Benefits of soy-based feeds for fetal estrogen levels and obesity in adulthood

Abstract only availableWe examined the effect of maternal exposure to naturally occurring estrogenic chemicals in diets on circulating levels of estradiol in mouse fetuses. An animal's specific response to estrogen can vary according to the time of exposure. The time when the fetus is sensitive to permanent “programming” effects of estrogen is called a “critical period” in development of organ systems. An important factor in the regulation of estrogen in the fetus is the composition of the mother's diet. Our hypothesis was that if a diet that was fed to pregnant mice during the fetal critical period contained estrogenic chemicals, these chemicals would “estrogenize” the fetus. In contrast to this prediction, a casein-based diet with virtually no estrogenic chemicals led to significantly higher levels of endogenous estradiol relative to a soy-based diet with very high levels of estrogenic chemicals. In a follow-up experiment we compared a soy-based diet containing estrogenic chemicals with a soy-based diet from which these estrogenic chemicals were extracted. The complete soy diet resulted in estrodiol levels of 60 pg/ml in fetal serum, while the extracted soy diet dramatically increased serum estradiol by over 50%. This finding shows that the naturally occurring estrogens in soy (phytoestrogens) fed to pregnant mice reduce endogenous estradiol levels in the fetuses. This is important since elevated levels of estradiol during fetal life "program" certain characteristics into the animal later on in adulthood. One of these characteristics is obesity. Obesity is associated with Type II diabetes, and the mice with elevated fetal estradiol levels show evidence of impaired glucose tolerance in later adulthood. These effects are relevant since obesity and diabetes are abnormalities in humans that are increasing.Life Sciences Undergraduate Research Opportunity Progra

Celecoxib concentration predicts decrease in prostaglandin E\u3csub\u3e2\u3c/sub\u3e concentrations in nipple aspirate fluid from high risk women

BACKGROUND: Epidemiologic studies suggest that long term low dose celecoxib use significantly lowers breast cancer risk. We previously demonstrated that 400 mg celecoxib taken twice daily for 2 weeks lowered circulating plasma and breast nipple aspirate fluid (NAF) prostaglandin (PG)E2 concentrations in post- but not premenopausal high risk women. We hypothesized that circulating concentrations of celecoxib influenced PGE2 response, and that plasma levels of the drug are influenced by menopausal status. To address these hypotheses, the aims of the study were to determine: 1) if circulating plasma concentrations of celecoxib correlated with the change in plasma or NAF PGE2 concentrations from baseline to end of treatment, and 2) whether menopausal status influenced circulating levels of celecoxib. METHODS: Matched NAF and plasma were collected from 46 high risk women who were administered celecoxib twice daily for two weeks, 20 subjects receiving 200 mg and 26 subjects 400 mg of the agent. NAF and plasma samples were collected before and 2 weeks after taking celecoxib. RESULTS: In women taking 400 mg bid celecoxib, plasma concentrations of the agent correlated inversely with the change in NAF PGE2 levels from pre- to posttreatment. Nonsignificant trends toward higher celecoxib levels were observed in post- compared to premenopausal women. There was a significant decrease in NAF but not plasma PGE2 concentrations in postmenopausal women who took 400 mg celecoxib (p = 0.03). CONCLUSION: In high risk women taking 400 mg celecoxib twice daily, plasma concentrations of celecoxib correlated with downregulation of PGE2 production by breast tissue. Strategies synergistic with celecoxib to downregulate PGE2 are of interest, in order to minimize the celecoxib dose required to have an effect

