By the year 2025, 19.5% of the population of the U.S. will be post-menopausal aged women. Many health risks are associated with menopause, thus, research into menopause and aging in women is of prime interest. Investigations of menopause-associated disorders in a relevant animal model would be particularly useful. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) has been well characterized and found to induce pre-mature ovarian failure in mice and rats by accelerating the natural process of atresia (apoptosis). More recently, preliminary data have demonstrated that VCD-induced follicle loss in mice can cause depletion of primordial follicles within 15 days of daily dosing. This results in complete ovarian failure within 46 days of the onset of dosing, and the animals retain residual ovarian tissue. Physiological end points related to several menopause-associated disorders, including osteoporosis, cardiovascular disease, and ovarian cancer have been observed in VCD-treated mice. The majority of women enter menopause by a gradual depletion of ovarian function and they retain residual ovarian tissue. Thus, a follicle-deplete, ovary-intact animal would most closely mimic the natural progression through peri-menopause and into the post-menopausal stage of life. It is proposed here to conduct studies to more completely characterize the physiological end points that have already been seen. The hypothesis to be tested is that the VCD-treated mouse will serve as a highly relevant animal model for studies aimed at understanding many of the facets of menopause.
Four Specific Aims have been proposed:
Specific Aim 1 : To determine events surrounding the period of impending ovarian failure (model for peri-menopause) Specific Aim 2: To investigate mechanisms by which osteocalcin levels are elevated (model for osteoporosis) Specific Aim 3: To characterize the development of aortic lesions (model for cardiovascular disease) Specific Aim 4: To evaluate changes resulting from proliferation of the ovarian surface epithelium (model for ovarian cancer). The studies proposed here will provide evidence in the follicle-deplete, ovary-intact mouse as to what aspects of menopausal physiology and pathology are particularly relevant for designing future studies aimed at mechanistic or therapeutic issues. Characterization of the VCD-treated mouse will, therefore, make a profound contribution to the study of menopause-related pathologies and, therefore, to women's health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG021948-04
Application #
7025011
Study Section
Special Emphasis Panel (ZRG1-END (01))
Program Officer
Fuldner, Rebecca A
Project Start
2003-05-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$341,116
Indirect Cost
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Brooks, H L; Pollow, D P; Hoyer, P B (2016) The VCD Mouse Model of Menopause and Perimenopause for the Study of Sex Differences in Cardiovascular Disease and the Metabolic Syndrome. Physiology (Bethesda) 31:250-7
Diamond-Stanic, Maggie K; Romero-Aleshire, Melissa J; Hoyer, Patricia B et al. (2011) Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause. Am J Physiol Renal Physiol 300:F139-46
Craig, Zelieann R; Marion, Samuel L; Funk, Janet L et al. (2010) Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice. J Osteoporos 2010:
Appt, Susan E; Chen, Haiying; Goode, Amanda K et al. (2010) The effect of diet and cardiovascular risk on ovarian aging in cynomolgus monkeys (Macaca fascicularis). Menopause 17:741-8
Hariri, Lida P; Liebmann, Erica R; Marion, Samuel L et al. (2010) Simultaneous optical coherence tomography and laser induced fluorescence imaging in rat model of ovarian carcinogenesis. Cancer Biol Ther 10:438-47
Craig, Zelieann R; Davis, John R; Marion, Samuel L et al. (2010) 7,12-dimethylbenz[a]anthracene induces sertoli-leydig-cell tumors in the follicle-depleted ovaries of mice treated with 4-vinylcyclohexene diepoxide. Comp Med 60:10-7
Appt, Susan E; Clarkson, Thomas B; Hoyer, Patricia B et al. (2010) Experimental induction of reduced ovarian reserve in a nonhuman primate model (Macaca fascicularis). Comp Med 60:380-8
Romero-Aleshire, Melissa J; Diamond-Stanic, Maggie K; Hasty, Alyssa H et al. (2009) Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 297:R587-92
Appt, Susan E; Clarkson, Thomas B; Chen, Haiying et al. (2009) Serum antimüllerian hormone predicts ovarian reserve in a monkey model. Menopause 16:597-601
Rivera, Zelieann; Christian, Patricia J; Marion, Sam L et al. (2009) Steroidogenic capacity of residual ovarian tissue in 4-vinylcyclohexene diepoxide-treated mice. Biol Reprod 80:328-36

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