Dj. Liao et al., Diethylnitrosamine causes pituitary damage, disturbs hormone levels, and reduces sexual dimorphism of certain liver functions in the rat, ENVIR H PER, 109(9), 2001, pp. 943-947
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.