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*
Department of Pharmacology and Toxicology and the Comprehensive Cancer Center, and
Department of Pathology, University of Alabama at Birmingham, AL 35294
3To whom correspondence should be addressed. E-mail: coral.lamartiniere{at}ccc.uab.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-reductase type II activity were not altered in the prostate. This suggested that prostate differentiation, and not toxicity, had occurred. DES in the diet reduced and testosterone injections elevated relative prostate weights and perimeters of the dorsal, LP1, lateral prostate type 2 and DP1 expression. DHT increased relative prostate weights but did not significantly increase individual lobe perimeter. Unlike DES, maximally tolerated doses of genistein in the diet were not toxic to the rat prostate.
KEY WORDS: • genistein • diethylstilbesterol • prostate • 5-reductase • morphology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), but the incidence of precancerous lesions is similar for these populations (2
). There is also an inverse relationship between the age at which Asian men immigrate to the United States and the risk of developing clinically apparent prostate cancer. Asian men who immigrate at young ages have the same risk as American men (3
). It has been suggested that departure from a traditional soy-containing diet and adoption of a Western diet earlier in life may explain why Asian men residing in the United States for longer periods are not protected against prostate cancer.
Genistein, one of the major phytoestrogen components of soy, protects against hormone-dependent cancers, including that of the prostate (1
,4
). Prostate tumor incidence is significantly reduced in transgenic (5
) and chemically induced (6
) rat models after ingestion of genistein in the diet at nutritionally relevant concentrations. This report investigates the effects of genistein on the development and function of the rat dorsolateral prostate (DLP), the embryological homologue to the human prostate (7
). Diethylstilbestrol (DES)4
(3
), testosterone and dihydrotestosterone (DHT) treatments were selected for their known effects on the male reproductive tract (8
,9
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) (Harlan Teklad, Madison, WI). Offspring were weaned on d 21 postpartum.
For dietary treatments, chemically synthesized genistein (98.5% pure; Hoffmann-LaRoche, Basel, Switzerland) was added to the AIN-76A diet to achieve concentrations of 0, 250 or 1000 mg/kg. Rats fed genistein at concentrations of 250 mg/kg have serum concentrations at the high physiological level, whereas consumption of the 1000 mg/kg genistein diet results in concentrations that are at the extreme of those found in humans consuming soy products (11
,12
). Rats were fed genistein or a 75 µg/kg DES (Sigma-Aldrich, St. Louis, MO) diet from d 21 to 35 postpartum and were killed on d 35. Daily DES exposure was similar to that previously reported to alter the male reproductive tract (8
). Other treatments included subcutaneous injections of 10 mg of testosterone (Sigma-Aldrich)/(kg body·d), 2 mg DHT (Sigma-Aldrich)/(kg body·d) or an equivalent volume of dimethylsulfoxide (DMSO; Sigma-Aldrich) vehicle alone as a control from d 26 to 35 postpartum. Testosterone concentrations were similar to those that have been reported to autoregulate the androgen receptor (13
). Eighty percent lower DHT concentrations were investigated based on greater proportional stimulation of prostate growth compared with testosterone (14
). For injection experiments rats were fed the AIN-76A diet.
Prostate morphology was evaluated as described by Sugimura et al. (15
). We investigated effects on only the DLP based on previous observations that this is the embryologic homologue to the human prostate (7
). The prostatic complex was removed and placed in calcium- and magnesium-free PBS (Gibco, Grand Island, NY) containing 10 g/L collagenase (Gibco) for 30 min at room temperature. The DLP was separated into the dorsal prostate (DP), lateral prostate type 1 (LP1) and lateral prostate type 2 (LP2) lobes under a SMZ-1B dissecting microscope (Nikon, East Rutherford, NJ), and preliminary measurements for length and bud diameter were made (Fig. 1
). Individual lobes were fixed in formalin and whole mounts were prepared and stained with alum carmine (16
). Photographs were taken with a Coolpix 990 camera (Nikon) mounted on the dissecting microscope. Bud perimeter and main duct length were measured using Scion Image Software (Scion, Frederick, MD).
