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

Abstract

The acute toxicity of diethylnitrosamine (DEN) to the liver has been well documented in the literature, but whether DEN also affects the endocrine parameters has been addressed in only a few studies. We thus investigated the effects of DEN on pituitary, serum hormone levels, and certain sex-differentiated liver enzymes in this study. Adult male Wister rats were intraperitoneally 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 anterior pituitary in male animals exhibited cellular damage, including disrupted organelles and cellular structure, as well as pyknotic or lytic nuclei. Many undamaged secretory cells exhibited dilated endoplasmic reticula, hypertrophic Golgi complexes, and peripheral location of secretory granules, which usually are morphologic features of increased cellular activities. In male rats, the serum level of total testosterone decreased and the corticosterone increased 1 day after DEN treatment. The serum level of growth hormone (GH) decreased and the prolactin level increased on day 3. The hepatic expression of the male-specific cytochrome P450 2C11 (CYP2C11) decreased to 1-5% of the normal levels during the first week and was still 50% lower than the normal level on day 35, whereas the female-specific CYP2C12 expression increased only slightly. Activities of the male predominant 16alpha, 16beta, and 6beta hydroxylation of androstenedione by microsome decreased in an in vitro assay, whereas the non-sex-differentiated 7alpha hydroxylation and the female-predominant 5alpha reduction of androstenedione were unaffected. In female rats, decreased serum GH level was observed on day 7. The CYP2C12 expression in females was decreased to about 1% and 80% of the normal levels on day 7 and day 35, respectively, but the CYP2C11 expression was unchanged. These data suggest that in male rats, DEN treatment may cause pituitary damage, disturb serum hormone levels, and induce long-lasting reduction of sexual dimorphism in certain liver functions.

Effects of Echinacea purpurea on Hepatic and Renal Toxicity Induced by Diethylnitrosamine in Rats

“…In the present investigation, DEN induced hepatocellular damage is clearly evidenced by the marked elevation in the activity of serum AST, ALT and ALP which is in agreement with other researches (4,5,(14)(15)(16). These enzymes are the most sensitive markers employed in the diagnosis of hepatic damage because they are cytoplasmic in location and are released into the circulation after cellular damage (3,17). Current study demonstrated that treatment with EPE for 30 days reduced different parameters in EPE + DEN group and these decreases were significant in AST, BUN and total and direct bilirubin (P < 0.05).…”

Effects of Echinacea purpurea on Hepatic and Renal Toxicity Induced by Diethylnitrosamine in Rats

“…In the present investigation, DEN induced hepatocellular damage is clearly evidenced by the marked elevation in the activity of serum AST, ALT and ALP which is in agreement with other researches (4, 5, 14-16). These enzymes are the most sensitive markers employed in the diagnosis of hepatic damage because they are cytoplasmic in location and are released into the circulation after cellular damage (3, 17). Current study demonstrated that treatment with EPE for 30 days reduced different parameters in EPE + DEN group and these decreases were significant in AST, BUN and total and direct bilirubin ( P < 0.05).…”

Reproductive outcome in a cohort of male and female rubber workers: a registry study

“…Experimentally, diethylnitrosamine has been shown to be hormonally active (Liao et al 2001), as well as phthalates (Hoppin et al 2002). There is evidence from animal data that phthalates have adverse reproductive eVects in males (Foeter et al 2001;Gray et al 2000;Mylchreest et al 2002;Nagao et al 2000), and possibly also females (Ema and Miyawaki 2001).…”