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Diet, Phytoestrogen and Gene Nutrient Interactions in Relation to Cancer: A Prospective Study


To investigate the risks of breast and bowel cancer associated with phytoestrogens in a UK population exposed to low levels of phytoestrogens.

Approaches: <OL> <LI>

A highly sensitive and rapid method for the analysis of phytoestrogens by a single solid phase extraction then GC/MS or LC/MS, incorporating 13C labelled standards in urine and plasma was developed.

<LI> This method was applied to previously collected stored plasma and urine samples in a prospective study of diet and cancer (European Prospective Investigation of Cancer, EPIC Norfolk) using a nested case control study design. Using published isoflavone food analyses from a previously funded FSA project, a dietary data base was formed in order that food intake could be calculated from 7 day diaries collected in EPIC.

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Key Findings:

An accurate, sensitive, fast and inexpensive method was developed with limits of detection ranging from 1 to 5 ng/ml in urine by GC/MS and from 40 to 111 pg/ml in plasma by LC/MS. About 100 samples per week could be analysed using only 200ul of sample and at relatively low cost. This analytical system, funded by the Agency, will have profound effects on the ability to investigate in epidemiological studies the health effects of phytoestrogens in a number of human diseases of late and middle age, such as osteoporosis, cardiovascular disease and breast, prostate, and bowel cancer.

There were very high (r>0.8) correlations between phytoestrogens measured in spot urine samples and phytoestrogens in plasma. This means that either can be used as biomarkers of phytoestrogen exposure if dietary intakes are not available. The correlations between diet and plasma and diet and urine were lower (in the order of r = 0.3) probably due to inaccuracies in the dietary data base which was formulated from analyses made prior to the introduction of 13C standards. Nevertheless, there were significant trends (p<0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes.
Contrary to expectations, exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, relative risk increased by 20 to 45%; (log2 relative risk 1.344 (1.063-1.699) p = 0.013 for urine equol and 1.455 (1.051-2.017) p = 0.024 for serum equol) and for serum daidzein log2 1.220 (1.005 – 1.481) p = 0.044. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies. Associations with diet followed a similar trend but the relative risks were not significant.
There was evidence of an interaction between a genetic variant and phytoestrogens on influencing serum estradiol levels in women. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein and serum daidzein and glycitein were negatively correlated with plasma estradiol (R=-0.199 to -0.277, p<0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R= -0.597 to -0.834, p<0.03) who had elevated estradiol levels.
In prostate cancer there were no significant elevations of prostate cancer risk with phytoestrogen exposure from diet, urine or plasma although there was a suggestion that levels of one phytoestrogen, equol, were associated with an increased risk, as in breast cancer. Men with CC genotype for ESR1 PvuII polymorphism were found to have significantly higher risk for prostate cancer (adjusted odds ratio = 4.49 (1.51- 13.3) p=0.007) compared to men with TT genotype. In addition, phytoestrogens appeared to interact with CYP19 polymorphism to affect testosterone levels in men. Equol and enterolactone levels were positively correlated with plasma testosterone levels (R=0.288 to 0.452, p<0.05) in men with TT genotype for the CYP19 3’ untranslated region t-c polymorphism but not in men with CC and CT genotypes.
These studies were insufficiently powered to reliably investigate interactions with genetic variants and the findings in relation to breast and prostate cancer require confirmation in larger studies, which are on-going.
<P>The final report, "<a href="; target="_new">Diet, Phytoestrogen and Gene Nutrient Interactions in Relation to Cancer: A Prospective Study</A>" is available at Foodbase, an open access repository of the <acronym title="Food Standards Agency"> FSA</acronym>.<P>

Find more about this project and other FSA food safety-related projects at the <a href="; target="_blank">Food Standards Agency Research webpage</a>.

MRC Dunn Nutrition Unit
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