A human relevent rat model of breast cancer

Abstract only availableBecause women experience a bewildering array of chemicals, foods and lifestyles, only profound effects on preventing or promoting breast cancer are detectible in human studies. Subtle or delayed effects can be detected in animal models. Mammary tumors in ACI rats share important similarities with the majority of human breast cancers. The link between life time estrogen exposure and breast cancer risk in humans is well established. A high percentage of human breast cancers express ER, are stimulated to grow by the addition of exogenous estrogen, and respond to the antiestrogen tamoxifen. The ACI rat is the only rodent model in which estrogen-sensitive tumors are induced by estrogen. The ACI.COP-Ept2 substrain, derived from the ACI rat, develops mammary tumors similar to those of the ACI rat, but with reduced pituitary hyperplasia. We show that estrogen-induced mammary tumors in ACI.COP-Ept2 express ERα and respond to tamoxifen. Furthermore, tumors express ERβ, progesterone receptor and Her2/neu. The average latency was 183±6 days (n=24) and average tumor burden 1,107±415 mm3. The similarities of ACI.COP-Ept2 tumors to human breast cancers make this a valuable model for determining which of the myriad of lifestyle and diet choices reportedly protecting women from breast cancer actually reduce cancer incidence.Food for the 21st Century Undergraduate Research Program in Nutritional Science

Estradiol and Bisphenol A Stimulate Androgen Receptor and Estrogen Receptor Gene Expression in Fetal Mouse Prostate Mesenchyme Cells

doi:10.1289/ehp.9804Hormonal alterations during development have lifelong effects on the prostate gland. Endogenous estrogens, including 17β-estradiol (E2), and synthetic estrogenic endocrine disruptors, such as bisphenol A (BPA), have similar effects on prostate development. Increasing exposure to estrogens within the low-dose, physiologic range results in permanent increases in the size and androgen responsiveness of the prostate, whereas exposure within the high-dose, pharmacologic range has the opposite effects

Soy isoflavones have an antiestrogenic effect and alter mammary promoter hypermethylation in healthy premenopausal women1

We hypothesized that soy isoflavones would have dose related estrogenic and methylation effects. 34 healthy premenopausal women were prospectively enrolled and randomized in double-blind fashion to receive either 40 mg or 140 mg isoflavones daily through one menstrual cycle. Breast specific (NAF) and systemic (serum) estrogenic effects were assessed measuring the estrogenic marker complement (C)3 and changes in cytology, while methylation effects were evaluated in mammary ductoscopy (MD) specimens using methylation specific PCR assessment of five genes (p16, RASSF1A, RARβ2, ER, and CCND2) associated with breast carcinogenesis. Serum genistein significantly increased post treatment in women consuming both isoflavone doses. Neither NAF nor MD cytology significantly changed after either low or high dose isoflavones. Serum C3 levels post treatment were inversely related to change in serum genistein (r= -0.76, p=0.0045) in women consuming low dose isoflavones. RARβ2 hypermethylation increased post treatment correlated with the post treatment level of genistein among all subjects (r=0.67, p=0.0017) and in women receiving high dose isoflavones (r=0.68, p=0.021). At the low dose, CCND2 hypermethylation increase correlated with post treatment genistein levels (r=0.79, p=0.011). The inverse correlation between C3 and genistein suggests an antiestrogenic effect. Isoflavones induced dose specific changes in RARβ2 and CCND2 gene methylation which correlated with genistein levels. This work provides novel insights into estrogenic and methylation effects of dietary isoflavones.

Low Phytoestrogen Levels in Feed Increase Fetal Serum Estradiol Resulting in the “Fetal Estrogenization Syndrome” and Obesity in CD-1 Mice

doi:10.1289/ehp.10448Although estrogenic chemicals can disrupt development of the reproductive system, there is debate about whether phytoestrogens in soy are beneficial, benign, or harmful. We compared reproductive and metabolic characteristics in male and female mice reared and maintained on non-soy low-phytoestrogen feed or soy-based high-phytoestrogen feed. Removing phytoestrogens from mouse feed produces an obese phenotype consistent with metabolic syndrome, and the associated reproductive system abnormalities are consistent with FES due to elevated endogenous fetal estradiol. Laboratory rodents may have become adapted to high-phytoestrogen intake over many generations of being fed soy-based commercial feed; removing all phytoestrogens from feed leads to alterations that could disrupt many types of biomedical research

