Zeranol (Z) is a non-steroidal agent with estrogenic activity (E2) that is used as an anobolic growth promoter in the U.S. beef industries. Consumption of bio-active Z containing-beef has a potential risk in human normal and cancerous breast cells. Previous work suggests that PTP gamma (PTPG) is an E2-regulated breast cancer suppressor gene. Z is capable in down-regulating the PTPG both in mRNA and protein levels in human normal and cancerous breast tissues and cells. The overall HYPOTHESIS to be evaluated is that the consumption of beef products, derived from Z-implanted beef cattle may possess a potential health impact on human consumers, particularly with respect to reproductive endocrinology and hormone-sensitive breast tissues.
Specific Aims : (1): Define epigenetic and gene expression alterations in primary cultured normal human breast epithelial cells, stromal cells, and tissues exposed to serum and meat extracts collected from Zimplanted beef heifers. (2): Define DNA methylation changes in the estrogen inducible mammary tumor ACI rat model exposed to bio-active Z-containing diets formulated from Z-implanted beef heifers. (3) Investigate mammary tumorigenesis in the estrogen inducible mammary tumor ACI rat model after long-term consumption of low level of bio-active Z containing experimental diets formulated from meat collected from Z- implanted beef heifers. The team of researchers assembles expertise in 3 areas to systematically study the mitogenic effects of Z in reproductive and hormone sensitive breast. These include modeling of in vitro and in vivo effects of Z (Lin), mapping and quantification of global and unique epigenetic alterations in gene promoters (Huang &Yan), and comparative quantification of global gene expression and identification of biomarkers (Wick). Significance: The proposed experiments will provide a clear linkage between bio-active dietary Z and PTPG down-regulation to eventual tumorigenesis via epigenetic regulation of the expression of PTPG and other tumor relevant genes. To translate our findings from bench top to bedside, selected biomarkers uncovered from the in vitro experiments will be further validated by proteomic analysis. It is our intent to provide comprehensive data (exposure levels during Z-implantation and after Z withdrawal from the beef heifers) to raise awareness of environmental exposure to the estrogen mimic, beef growth promoter, Z.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015212-04
Application #
7650131
Study Section
Special Emphasis Panel (ZES1-LWJ-E (EP))
Program Officer
Tyson, Frederick L
Project Start
2006-09-25
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$345,199
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Shidaifat, Falah; Kulp, Samuel K; Lin, Young C (2013) Zeranol induces deleterious effects on the testes and the prostate gland of mature rats. Endocr Res 38:232-41
Shidaifat, Falah; Lin, Young C (2012) Testosterone effect on the expression of genes that mediate testosterone metabolism and genes that mediate the effect of those metabolites on the prostate. Life Sci 91:194-8
Ye, Weiping; Xu, Pingping; Zhong, Saiyi et al. (2011) In vitro transformation of MCF-10A cells by sera harvested from heifers two months post-Zeranol implantation. Int J Oncol 38:985-92
Zhong, Saiyi; Ye, Wei-Ping; Feng, Eric et al. (2011) Serum derived from zeranol-implanted ACI rats promotes the growth of human breast cancer cells in vitro. Anticancer Res 31:481-6
Zhong, Saiyi; Ye, Weiping; Lin, Shu-Hong et al. (2011) Zeranol induces cell proliferation and protein disulfide isomerase expression in mammary gland of ACI rat. Anticancer Res 31:1659-65
Ye, Weiping; Xu, Pingping; Jen, Robert et al. (2011) Zeranol down-regulates p53 expression in primary cultured human breast cancer epithelial cells through epigenetic modification. Int J Mol Sci 12:1519-32
Li, Hong; Piao, Longzhu; Xu, Pingping et al. (2011) Liposomes containing (-)-gossypol-enriched cottonseed oil suppress Bcl-2 and Bcl-xL expression in breast cancer cells. Pharm Res 28:3256-64
Zhong, Saiyi; Ye, Wei-Ping; Xu, Ping-Ping et al. (2010) Aromatase expression in leptin-pretreated human breast pre-adipocytes is enhanced by zeranol and suppressed by (-)-gossypol. Anticancer Res 30:5077-84
Shu, Sherry T; Sugimoto, Yasuro; Liu, Suling et al. (2010) Function and regulatory mechanisms of the candidate tumor suppressor receptor protein tyrosine phosphatase gamma (PTPRG) in breast cancer cells. Anticancer Res 30:1937-46
Ye, Weiping; Xu, Pingping; Threlfall, Walter R et al. (2009) Zeranol enhances the proliferation of pre-adipocytes in beef heifers. Anticancer Res 29:5045-52

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