Subchronic exposure to phytoestrogens alone and in combination with diethylstilbestrol - pituitary tumor induction in Fischer 344 rats

Abstract

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 estrogenresponsive tissue abnormalities caused by DES overstimulation, and appear to exacerbate DES-induced nuclear changes. BackgroundSteroid hormones such as the dominant physiologic estrogen, estradiol (E 2 ) have many effects on pituitary function, including regulation of most pituitary hormones and proliferation of several pituitary cell types

Combinations of Physiologic Estrogens with Xenoestrogens Alter ERK Phosphorylation Profiles in Rat Pituitary Cells

“…Estrogens and XEs cause these cells to proliferate and also activate ERKs and other MAPKs, as we have shown previously ( Jeng and Watson 2009 ; Kochukov et al 2009 ; Watson et al 2008 ), although some phytoestrogens inhibit proliferation when combined with physiologic estrogens ( Jeng et al 2010 ; Jeng et al 2009 ). Often ERKs are designated as the MAPKs most responsible for cell proliferation, with some exceptions to this generalization ( Zhou et al 2007 ).…”

Mixtures of xenoestrogens disrupt estradiol-induced non-genomic signaling and downstream functions in pituitary cells

“…We previously determined that BPS, BPA, and NP had similar high potencies, compared to E 2 , for initiating the phospho-activation of ERK and JNK across a wide range of concentrations and times [28,31,32,37,38,40,45]. Non-monotonic dose–response curves were seen, as low concentrations of individual XEs produced high MAPK activation, decreasing as concentrations increased.…”

Combinations of physiologic estrogens with xenoestrogens alter calcium and kinase responses, prolactin release, and membrane estrogen receptor trafficking in rat pituitary cells

“…There are also many more studies describing the activities of these compounds at much higher concentrations, which may or may not act via receptors, but have limited applicability to our concern about prevalent environmental concentrations. Lifelong exposure to E 2 and potent synthetic estrogens is also known to be an important consideration for the development of cancers in reproductive tissues [ 52 - 55 ], so there is a possibility that xenoestrogens could likewise contribute to these types of disease. Xenoestrogens can cause proliferation of cells, as we demonstrated for octylphenol (OP), nonylphenol (NP), and BPA in our GH 3 /B6/F10 cell model ([ 15 ] and reports cited therein).…”