Bisphenol A Is Released from Used Polycarbonate Animal Cages into Water at Room Temperature

doi:10.1289/ehp.5993Bisphenol A (BPA) is a monomer with estrogenic activity that is used in the production of food packaging, dental sealants, polycarbonate plastic, and many other products. The monomer has previously been reported to hydrolyze and leach from these products under high heat and alkaline conditions, and the amount of leaching increases as a function of use. We examined whether new and used polycarbonate animal cages passively release bioactive levels of BPA into water at room temperature and neutral pH. Purified water was incubated at room temperature in new polycarbonate and polysulfone cages and used (discolored) polycarbonate cages, as well as control (glass and used polypropylene) containers. The resulting water samples were characterized with gas chromatography/mass spectrometry (GC/MS) and tested for estrogenic activity using an MCF-7 human breast cancer cell proliferation assay. Significant estrogenic activity, identifiable as BPA by GC/MS (up to 310 µg/L), was released from used polycarbonate animal cages. Detectable levels of BPA were released from new polycarbonate cages (up to 0.3 µg/L) as well as new polysulfone cages (1.5 µg/L), whereas no BPA was detected in water incubated in glass and used polypropylene cages. Finally, BPA exposure as a result of being housed in used polycarbonate cages produced a 16% increase in uterine weight in prepubertal female mice relative to females housed in used polypropylene cages, although the difference was not statistically significant. Our findings suggest that laboratory animals maintained in polycarbonate and polysulfone cages are exposed to BPA via leaching, with exposure reaching the highest levels in old cages.Support during the preparation of this manuscript was provided by grants from the National Institutes of Health (CA50354) and the University of Missouri (VMFC0018) to W.V.W., NIH (ES08293 and ES11283) to F.v.S., and the U.S.G.S

Low Phytoestrogen Levels in Feed Increase Fetal Serum Estradiol Resulting in the “Fetal Estrogenization Syndrome” and Obesity in CD-1 Mice

doi:10.1289/ehp.10448Although estrogenic chemicals can disrupt development of the reproductive system, there is debate about whether phytoestrogens in soy are beneficial, benign, or harmful. We compared reproductive and metabolic characteristics in male and female mice reared and maintained on non-soy low-phytoestrogen feed or soy-based high-phytoestrogen feed. Removing phytoestrogens from mouse feed produces an obese phenotype consistent with metabolic syndrome, and the associated reproductive system abnormalities are consistent with FES due to elevated endogenous fetal estradiol. Laboratory rodents may have become adapted to high-phytoestrogen intake over many generations of being fed soy-based commercial feed; removing all phytoestrogens from feed leads to alterations that could disrupt many types of biomedical research

Celecoxib concentration predicts decrease in prostaglandin E2 concentrations in nipple aspirate fluid from high risk women

<p>Abstract</p> <p>Background</p> <p>Epidemiologic studies suggest that long term low dose celecoxib use significantly lowers breast cancer risk. We previously demonstrated that 400 mg celecoxib taken twice daily for 2 weeks lowered circulating plasma and breast nipple aspirate fluid (NAF) prostaglandin (PG)E₂concentrations in post- but not premenopausal high risk women. We hypothesized that circulating concentrations of celecoxib influenced PGE₂response, and that plasma levels of the drug are influenced by menopausal status. To address these hypotheses, the aims of the study were to determine: 1) if circulating plasma concentrations of celecoxib correlated with the change in plasma or NAF PGE₂concentrations from baseline to end of treatment, and 2) whether menopausal status influenced circulating levels of celecoxib.</p> <p>Methods</p> <p>Matched NAF and plasma were collected from 46 high risk women who were administered celecoxib twice daily for two weeks, 20 subjects receiving 200 mg and 26 subjects 400 mg of the agent. NAF and plasma samples were collected before and 2 weeks after taking celecoxib.</p> <p>Results</p> <p>In women taking 400 mg bid celecoxib, plasma concentrations of the agent correlated inversely with the change in NAF PGE₂levels from pre- to posttreatment. Nonsignificant trends toward higher celecoxib levels were observed in post- compared to premenopausal women. There was a significant decrease in NAF but not plasma PGE₂concentrations in postmenopausal women who took 400 mg celecoxib (p = 0.03).</p> <p>Conclusion</p> <p>In high risk women taking 400 mg celecoxib twice daily, plasma concentrations of celecoxib correlated with downregulation of PGE₂production by breast tissue. Strategies synergistic with celecoxib to downregulate PGE₂are of interest, in order to minimize the celecoxib dose required to have an effect.</p