Endocrine disruptive (ED) agents in ground corncob bedding and foods block male and female sexual behavior and cyclicity in the rat and stimulate breast and prostate cancer cell proliferation. These agents separate into two components (Peak I-CM and Peak II-CM) during HPLC. The mitogenic agents in Peak I-CM (THF-diols) were identified as an isomeric mixture of 9, (12)-oxy-10, 13-dihydroxystearic acid and 10, (13)-oxy-9, 12-dihydroxystearic acids which block male and female sexual behavior and cyclicity. The mitogenic agents in Peak II-CM (LTX-diols) were identified as an isomeric mixture of leukotoxin-diol (LTX-diol) and isoleukotoxin-diol (iLTX-diol) that will be assessed as EDs in the proposed studies. The objectives of the proposed research are to identify the most biologically active synthetic THF-diol and LTX-diol isomers, define the nature of their interaction in modulating endocrine function and breast cancer cell proliferation and define specific biochemical sites regulated by these compounds in these systems. The most active THF-diol and LTX-diol isomer will be isolated and identified separately (Specific Aim 1) and whether they act additively or synergistically to stimulate breast cancer cell proliferation (cell cycle transition and apoptosis) and modify male and female sexual behavior and cyclicity will be determined (Specific Aim 2). The concentrations of THF-diol and/or LTX-diol isomers in tissues and blood from rats given """"""""ED"""""""" doses of the compounds will be quantified by GC/MS and whether LTX-diols are precursors to THF-diols in rats will be studied (Specific Aim 3). The abilities of THF-diol and LTX-diol isomers to promote dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats (Specific Aim 4), and to stimulate the proliferation (cell cycle transition and apoptosis) of estrogen receptor (ER) positive (MCF-7) or ER-negative (MDA-MB-231 cells) breast cancer cells in vitro or in vivo (in nude mice) by modulating phospholipase A2 (PoA), cyclooxygenase (COX), lipoxygenase (LOX) and aromatase will be evaluated (Specific Aim 5). Leukotoxins are known to affect NO release and it is possible that LTX-diol and THFdiol isomers inhibit female sexual behavior (Lordosis) by disrupting nitric oxide (NO) dependent pathways controlling LHRH release. This will be evaluated (Specific Aim 6). If THF-diols and LTX-diols impact endocrine and cell regulatory pathways by controlling LHRH release and lipogenic products that control cell proliferation, they likely have a major impact on behavioral and reproductive response profiles and cancer growth rates in experimental animals. Over the last decade, linoleic acid has replaced stearic acid in our diet. As metabolites of linoleic acid, increased intake of THF-diols and LTX-diols may influence human health and development. The proposed studies represent a critical step in defining target pathways for ultimately determining the mechanism of action of these compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009964-05
Application #
6803232
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Reinlib, Leslie J
Project Start
1999-09-30
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$328,035
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Shoulars, Kevin; Rodriguez, Mary Ann; Thompson, Trellis et al. (2010) Regulation of cell cycle and RNA transcription genes identified by microarray analysis of PC-3 human prostate cancer cells treated with luteolin. J Steroid Biochem Mol Biol 118:41-50
Shoulars, Kevin; Rodriguez, Mary Ann; Thompson, Trellis et al. (2008) Regulation of the nitric oxide pathway genes by tetrahydrofurandiols: microarray analysis of MCF-7 human breast cancer cells. Cancer Lett 264:265-73
Markaverich, Barry M; Crowley, Jan; Rodriquez, Mary et al. (2007) Tetrahydrofurandiol stimulation of phospholipase A2, lipoxygenase, and cyclooxygenase gene expression and MCF-7 human breast cancer cell proliferation. Environ Health Perspect 115:1727-31
Markaverich, Barry M; Alejandro, Mary; Thompson, Trellis et al. (2007) Tetrahydrofurandiols (THF-diols), leukotoxindiols (LTX-diols), and endocrine disruption in rats. Environ Health Perspect 115:702-8
Markaverich, Barry M; Shoulars, Kevin; Alejandro, Mary-Ann (2006) Nuclear type II [3H]estradiol binding site ligands: inhibition of ER-positive and ER-negative cell proliferation and c-Myc and cyclin D1 gene expression. Steroids 71:865-74
Shoulars, Kevin; Rodriguez, Mary Ann; Crowley, Jan et al. (2006) Reconstitution of the type II [3H]estradiol binding site with recombinant histone H4. J Steroid Biochem Mol Biol 99:1-8
Shoulars, Kevin; Rodrigues, Mary Ann; Crowley, Jan R et al. (2005) Nuclear type II [3H]estradiol binding sites: a histone H3-H4 complex. J Steroid Biochem Mol Biol 96:19-30
Markaverich, Barry M; Crowley, Jan R; Alejandro, Mary A et al. (2005) Leukotoxin diols from ground corncob bedding disrupt estrous cyclicity in rats and stimulate MCF-7 breast cancer cell proliferation. Environ Health Perspect 113:1698-704
Mani, Shaila K; Reyna, Andrea M; Alejandro, Mary A et al. (2005) Disruption of male sexual behavior in rats by tetrahydrofurandiols (THF-diols). Steroids 70:750-4
Shoulars, Kevin; Brown, Trellis; Alejandro, Mary Ann et al. (2002) Identification of nuclear type II [(3)H]estradiol binding sites as histone H4. Biochem Biophys Res Commun 296:1083-90

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