Subchronic exposure to phytoestrogens alone and in combination with diethylstilbestrol - pituitary tumor induction in Fischer 344 rats.
BACKGROUND
Subchronic administration of the potent pharmaceutical estrogen diethylstilbestrol (DES) to female Fischer 344 (F344) rats induces growth of large, hemorrhagic pituitaries that progress to tumors. Phytoestrogens (dietary plant estrogens) are hypothesized to be potential tumor inhibitors in tissues prone to estrogen-induced cancers, and have been suggested as "safer" estrogen replacements. However, it is unknown if they might themselves establish or exacerbate the growth of estrogen-responsive cancers, such as in pituitary.


METHODS
We implanted rats with silastic capsules containing 5 mg of four different phytoestrogens - either coumestrol, daidzein, genistein, or trans-resveratrol, in the presence or absence of DES. We examined pituitary and other organ weights, blood levels of prolactin (PRL) and growth hormone (GH), body weights, and pituitary tissue histology.


RESULTS
Blood level measurements of the administered phytoestrogens confirmed successful exposure of the animals to high levels of these compounds. By themselves, no phytoestrogen increased pituitary weights or serum PRL levels after 10 weeks of treatment. DES, genistein, and resveratrol increased GH levels during this time. Phytoestrogens neither changed any wet organ weight (uterus, ovary, cervix, liver, and kidney) after 10 weeks of treatment, nor reversed the adverse effects of DES on pituitaries, GH and PRL levels, or body weight gain after 8 weeks of co-treatment. However, they did reverse the DES-induced weight increase on the ovary and cervix. Morphometric examination of pituitaries revealed that treatment with DES, either alone or in combination with phytoestrogens, caused gross structural changes that included decreases in tissue cell density, increases in vascularity, and multiple hemorrhagic areas. DES, especially in combination with phytoestrogens, caused the development of larger and more heterogeneous nuclear sizes in pituitary.


CONCLUSIONS
High levels of phytoestrogens by themselves did not cause pituitary precancerous growth or change weights of other estrogen-sensitive organs, though when combined with DES, they counteracted the growth effects of DES on reproductive organs. In the pituitary, phytoestrogens did not reverse the effects of DES, but they did increase the sizes and size heterogeneity of nuclei. Therefore, phytoestrogens may oppose some but not all estrogen-responsive tissue abnormalities caused by DES overstimulation, and appear to exacerbate DES-induced nuclear changes.
Jeng
Yow-Jiun
YJ
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA. cswatson@utmb.edu.
Kochukov
Mikhail
M
Nauduri
Dhananjaya
D
Kaphalia
Bhupendra S
BS
Watson
Cheryl S
CS
Mt Sinai J Med. 2004 May;71(3):155-61
15164127
Int J Cancer. 2001 Sep 20;95(5):282-5
11494225
J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Oct 25;796(1):71-86
14552818
Biol Reprod. 2005 Oct;73(4):790-7
15972881
Toxicol Pathol. 1998 Nov-Dec;26(6):759-68
9864093
Acta Anat (Basel). 1991;142(1):19-24
1781235
Mamm Genome. 2005 Nov;16(11):865-72
16284802
Exp Biol Med (Maywood). 2002 Jul;227(7):492-9
12094014
Mamm Genome. 1997;8(11):823-9
9337394
Anat Histol Embryol. 1994 Sep;23(3):257-68
7864399
Endocr Rev. 2004 Oct;25(5):693-721
15466938
Mamm Genome. 2002 Nov;13(11):664-6
12461653
Phytother Res. 2003 Sep;17(8):845-69
13680814
Epidemiol Rev. 1993;15(1):48-65
8405212
JAMA. 2009 Dec 9;302(22):2437-43
19996398
Am J Anat. 1980 May;158(1):3-13
7191203
J Natl Cancer Inst. 1993 Nov 17;85(22):1819-27
8230262
Reprod Biol Endocrinol. 2006 May 17;4:28
16707016
J Neurosci. 2001 May 1;21(9):3207-14
11312305
J Nutr. 2000 Aug;130(8):1963-70
10917909
J Endocrinol. 1997 Feb;152(2):193-9
9071976
Exp Biol Med (Maywood). 2004 Dec;229(11):1127-35
15564439
J Nutr. 2002 Aug;132(8):2246-50
12163670
BMC Cancer. 2009 Sep 18;9:334
19765307
J Infect Dis. 2001 May 15;183(10):1437-44
11319680
Phytochemistry. 2004 Apr;65(8):995-1016
15110680
Biol Reprod. 1979 Mar;20(2):261-8
454737
Front Biosci. 1998 Aug 06;3:d934-43
9696884
Anal Chem. 1999 Feb 1;71(3):747-50
9989391
J Mol Signal. 2009 Apr 28;4:2
19400946
Xenobiotica. 2006 Feb-Mar;36(2-3):119-218
16702112
Food Addit Contam. 1985 Apr-Jun;2(2):73-106
4018320
J Clin Endocrinol Metab. 1998 May;83(5):1662-7
9589674
Acta Endocrinol (Copenh). 1991 Feb;124(2):129-35
2003372
Environ Health Perspect. 2001 Mar;109 Suppl 1:5-20
11250801
Toxicol Pathol. 2001 Jan-Feb;29(1):77-83
11215687
Mol Nutr Food Res. 2005 May;49(5):482-94
15779067
Drug Metab Dispos. 2004 Dec;32(12):1377-82
15333514
Phytother Res. 2006 Aug;20(8):665-9
16691630
Acta Neurobiol Exp (Wars). 2007;67(4):411-9
18320719
J Am Coll Cardiol. 2000 May;35(6):1403-10
10807439
Arch Biochem Biophys. 1993 Jul;304(1):248-56
8323288
Endocrinology. 1981 Nov;109(5):1708-14
7297501
J Clin Invest. 2002 Jan;109(2):277-83
11805140
Toxicol Pathol. 1997 Sep-Oct;25(5):462-9
9323835
Toxicol Appl Pharmacol. 2007 Jul 1;222(1):25-32
17490695
Maturitas. 2003 Mar 14;44 Suppl 1:S9-20
12609555
Prog Clin Biol Res. 1997;396:233-43
9108601
Carcinogenesis. 2008 Oct;29(10):1862-8
18544561
Am J Obstet Gynecol. 1999 Mar;180(3 Pt 1):737-43
10076156
Pharm Res. 2002 Dec;19(12):1907-14
12523673
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):8112-6
8755612