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-Reductase activity was determined in the dorsolateral lobe of the pubertal rat prostate as described by Evans et al. (17
). Fresh tissues were homogenized in Tris buffer [10 mmol/L with 1 mmol/L EDTA (pH 7.4)] and centrifuged at 800 x g for 10 min to remove cell debris. Reactions contained 5 µL of supernatant, 50 nmol/L [L-1ß,2ß-3H(N)]testosterone (New England Nuclear, Boston, MA) and 1 mmol/L NADPH in 245 µL of citrate buffer [0.1 mol/L Tris-HCl, 0.1 mol/L sodium citrate (pH 5.5)]. Reactions were incubated at 25°C for 2 h and then terminated, and steroids were extracted twice with 1.5 mL of ethyl acetate. Pooled extracts were evaporated completely under a stream of air and resuspended in 200 µL of ethanol. A total of 20 µL of each sample was separated on a thin layer chromatography plate (Sigma-Aldrich) using three passes of benzene:ethyl acetate (3:1). Areas migrating in the range of testosterone and DHT standards were scraped from the plate and counted in 5 mL of ScintiSafe liquid scintillation cocktail (Fisher Scientific, Atlanta, GA). Activity was determined as the percentage of DHT formed out of total androgens (testosterone plus DHT) per sample and is expressed relative to the mean activity of controls. We counted all regions of the migrated samples on the plate to account for product formation in addition to DHT.
RNA was isolated from the DLP using the TRIzol reagent protocol (Gibco). mRNA concentration and sample purity were calculated using the A260/280 ratio, and only samples with a ratio 
1.65 were used for the remainder of the procedure. cDNA was reverse transcribed using the Superscript Preamplification System (Gibco). The following primers were synthesized by Sigma Genosys (The Woodlands, TX): ß-actin primer 1 (5'-ATGGATGACGATATCGCTG-3') and primer 2 (5'-ATGAGGTAGTCTGTCAGGT-3') (18
); dorsal protein 1 (DP1) primer 1 (5'-TAGCATCGCAAGAACATCAGCACC-3') and primer 2 (5'-TGGTTGACCTTGCTTGTGCTCG-3'), which were designed using GeneJockey, Ferguson, MO, and Amplify, Madison, WI. Kinetic analysis was performed for each marker so that the number of cycles corresponded to the exponential range of amplification for each treatment (22 cycles for ß-actin; 16 cycles for DP1). For each cycle we used 94°C for 1 min for primer dissociation and 30 s for primer annealing (60°C for ß-actin, 67°C for DP1, and 30 s at 72°C for elongation). The polymerase chain reaction (PCR) mixture contained 3 µL of cDNA, 1.5 mmol/L MgCl2 buffer, 1 µmol/L of each primer, 0.125 mmol/L of each dNTP (dATP, dGTP, dCTP and dTTP), 10% glycerol and Taq polymerase (PerkinElmer, Branchburg, NJ). After PCR, each sample was subjected to electrophoresis on a 1.5% agarose gel using Amplisize DNA ladder (BioRad, Hercules, CA) as a marker for verification of product fragment size. Bands were visualized using ethidium bromide and gels were photographed under UV light. Band intensity was determined by densitometry and values are expressed as a raw value and as a ratio to the housekeeping gene ß-actin. Because of the small size and the prolonged processing required to isolate the LP1 from the intact DLP, DP1 mRNA expression could be analyzed only in the whole DLP rather than in individual lobes.
Sex steroids
Serum samples were frozen until analysis. Testosterone and DHT concentrations were measured with a kit (DSL, Webster, TX) according to the manufacturer’s protocols.
Statistics
Data were analyzed by one-way ANOVA and individual treatment groups were compared with the respective controls using Dunnett’s test (SigmaStat; Jandel Scientific, San Rafael, CA). Injection controls were rats injected with DMSO alone, whereas dietary controls were those fed the AIN-76A diet alone. Differences were considered significant at P < 0.05. Because there were no differences between the DMSO and AIN-76A control groups, data were reported using the mean ± SEM of only the AIN-76A group only for clarity.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Intake of 250 and 1000 mg/kg genistein for 2 wk did not alter relative DLP weights compared with rats not fed genistein (Table 1
). When administered in the diet, DES reduced relative DLP weight, and injections of the androgens, testosterone and DHT elevated relative DLP weight (P < 0.001).
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Dietary genistein did not alter circulating testosterone and DHT concentrations, whereas rats fed DES had 93% lower circulating testosterone concentrations and 71% lower DHT levels than controls (P < 0.01; Table 1
). Injections of male rats with testosterone increased (P < 0.01) circulating testosterone and DHT levels. DHT injections increased DHT, but not testosterone levels, compared with control rats.
