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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>We implanted rats with silastic capsules containing 5 mg of four different phytoestrogens - either coumestrol, daidzein, genistein, or <it>trans</it>-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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p

Spatial and Sex-Dependent Responses of Adult Endogenous Neural Stem Cells to Alcohol Consumption

Summary: Chronic alcohol abuse results in alcohol-related neurodegeneration, and critical gaps in our knowledge hinder therapeutic development. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that contribute to brain maintenance and recovery. While it is known that alcohol alters NSCs, little is known about how NSC response to alcohol is related to sex, brain region, and stage of differentiation. Understanding these relationships will aid in therapeutic development. Here, we used an inducible transgenic mouse model to track the stages of differentiation of adult endogenous NSCs and observed distinct NSC behaviors in three brain regions (subventricular zone, subgranular zone, and tanycyte layer) after long-term alcohol consumption. Particularly, chronic alcohol consumption profoundly affected the survival of NSCs in the subventricular zone and altered NSC differentiation in all three regions. Significant differences between male and female mice were further discovered. : Wu and colleagues demonstrate that adult endogenous neural stem cells in three key brain regions have individual responses to alcohol consumption. Further, they show that these regional changes are affected by the sex of mice. Keywords: neural stem cell, chronic alcohol, subgranular zone, subventricular zone, tanycyte, sex differences, neuronal differentiatio