Benzo(a)pyrene-induced early cytopathologic changes and peroxidase activity in the endometrium of ovariectomized rats

Abstract

The present study was designed to investigate whether benzo(a)pyrene (BP) alone would have cytopathologic effects on the endometrium of ovariectomized rats, and whether DES can modulate or facilitate this cytopathology. The morphology and cytochemically detectable peroxidase activity in the endometrial epithelium of castrated rats were studied 24 hr after sc administration of three to six doses on consecutive days (one dose per day) either of corn oil, BP (50 mg/kg/day), DES (20 μg/kg/day), or a combination of the latter two agents. BP alone induced mitosis, peroxidase activity, and focal squamous cell metaplasia in the endometrial epithelium of castrated rats. Peroxidase activity was weak in the granular endoplasmic reticulum of the normal epithelial cells after three and six doses of BP. However, in the focal metaplasia, the superficial squamous cells contained strong peroxidase activity after six consecutive daily doses of BP. The focal metaplasia present only after six doses of BP consisted of three to four layers of squamous cells and one to two layers of basal cells. DES-treated animals showed no formation of metaplasia or structural alterations in the epithelium, but intense peroxidase activity was present in epithelial cells after three or six daily doses. The castrates treated with three or six combined doses of BP and DES showed significant ultrastructural changes in the epithelial cells. Vacuolization of the cisternae of the granular endoplasmic reticulum was observed in the epithelial cells after three doses of BP-DES. Distinct dilation and degranulation of the granular endoplasmic reticulum as well as enlargement of mitochondria were found in all the epithelial cells of the pseudostratified hyperplastic epithelium after six consecutive daily doses of the combination, BP-DES. These ultrastructural aberrations are clearly indicative of a cytotoxic effect of BP on the endometrial epithelial cells. Collectively these findings suggest that sc administration of BP induces peroxidase activity which may lead indirectly to lesions in the endometrium of ovariectomized rats, and DES may enhance the cytotoxicity of BP by a similar mechanism.