Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat

The acute toxicity of diethylnitrosamine (DEN) to the liver has been well d ocumented in the literature, but whether DEN also affects the endocrine par ameters has been addressed in only a few studies. We thus investigated the effects of DEN on pituitary, serum hormone levels, and certain sex-differen tiated liver enzymes in this study. Adult male Wister rats were intraperito neally injected with DEN at a single dose of 200 mg/kg and were sacrificed at 1, 3, 7, and 35 days after injection; DEN-treated females were included as controls at days 7 and 35. Electron microscopic observation showed that during the first week after injection, all types of granular cells of the a nterior pituitary in male animals exhibited cellular damage, including disr upted organelles and cellular structure, as well as pyknotic or lytic nucle i. Many undamaged secretory cells exhibited dilated endoplasmic reticula, h ypertrophic Golgi complexes, and peripheral location of secretory granules, which usually are morphologic features of increased cellular activities. I n male rats, the serum level of total testosterone decreased and the cortic osterone increased I day after DEN treatment. The serum level of growth hor mone (GH) decreased and the prolactin level increased on day 3. The hepatic expression of the male-specific cytochrome P450 2C11 (CYP2C11) decreased t o 1-5% of the normal levels during the first week and was still 50% lower t han the normal level on day 35, whereas the female-specific CYP2C12 express ion increased only slightly. Activities of the male predominant 16 alpha, 1 6 beta, and 6 beta hydroxylation of androstenedione by microsome decreased in an in vitro assay, whereas the non-sex-differentiated 7 alpha hydroxylat ion and the female-predominant 5 alpha reduction of androstenedione were un affected. In female rats, decreased serum GH level was observed on day 7. T he CYP2C12 expression in females was decreased to about 1% and 80% of the n ormal levels on day 7 and day 35, respectively, but the CYP2C11 expression was unchanged. These data suggest that in male rats, DEN treatment may caus e pituitary damage, disturb serum hormone levels, and induce long-lasting r eduction of sexual dimorphism in certain liver functions.