This Program Project will use rodent models to evaluate the effects of exposure to dietary estrogens at various points in the lifespan on disease processes associated with aging. These include breast tumor growth, obesity and cognitive decline, which is the focus of this project. The central premise is that the dose, timing of exposure during the lifespan and target tissue will determine whether the biological effects are beneficial or detrimental. Doses and exposure periods that have beneficial effects in one tissue may have detrimental effects in others. The initial specific aim of this project is to characterize the effects of low and high physiologic doses of estrogen replacement on cognitive function in ovariectomized young, middle-aged and old female rats. These studies will establish a detailed profile of estrogen actions on a broad range of cognitive functions, determine whether the profile of effects differs in young, middle-aged and old rats, and elucidate the effects of low vs. high physiologic levels of estrogen in young middle-aged and old rats. The focus will be on tests of executive functions such as cognitive flexibility, working memory, attention, and response inhibition. The role of estrogens in regulating these aspects of cognition is not well understood, particularly in rodent models. Detailed analysis of response patterns across trials will help to identify the underlying behavioral mechanisms response for estrogen-mediated changes in cognition.
The second aim i s to test ovariectomized young, middle-aged and old rats exposed to low, medium or high physiologic doses of soy isoflavones on the same battery of tests. Pure soy isoflavones including genistein and equol will be tested first followed by the commercial mixture, Novasoy. These studies will establish a profile of soy effects of soy isoflavones on cognition and identify differences between these compounds and estradiol. An ancillary goal is to measure adipose deposition in the same rats that are tested for cognitive function. Assessing two critical health endpoints in the same animals will allow us to determine how the dose-response and pattern of beneficial vs. harmful effects for the two endpoints are related.
The final aim i s to use selective estrogen receptor alpha (ERalpha) and beta (ERbeta) antagonists to investigate the role of ERalpha and ERbeta in mediating the actions of soy isoflavones on cognition. Because soy isoflavones show selectivity for ERbeta, we expect them to differentially effect cognitive functions regulated primarily by ERbeta. Together with the other projects in this program these studies will help to define the risk and benefits to older women from consuming dietary estrogens.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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University of Illinois Urbana-Champaign
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Pisani, Samantha L; Neese, Steven L; Katzenellenbogen, John A et al. (2016) Estrogen Receptor-Selective Agonists Modulate Learning in Female Rats in a Dose- and Task-Specific Manner. Endocrinology 157:292-303
Ferguson, Lynnette R; Chen, Helen; Collins, Andrew R et al. (2015) Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol 35 Suppl:S5-S24
Andrade, Juan E; Ju, Young H; Baker, Chandra et al. (2015) Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model. Mol Nutr Food Res 59:413-23
Korol, Donna L; Pisani, Samantha L (2015) Estrogens and cognition: Friends or foes?: An evaluation of the opposing effects of estrogens on learning and memory. Horm Behav 74:105-15
Yang, Xujuan; Belosay, Aashvini; Du, Mengyuan et al. (2013) Estradiol increases ER-negative breast cancer metastasis in an experimental model. Clin Exp Metastasis 30:711-21
Neese, Steven L; Bandara, Suren B; Schantz, Susan L (2013) Working memory in bisphenol-A treated middle-aged ovariectomized rats. Neurotoxicol Teratol 35:46-53
Neese, Steven L; Korol, Donna L; Schantz, Susan L (2013) Voluntary exercise impairs initial delayed spatial alternation performance in estradiol treated ovariectomized middle-aged rats. Horm Behav 64:579-88
Pisani, Samantha L; Neese, Steven L; Doerge, Daniel R et al. (2012) Acute genistein treatment mimics the effects of estradiol by enhancing place learning and impairing response learning in young adult female rats. Horm Behav 62:491-9
Bergamaschi, A; Katzenellenbogen, B S (2012) Tamoxifen downregulation of miR-451 increases 14-3-3? and promotes breast cancer cell survival and endocrine resistance. Oncogene 31:39-47
Neese, Steven L; Bandara, Suren B; Doerge, Daniel R et al. (2012) Effects of multiple daily genistein treatments on delayed alternation and a differential reinforcement of low rates of responding task in middle-aged rats. Neurotoxicol Teratol 34:187-95

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