Long-term Dietary Cadmium Intake and Postmenopausal Endometrial Cancer Incidence: A Population-Based Prospective Cohort Study Agneta A ˚ kesson, Bettina Julin, and Alicja Wolk Institute of Environmental Medicine, Division of Nutritional Epidemiology, Karolinska Institutet, Stockholm, Sweden Abstract Environmental pollutants mimicking the effects of estrogen aresuggestedtocontributetothehighincidenceofhormone- related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-A, has been shown in vivo . We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population- based prospective cohort of 30,210 postmenopausal women freeofcancerdiagnoseatbaseline(1987)andwhocompleted a food frequency questionnaire at baseline and in 1997. We estimatedthedietarycadmiumintakebasedonthequestion- nairedataandthecadmiumcontentinallfoods.During16.0 years(484,274person-years)offollow-upbetweenthebaseline and mid-2006, we ascertained 378 incident cases of endome- trioid adenocarcinoma. The average estimated dietary cad- miumintakewas15 Mg/day(80%fromcerealsandvegetables). Cadmiumintakewasstatisticallysignificantlyassociatedwith increased risk of endometrial cancer in all women; the multivariate relative risk (RR) was 1.39 [95% confidence interval (CI), 1.04–1.86; P trend = 0.019], comparing highest tertileversuslowest.Amongnever-smokingwomenwithbody massindex(BMI)of<27kg/m 2 ,theRRwas1.86(95%CI,1.13– 3.08; P trend = 0.009). We observed a 2.9-fold increased risk (95%CI,1.05–7.79)associatedwithlong-termcadmiumintake consistently above the median at both baseline 1987 and in 1997innever-smokingwomenwithlowbioavailableestrogen (BMI of <27 kg/m 2 and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers. [Cancer Res 2008;68(15):6435–41] Introduction It has been suggested that environmental pollutants that mimic the effects of estrogen contribute to the high incidence of hormone-related cancers in Western populations (1). Although this hypothesis has received extensive media attention, data have hitherto been sparse in supporting such associations in humans (2). More recently, cadmium, one of the most serious environ- mental pollutants (1, 3), was proposed as a potent metallestrogen (1, 4–6). Cadmium increases estrogen receptor a–mediated cell proliferation (7) and possessed mutagenic properties (8, 9). Although some in vitro estrogenicity assays showed no activity (10), environmentally relevant doses of cadmium induced several well-characterized estrogenic responses in vivo , including in- creased uterine weight, hyperplasia, and hypertrophy of the endometrial lining, induction of uterine progesterone receptor, and complement C3 gene expression in animals (4). In addition, after in utero exposure, cadmium affected mammary gland development and early onset of puberty in female offspring— both prototypical endocrine disruptor–like responses (4). Cadmi- um has been widely dispersed into the environment through industrial emission, waste incineration, and combustion of fossil fuels. Even in industrially nonpolluted areas, farm land may become contaminated by airborne deposition and by use of cadmium-containing fertilizers and sewage sludge. A high accumulation in agricultural crops results in the fact that plant foods contribute to >80% of the total cadmium intake, with bread, cereals, potatoes, roots, and vegetables being the major sources (11). Endometrial cancer is the cancer most suited for exploring potential estrogenic effects of cadmium. Estrogen unopposed by progesterone or synthetic progestins is the main factor influencing the risk of this cancer (12). We examined prospectively whether the estrogenic properties of cadmium could be confirmed by a direct association between food- cadmium and increased risk of endometrial cancer in the large population-based Swedish Mammography Cohort. Subjects and Methods Study population. The Swedish Mammography Cohort was established between 1987 and 1990, when all women who were born between 1914 and 1948 and residing in two counties in Central Sweden received a mailed questionnaire concerning diet, weight, height, education, and parity; 66,651 women responded to the questionnaire (74% response rate). Supplementary information on age at menarche and menopause and postmenopausal hormone use was obtained in part of the cohort. A follow-up questionnaire was sent to all 56,030 participants who were still alive and living in the study area in the autumn of 1997 to update dietary data and to collect information on other life-style factors, including smoking habits, physical activity, age at menarche and menopause, use of postmenopausal hormones, and medical history of diabetes mellitus (additional diabetes information was obtained by computerized linkage of the cohort with the National Hospital Discharge Registry). The response rate was 70%. The study was approved by the Regional Ethical Review Board in Stockholm, Sweden. Assessment of diet and covariates. At baseline, a 67-item food frequency questionnaire (FFQ) was used to assess dietary intake. An expanded 96-item FFQ was used to update information on dietary intake in 1997. The baseline FFQ has been validated in a subsample of 129 women randomly chosen from the study population. The Pearson correlation coefficients (r ) between the FFQ and the mean of 4 1-wk weighted diet Requests for reprints: Agneta A ˚ kesson, Institute of Environmental Medicine, Division of Nutritional Epidemiology, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden. Phone: 46-8-524-875-42; Fax: 46-8-30-45-71; E-mail: Agneta.Akesson@ki.se. I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-0329 www.aacrjournals.org 6435 Cancer Res 2008; 68: (15). 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