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Phytoestrogen Exposure Is Associated with Circulating Sex Hormone Levels in Postmenopausal Women and Interact with ESR1 and NR1I2 Gene Variants

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Phytoestrogen Exposure Is Associated with Circulating Sex Hormone Levels in Postmenopausal Women and Interact with ESR1 and NR1I2 Gene Variants 1009 Phytoestrogen Exposure Is Associated with Circulating Sex Hormone Levels in Postmenopausal Women and Interact with ESR1 and NR1I2 Gene Variants Yen-Ling Low,1 Alison M. Dunning,2 Mitch Dowsett,3 Elizabeth Folkerd,3 Deborah Doody,3 James Taylor,1 Amit Bhaniani,4 Robert Luben,4 Kay-Tee Khaw,4 Nick J. Wareham,4 and Sheila A. Bingham1,4 1Medical Research Council Dunn Human Nutrition Unit; 2Cancer Research-UK Department of Oncology,Strangeways Research Laboratory; 3Institute of Cancer Research,London,United Kingdom; and 4European Prospective Investigation of Cancer and Nutrition-Norfolk,Strangeways Research Laboratory,Cambridge,United Kingdom Abstract h 2 P In this large cross-sectional study, we investigated the levels ( p = 1.2%; < 0.001) and negativelyassociated with h 2 P relationship between phytoestrogen exposure and circulat- plasma testosterone ( p = 0.2%; = 0.042). Equol was h 2 ing sex hormones and sex hormone-binding globulin negativelyassociated with plasma estradiol levels ( p = 0.3%; (SHBG) levels in 1988 healthypostmenopausal women and P = 0.028), whereas O-desmethylangolensin was positively h 2 P their interactions with polymorphisms in genes involved in associated with plasma estradiol level ( p = 0.3%; = 0.010). estrogen signaling. Plasma estradiol, testosterone, androste- There were significant phytoestrogen interactions with poly- nedione, estrone, and SHBG were measured. Urinarylevels morphisms in ESR1 and NR1I2 genes in affecting estrone of five isoflavones (daidzein, genistein, glycitein, O-desme- levels. We conclude that phytoestrogens modulate sex thylangolensin, and equol) and two lignans (enterodiol and hormone and SHBG levels in postmenopausal women and enterolactone) were measured and used as biomarkers interact with gene variants involved in estrogen signaling. for dietaryintakes. Eighteen polymorphisms in ESR1, Such phytoestrogen-gene interactions may explain the ESR2, and NR1I2 genes were genotyped. Results showed conflicting literature on the hormonal effects of phytoestro- that lignans were positivelyassociated with plasma SHBG gens. (Cancer Epidemiol Biomarkers Prev 2007;16(5):1009–16) Introduction Phytoestrogens are diphenolic compounds in plants that NR1I2 (nuclear receptor subfamily 1, group I, member 2) gene. On subsequently form part of the human diet. Dietary phytoes- activation through ligand binding,PXR binds to the response trogens can be classified principally into isoflavones and element and induces the expression of CYP3A4, which plays a lignans. Isoflavones are found mainly in legumes,with major role in the hydroxylation of both estrone and estradiol. exceptionally high amounts in soy. Lignans are widespread PXR is mainly expressed in the liver and gut,the main sites of in many grains,fruit,and vegetables with flaxseed being the phytoestrogen exposure and metabolism. Phytoestrogens are richest source. able to bind to PXR in vitro (9-11). Hence,it is plausible that Phytoestrogens are structurally similar to 17h-estradiol and phytoestrogens may modulate estrogen levels through signal- have been postulated to possess hormonal properties that ing via PXR binding. might protect against breast cancer (1,2). Phytoestrogens may We have recently investigated diet-gene interactions be- directly modulate concentrations of circulating estradiol and tween phytoestrogen exposure and sex hormone metabolism sex hormone-binding globulin (SHBG) by inhibiting enzymes genes (CYP19, HSD17B1,and SHBG) and found significant involved in estrogen biosynthesis and metabolism (3) and interaction between isoflavones and SHBG D356N polymor- stimulating SHBG production (4-6). In addition,phytoestro- phism in affecting circulating SHBG levels in postmenopausal gens may exert its hormonal effects through direct signaling. women (12). Lesser is known about interactions between Phytoestrogens have been shown to bind to both estrogen phytoestrogens and estrogen signaling genes. In a previous receptor a and estrogen receptor h (7),which are encoded by study on 125 postmenopausal women,we found that ESR1 and ESR2 genes,respectively. In 1998,a new receptor isoflavone exposure correlated positively with plasma estra- known as the pregnane X receptor (PXR; also known as the diol and observed evidence of interaction with ESR1 PvuII steroid and xenobiotic receptor) has been discovered. PXR is a polymorphism (13). However,the study was small and only a broad-specificity,orphan nuclear receptor (8). Its ligands few polymorphisms were investigated. The interaction with include a wide variety of structurally