The primary objective of this work is to establish the time during the life cycle when dietary fat is maximally effective in altering the frequency of female reproductive system cancer. The relevance of this to human health is in relation to providing guidance on the most critical time to control dietary fat intake for cancer prevention. A second purpose of the work is to establish an animal model to investigate the mechanism of dietary fat effect on cancer, so that preventive measures can eventually be worked out for persons already programmed for an increased cancer rate due to excessive dietary fat exposure. Epidemiologic data indicate that the sensitive period to dietary fat for female reproductive system cancer is early in life. Preliminary results with an experiment on mice indicates that the period from shortly before to shortly after pregnancy covers a developmental stage of exceptional sensitivity to the programming of cancer by dietary fat. A more exact demonstration of the sensitive period will be attempted by : (1) embryo transfers tp test for a germ cell effect. (2) high fat exposure limited to fetal development to test this period specifically, and (3) a fostering experiment to test the nursing period. In all cases, animals exposed to low fat diet will be compared to animals exposed to a high fat diet. In addition, the possibility of a multigenerational and cumulative effect will be explored by raising second generation offspring without, or with exposure to high and low fat diets during the second pregnancy. An inherent advantage to these experiments is the establishment of an animal model for studies on the mechanisms by which early exposure to a high fat diet programs the individual for an increased susceptibility to cancer later in life. The test subjects utilized in the experiment that produced the preliminary results were female offspring of female CD-1 mice exposed prenatally to diethylstilbestrol. These second generation offspring have an increased susceptibility to uterine cancer and high dietary fat produces an increased cancer rate of sufficient magnitude to keep the required number of test subjects within practical limits.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039456-04
Application #
3178457
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1989-05-01
Project End
1994-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Walker, Bruce E; Edwards, Stephanie N (2003) Reproductive system tumors in mice exposed to various types of fat perinatally. Anticancer Res 23:4689-91
Walker, B E; Kurth, L A (1997) Multigenerational effects of dietary fat carcinogenesis in mice. Cancer Res 57:4162-3
Walker, B E; Haven, M I (1997) Intensity of multigenerational carcinogenesis from diethylstilbestrol in mice. Carcinogenesis 18:791-3
Walker, B E; Zhou, M (1997) Stage of susceptibility to carcinogenicity of prenatal dietary fat exposure tested by blastocyst transfer. Cancer Lett 112:177-80
Walker, B E; Kurth, L A (1996) Effects of fostering on the increased tumor incidence produced by a maternal diet high in fat. Nutr Cancer 26:31-5
Walker, B E; Kurth, L A (1995) Increased reproductive tract tumors in the female offspring of mice fed a high fat diet during the fetal stage of pregnancy. Cancer Lett 97:57-60
Walker, B E; Kurth, L A (1995) Multi-generational carcinogenesis from diethylstilbestrol investigated by blastocyst transfers in mice. Int J Cancer 61:249-52
Walker, B E; Kurth, L A (1993) Pituitary tumors in mice exposed prenatally to diethylstilbestrol. Cancer Res 53:1546-9
Zhou, M; Walker, B E (1993) Potentiation of triamcinolone-induced cleft palate in mice by maternal high dietary fat. Teratology 48:53-7
Smith, D A; Walker, B E (1992) Evidence of hypothalamic involvement in the mechanism of transplacental carcinogenesis by diethylstilbestrol. Cancer Lett 67:55-9

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