Prostate morphogenesis
Analysis of prostate branching morphogenesis revealed 23% smaller buds of the LP1, but not LP2 or DP, in rats fed 1000 mg/kg genistein (Fig. 2
). LP1 bud perimeter was also reduced 35% by DES compared with controls. Injections of testosterone increased LP1 bud size 33% (P < 0.001) and DHT tended to increase LP1 bud size (P = 0.07). Length of the main, unbranched duct of the LP1 was also increased by testosterone and DHT and reduced by DES but was unaltered by genistein (data not shown). Buds of the LP2 were 32% smaller in rats fed DES and 39% larger in rats injected with testosterone (P < 0.001). DP buds were smaller (42%) in rats fed DES and were 15% larger in the testosterone group (P < 0.001). Neither the genistein diets nor injection of DHT significantly altered the size of the lobes of the LP2 or the DP (Fig. 2)
.
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Comparisons between morphological alterations and prostate function were delineated using DP1, a marker of prostate differentiation (19
). Reverse transcription PCR analysis indicated that rats fed DES had 77% lower expression of DP1 mRNA than rats fed the control diet alone, whereas testosterone increased expression 279% compared with controls (P < 0.001). Neither the genistein-containing diets nor DHT injections altered DP1 expression.
Because 5-reductase type II is the predominant isoform in the rat prostate and plays a prominent role in sex steroid metabolism, its activity was measured in DLP of rats fed genistein. The activity of 5-reductase type II tended to be reduced (P < 0.08) by 10 and 14% in the 250 mg/kg and 1000 mg/kg genistein diet groups, respectively.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,21
). In our study we confirmed previous reports that DLP in rats fed DES were significantly smaller than in rats fed estrogen-free diets (22
). However, exposure to genistein in the diet at concentrations up to the maximally tolerated dose in rats (23
) and mice (5
) that result in serum concentrations at the upper limit of humans consuming soy products (11
,12
) did not reduce DLP weight, apparently because of its weak estrogenic properties. Reduction in prostate weight following exposure to estrogens, including DES, is generally associated with a reduction of testosterone in the circulation (8
). In the current study, serum from rats fed DES had testosterone levels <10% of controls. However, there was no reduction in circulating androgens after exposure to genistein in the diet. We have previously demonstrated that most of the genistein in the circulation after dietary exposure is in the conjugated form (24
), which is less biologically active and may minimize feedback inhibition of luteinizing hormone. Injections of pharmacological concentrations of 100 mg genistein/(kg body·d) in male rats increased the fraction present as the aglycone, or unconjugated form, resulting in reduced circulating testosterone levels (25
).
We also investigated morphological parameters to identify subtle effects on prostate growth. Throughout pubertal development, prostatic buds elongate and undergo ductal branching morphogenesis, and epithelial cells cytodifferentiate in the presence of androgens to a functional state capable of secretory protein production (15
,26
,27
). In the rat DLP there are three morphologically distinct lobes that produce secretory products in a lobe-specific manner: the DP, LP1 and LP2 (15
,26
,27
). Bud perimeters were reduced in all lobes in the DLP of rats fed DES, similar to the effects reported previously (22
), and were increased by testosterone injection. In general, prostate bud perimeter corresponded with prostate weight and circulating testosterone concentrations. Despite the slight elevation in testosterone levels, rats fed the high dose of genistein had a smaller LP1 bud perimeter, which may reflect the slightly smaller DLP weights in rats at this age.
To determine whether the reduction in prostate bud perimeter was associated with functional impairment, we investigated expression of the biomarker DP1, a major secretory glycoprotein of the LP1 and DP (27
). Initiation of DP1 expression occurs at 
30 d postpartum in the rat prostate (19
). Therefore, toxicity resulting in impaired gland development would be most obvious in rats investigated around d 35. DP1 expression was not altered in rats fed the low or high genistein-containing diets but was drastically reduced in rats fed DES. Reduced DP1 expression in DES-fed males reflected the undeveloped state of the prostates in these rats, which was further evidenced by analysis of the distal buds, which revealed little or no luminal compartment. Despite reduction in LP1 bud perimeter in rats fed genistein at the highest concentration, we were unable to investigate higher concentrations due to a reduction in food consumption that we (unpublished observations) and others (23
) have observed. Previous gross structural analysis has shown that reduced prostate weights are frequently associated with a reduction in the total prostatic glandular and stromal compartments (28
,29
). Although rats fed genistein have smaller distal tips, they maintained secretory capacity. A previous study in this laboratory also supports the notion of adequate prostatic function in that there were no significant affects in rats fed genistein (22
,30
). We conclude that reduced LP1 size is a reflection of differentiation and is not an adverse effect on function, because production of DP1 was not altered.