diverse,low-affinity PvuII polymorphism was hard to interpret as the PvuII exogenous and endogenous chemicals. PXR is encoded by the polymorphism lies in an intron and has no known function. It may be in linkage disequilibrium with another unknown polymorphism that may be functional. With the use of haplotype-tagging single nucleotide polymorphisms (SNP),it Received 10/24/06; revised 2/4/07; accepted 2/20/07. Grant support: UK Medical Research Council,Cancer Research UK and the Agency for would now be possible to examine the whole gene to identify Science,Technology and Research,Singapore. all SNPs that may be truly functional. The costs of publication of this article were defrayed in part by the payment of page charges. Hence,this large cross-sectional study has two aims: (a )to This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. investigate the relationship between phytoestrogen exposure Requests for reprints: Sheila A. Bingham,Medical Research Council Dunn Human Nutrition and circulating sex hormone levels in healthy postmenopausal Unit,Wellcome Trust/Medical Research Council Dunn Human Nutrition Unit Building, women and (b) to investigate if such relationships are modified Hills Road,Cambridge CB2 2XY,United Kingdom. Phone: 44-1223-252760; Fax: 44-1223-252765. E-mail: [email protected] by polymorphisms in genes involved in estrogen signaling. Copyright D 2007 American Association for Cancer Research. Phytoestrogen exposure was assessed using urinary phytoes- doi:10.1158/1055-9965.EPI-06-0899 trogens as biomarkers. These were studied in association with Cancer Epidemiol Biomarkers Prev 2007;16(5). May 2007 Downloaded from cebp.aacrjournals.org on September 24, 2021. © 2007 American Association for Cancer Research. 1010 Phytoestrogen-Gene Interactions with Sex Hormones circulating levels of estradiol,estrone,testosterone,androste- order: estradiol,testosterone,SHBG,androstenedione,and nedione,and SHBG and 18 polymorphisms in ESR1, ESR2, estrone. More than 98% of the subjects had sufficient plasma and NR1I2 genes. samples to complete the measurements of estradiol,testoster- one,and SHBG. Seventy-one percent of the subjects had sufficient plasma samples to complete androstenedione meas- Patients and Methods urements,whereas 55% of subjects had sufficient plasma samples for estrone measurements. StudySubjects. The European Prospective Investigation of Estradiol was measured from plasma by RIA after ether Cancer and Nutrition (EPIC) is a large multicenter prospective extraction (18). Testosterone was measured using a solid-phase study initiated in 1993 with the aim of investigating the RIA kit (Diagnostic Products). SHBG was measured using a relationship between diet and cancer (14). EPIC-Norfolk is part liquid-phase immunoradiometric kit (Orion Diagnostica). of the United Kingdom arm of this Europe-wide program (15). Androstenedione was measured using a solid-phase RIA kit Men and women ages 45 to 75 years resident in Norfolk, (Diagnostic Systems Laboratories). Estrone was extracted with United Kingdom were recruited in 1993 to 1997 using general ether and liquid column chromatography on a Lipidex 5000 practice age sex registers. Participants (30,452) completed a (Perkin-Elmer) with elution using chloroform/hexane/metha- health questionnaire and gave written informed consent. nol (50:50:1) and then measured using a RIA kit. CVs for assays Permission for the study was obtained from The Norfolk and were determined using nonblinded quality control samples. Norwich Hospital Ethics Committee. Individuals (25,630) The within-batch CVs ranged from 2.1% (SHBG) to 14% attended a medical examination and gave blood and an (estrone) and the between-batch CVs ranged from 7.4% untimed spot urine sample. All subjects were healthy at the (SHBG) to 22% (estrone). Details on detection limits and time of recruitment. Details on the study design and sample quality control have been described elsewhere (19). collection had been reported previously (15). Participants were Selection of SNPs for Genotyping. The ESR1 PvuII SNP invited to attend a follow-up health check in 1998 to 2000 and SNPs in ESR2 gene were selected based on available where updated health and dietary information was collected information on known SNPs in these genes at the time of and further blood and urine samples were taken. Subjects also genotyping. Additional SNPs were chosen in ESR1 gene as filled in a Physical Activity questionnaire and the information haplotype-tagging SNPs to tag the linkage disequilibrium was used to derive a self-reported physical activity index for block in ESR1 gene where the PvuII SNP is located. SNPs in each subject (16). the NR1I2 gene were chosen to efficiently tag the known SNPs For this study,we randomly selected 2003 healthy women in the gene. from a subset of women >55 years old who had reported no SNPs in ESR1 gene were identified from the National
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