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METHOXYCHLOR-INDUCED ALTERATIONS IN THE HISTOLOGICAL EXPRESSION OF ANGIOGENIC FACTORS IN PITUITARY AND UTERUS
Citation:
Goldman, J M., A S. Murr, A R. Buckalew, J E. Schmid, AND B D. Abbott. METHOXYCHLOR-INDUCED ALTERATIONS IN THE HISTOLOGICAL EXPRESSION OF ANGIOGENIC FACTORS IN PITUITARY AND UTERUS. Journal of Molecular Histology. Springer Science and Business Media B.V;Formerly Kluwer Academic Publishers B.V., , Germany, 35(4):363-375, (2004).
Description:
Within the reproductive system, estrogenic stimulation of uterine and pituitary tissue typically causes a proliferative response accompanied by an angiogenic induction of new blood vessels from existing ones, thereby providing nutrients and oxygen to the growing tissue. The proestrogenic pesticide methoxychlor, however, has shown a differential effect on proliferative activity. An increase in uterine growth is present, while the pituitary undergoes a decrease in size, even though the effect is accompanied by a characteristic estrogen-induced elevation in pituitary prolactin concentration. The focus of the current study was whether the observed differences in tissue growth between uterus and pituitary in response to methoxychlor administration were paralleled by a corresponding disparity in the expression of those growth factors (members of the vascular enothelial growth factor [VEGF] and angiopoietin [Ang] families and their receptors) that are involved in the angiogenic cascade. Adult Sprague Dawley female rats were administered methoxychlor (MXC, 0-200 mg/kg, oral) for 1 or 3 weeks. Immunohistochemical staining of uteri and pituitaries was performed under strictly controlled conditions for VEGF & its receptor VEGFR2 (Flk1), Ang1, Ang2 & their tyrosine kinase receptor Tie2, and the platelet endothelial adhesion factor PECAM-1 (as an index of vascularity). Image acquisition and densitometric assessments of staining intensity were conducted under blind conditions. The results showed uterine MXC-induced increases in the expression of VEGF, VEGFR2 and Ang1, changes consistent with a normal proliferative response to estrogenic stimulation. For VEGF, effects were most pronounced in the stromal region, showing a progressive increase by 3 weeks of exposure. VEGFR2 expression showed significant dose-related trends in luminal and glandular epithelia by 1 week. Similar effects at 1 week were evident for Ang1 in glandular epithelium. In the anterior pituitary, a dose-related increase in VEGF was present for the 1 and 3 week treatments. The number of pituitary vessels per unit area was also increased after 3 weeks, something that may have been related to a previously reported MXC-associated decrease in pituitary size. The effects indicate that even though the insecticide has not been found to cause an augmentation in pituitary growth that is characteristically induced by estradiol, an increase in the expression of at least one principal angiogenic factor is present.