The current dogma suggests that for testosterone to optimally influence prostate development it must be converted to the more potent androgen, DHT, by 5-reductase in the prostate before interacting with the androgen receptor. Previously it was demonstrated that genistein competitively inhibited 5-reductase activity in genital skin fibroblasts, albeit at supraphysiological concentrations (17
). In our studies, dietary genistein did not alter 5-reductase activity.
Based on the lack of significant effects of genistein on 5-reductase activity, it is difficult to explain the smaller LP1 bud perimeter without altered secretory capacity. In a previous investigation we reported down-regulation of the estrogen receptor without alterations to androgen receptor protein levels in the rat prostate (24
). Upregulation of prostatic estrogen receptor is associated with stromal proliferation, accompanied by reduction in epithelial differentiation (31
). Regulation of estrogen receptor confined to the stroma of the rat prostate without drastic reduction in estrogen receptor ß and the androgen receptor in the epithelium should result in reduced growth without direct effects on epithelial differentiation. Through the use of estrogen receptor knockout mice it has been demonstrated that estrogen receptor expression in the rat prostate is required for estrogenic toxicity and altered prostate growth, and that epithelial estrogen receptor ß and the androgen receptor reflect glandular differentiation (32
). Thus, preferential regulation of estrogen receptor compared with the androgen receptor may suggest such regulatory effects on growth rather than on differentiation. This suggests that diminished prostate lobular size in rats fed the higher dose of genistein observed in the current study may be due to estrogenic/antiandrogenic activity rather than through direct androgenic or antiandrogenic alterations. In contrast, through the slight modifications on androgen action in the prostate, consumption of a soy diet may provide protective effects only following prolonged exposure, with more obvious effects developing over time. This is supported by the observation that Asian men who immigrate to the United States no longer have reduced risk of prostate cancer and that the risk is inversely related to the age at arrival (3
).
The lower dose of genistein in the diet investigated in this current study resulted in 1785 nmol of total genistein/L serum (24
), which approximates the maximum concentrations (2500 nmol/L) detected in a group of Asian men consuming a traditional soy diet (11
). Also, similar concentrations have been reported in infants fed soy formula (2500 nmol genistein/L plasma) and may better approximate the period of prostate development investigated in this study (12
). The higher dose of genistein resulted in 9640 nmol genistein/L, which is likely to be at the upper limit of concentrations in humans. It is conceivable that alterations to prostate morphology observed using higher concentrations predict effects at concentrations that exceed "reasonable" human dietary exposure, and the result could be manifested later in life as altered prostatic function.
We conclude that exposure to DES in the diet significantly reduced prostate growth and function and reduced circulating testosterone concentrations. In contrast, genistein in the diet at concentrations that approximate those in the circulations of individuals consuming a soy diet did not adversely affect prostate growth or function or 5-reductase activity. It is likely that this lack of toxicity is reflective to the degree of conjugation of circulating genistein (24
) that does not reduce circulating androgens, a common effect of estrogen exposure in males (8
).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Portions of this research were presented at the Annual meeting of the American Association of Cancer Research [Fritz, W. A., Wang, J. & Lamartiniere, C. A. (2001) Dietary genistein reduces expression of the steroid biosynthetic enzymes, aromatase and 5-reductase in the male rat. Proc. Annu. Meet. Am. Assoc. Cancer Res. 42: 461.].
4 Abbreviations used: DES, diethylstilbestrol; DHT, dihydrotestosterone; DLP, dorsolateral prostate; DMSO, dimethylsulfoxide; DP, dorsal prostate; DP1, dorsal protein 1; LP1, lateral prostate type 1; LP2, lateral prostate type 2; PCR, polymerase chain reaction; T, testosterone
Manuscript received 12 April 2002. Initial review completed 3 May 2002. Revision accepted 12 July 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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