 1991) and used to generate a sample chromatogram to establish retention time of I3C oligomers dissolved in THF. HPLC separation of the I3C oligomers was achieved at 30° with a Beckman Ultrasphere C-18 analytical column, 4.6 mm x 25 cm, 5-µm pore size, and peaks detected by UV absorbance utilizing a Shimadzu SPD-6AV spectrophotometer, monitored at 280 nm by a UV/VIS detector (Kyoto, Japan). The flow rate was held constant at 1 ml/min. throughout the analysis. Initial conditions were 20% acetonitrile (solvent A), 80% water (solvent B). These conditions were held constant for 0.5 min, then a linear gradient to 15% solvent B was run over the next 29.5 min, held for 5 min, then returned to starting conditions over the next 10 min. At t = 45 min, the mobile phase was then gradually returned to the starting composition over the next 10 min. The identity of individual peaks was tentatively assigned based on identical retention times with standards we have previously characterized by GC-MS (Stresser et al., 1995
).
Electrophoresis and immunoblotting.
Microsomal proteins were resolved by SDS-PAGE (Laemmli, 1970), then electrophoretically transferred to nitrocellulose membranes (Towbin et al., 1979
). The membranes were incubated with rabbit antibody raised against either rat CYP1A1 (purchased from Human Biologics, Phoenix, AZ) or mouse CYP1B1 (a generous gift from Dr. Colin Jefcoate, University of Wisconsin). The blots were probed with a goat anti-rabbit secondary antibody conjugated to horseradish peroxidase (Biorad, Richmond, CA), then visualized by a chemiluminescence detection kit (Amersham Corporation, Arlington Heights, IL).
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RESULTS |
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DISCUSSION |
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We previously have isolated 3H-I3C derivatives from the livers of 3H-I3C-fed or gavaged animals (Dashwood et al., 1989; Stresser et al., 1995
). We now report the detection of at least one I3C derivative in the neonatal rat liver from I3C-fed mothers. Because animals were removed from the mother at birth and were not allowed to nurse, it is assumed that I3C derivatives are capable of traversing the maternal placenta. Further, we have shown that this transplacental exposure results in a sex-specific induction of CYP enzymes. CYP1A1 was induced to significant levels in male neonates only, whereas CYP1B1 was selectively induced in female litter mates.
The basis for the differential inducibility of these CYP1A1 and CYP1B1 enzymes in rat neonates is unknown. In addition to AhR and Arnt, a number of transacting coactivators and co-repressors could be expressed in a cell-, tissue-, and sex-specific manner, explaining the results observed in this study (Alexander et al., 1997; Bhattacharyya et al., 1995
; Eltom et al., 1999
; Kress and Greenlee, 1997
; Shehin et al., 2000
). Hakkola et al. (1997) reported expression of CYP1B1 in human placenta to be regulated independently from CYP1A1, although a sex-dependence was not investigated. Walker et al. (1995) noted a sex-dependent expression of CYP1B1 in the kidneys and livers of TCDD-treated adult Sprague-Dawley rat; however, no sex-dependent difference in CYP1A1 expression was noted. TCDD has been shown to be more hepatocarcinogenic in female rats than in males (Kociba et al., 1978
). Estrogen has been implicated as an important mediator of these sex-specific phenomena (Lucier et al., 1991
). Evidence suggests that CYP1A1 and CYP1B1 metabolize estrogen to 2-hydroxyestradiol and 4-hydroestradiol, respectively (Badawi et al., 2000
; Hanna et al., 2000
; Hayes et al., 1996
; Li et al., 2000
), which can then undergo free-radical generation by redox cycling (Bolton et al., 1998
; Zhu and Conney, 1998
). The resultant increase in oxidative stress from production of these catechol estrogens may contribute to the observed sex-dependent carcinogenicity of TCDD in exposed female rats. The induction of CYP1A1 and CYP1B1 in early development may play a significant role in the response of the fetus and neonate to the toxicity of xenobiotics. CYP1A1 and CYP1B1 metabolize a number of procarcinogens to reactive intermediates (Crespi et al., 1997
; Guengerich, 1992
; Kim et al., 1998
; Larsen et al., 1998
; Luch et al., 1998
; Shimada et al., 1996
). Transplacental and/or lactational exposure to I3C may enhance the risk (upon subsequent or concurrent exposure to such xenobiotics) for the development of disease, including cancer. Previous studies by Wilker et al. (1996) demonstrated that transplacental exposure of Sprague-Dawley rats to I3C resulted in alterations in reproductive parameters in adult males in a manner that was both similar and distinct from that exhibited by the potent AhR agonist TCDD. The results from this study support our finding of I3C bioavailability to the fetus with the potential for alterations in AhR-mediated signal transduction pathways.
Further studies are required to determine the possible role of sex-specific modulators of CYP1A1 and CYP1B1 expression. In addition, examination of the developmental patterns of induction of these enzymes in fetal tissues should be done to determine the tissue-specific potential for metabolic activation in the developing fetus. The fetus may be exposed to a large number of transplacental carcinogens (Autrup, 1993). One major class of rodent transplacental carcinogens is polycyclic aromatic hydrocarbons (Anderson et al., 1995
). Anderson, Miller, and coworkers have documented the critical role of fetal CYP1A1 induction during late gestational PAH exposure in the tumorigenic response (Anderson et al., 1985
; Miller et al., 1989
; 1990). This CYP1A1 induction is mediated by the fetal AhR in the mouse. To date, little information is available on the response of CYP1B1 to transplacental exposure to PAHs and the impact on tumor development. The data from our study would indicate that both CYP1A1 and CYP1B1 could play a role in the metabolism of xenobiotics to which the fetus is transplacentally exposed and, additionally, that the response could be sex dependent.
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ACKNOWLEDGMENTS |
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NOTES |
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