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Abstract
The aim of the present study was to evaluate the effects of the administration of a potent non-steroidal aromatase inhibitor, Fadrozole, on reproductive function of mice. The following items were investigated:-
1- The effects of administration of Fadrozole, on reproductive organs of immature mice in both male and female mice (sex organs weight, histological examination and hormonal assay)
2- The effects of administration of Fadrozole on sexual and aggressive behavior and fertility of adult mature male mice. Its effects on female reproductive organs, fertility, pregnancy and resultant feti were also investigated.
3- The effects of inhalation of air polluted with diesel exhaust during pregnancy (histological features, hormonal assay and effect on feti were studied).
Four experiments were carried out:-
The first experiment:
The aim of this experiment was to evaluate the effect of Fadrozole injection on reproductive functions of immature mice.
Twenty immature mice of both sexes (21 days old) were allocated into 4 groups each of 5 mice. Two control groups (male and female) were injected s/c daily with 0.1 ml saline per mouse for 35 days. The two treated groups were injected s/c daily with 25µg Fadrozole per mouse for 35 days. At day 36 the body weight and sex organ weights of all animals (control and treated) was recoded. Blood samples were collected, estradiol brain levels and plasma hormones (testosterone, estradiol and progesterone) were estimated. Results showed that injection of Fadrozole in male mice significantly increased plasma testosterone, improved testicular spermatogenic function, lowered brain and plasma estradiol levels. In females, brain and plasma estradiol levels were decreased. In the control group, it was found that male brain tissue has higher estradiol levels than that of females.
The second experiment: It includes 3 sub experiments:
Experiment A:
The aim of this experiment was to evaluate the effect of Fadrozole injection on sexual behavior.
Fifteen mature mice (60 days old) were allocated into three equal groups.
Males in the control group were injected s/c daily with 0.1 ml saline per mouse for 35 days. The treated males were similarly injected with 25µg Fadrozole per mouse. 10 minutes after the last saline or Fadrozole shot, each male was paired with a receptive control female for 30 min. under dim light. Mating behavior was recorded in both control and treated males. It was found that Fadrozole treated males failed to mount receptive females as compared with control males which successfully showed mounting behavior within two minutes. A single s.c. injection of 10 µg diethylstilboestrol 10 minutes before pairing with a receptive female induced mating behavior which indicate the importance of brain estrogen in the mating behavior in males.
Experiment B:
The aim of this experiment was to evaluate the effect of Fadrozole injection on the territorial aggressive behavior of males. Ten mature males mice were allocated into two groups: saline control and Fadrozole treated .Test male was placed first in the arena followed 30 minutes later by intruder male. The behavior of the host male was evaluated for aggressive and defending attitude. It was found that Fadrozole suppressed the defending and aggressive behavior in injected males as compared to controls.
Experiment C:
The aim of this experiment was to evaluate the effect of Fadrozole treatment on fertility of male and female mice. Control or Fadrozole treated males were separately paired with control or Fadrozole injected females for 35 days. The day of sperm detection in the vaginal smears was considered as day zero (0) of pregnancy. Pregnant females were isolated and allowed to deliver. The conception rate, the duration of pregnancy and the number of the pups were recorded. Fadrozole treatment of male or female mice improved pregnancy rate and increased the number of feti/ female without affecting the duration of pregnancy.
The third experiment:
This experiment was designed to study the effect of Fadrozole on pregnancy.
Pregnant females were injected daily with saline or 25µg Fadrozole per mouse from day 7 until day 18 of pregnancy. At day 19 of pregnancy, blood, maternal liver and placenta were collected. Feti were recovered from the uteri, weights and sex of fetuses were recorded. Testes of male feti were processed for histological examination. It was found that plasma progesterone levels of the Fadrozole Injected mice were significantly higher than those of controls while estradiol levels were significantly decreased.
Fadrozole injection in pregnant females resulted in significant lowering of fetal weights while placental weight was increased. In the placenta, Fadrozole treatment did not affect the total number of trophoblasts, it increased the proportion of trophoblastic giant cells which were degenerated. Differentiation of the fetal testis was improved markedly in the fetuses from the injected females .Improved organization of testicular tissue was in the form of more arrangement of germ cells in circular seminiferous tubules as well as increased number of interstitial cells.
The fourth experiment:
This experiment was designed to study the effect of inhalation of air polluted with diesel exhaust gas for 6 hours daily from day 7 till day 18 of pregnancy.
It was found that the average body weight and the number of feti/dam were significantly decreased than in those of the control group. Fetal and placental weights in the exhaust group were insignificantly decreased as compared to those of clean air control group. Light microscopy of the placenta clearly showed that the exhaust samples lacked the developing labyrinth. Extensive maternal blood spaces were evident and the density of fetal blood vessels was significantly decreased. The deciduas was much less affected than the labyrinth in the exhaust group, but decidual cells were smaller than in the control group .Differentiation of the fetal testis was delayed or disturbed markedly in the fetuses from the dams exposed to air polluted with diesel exhaust.
In conclusion, the present study provided evidence which support the following:-
1. Aromatse inhibition in males may interfere with mating behavior, aggressive behavior and may improve spermatogenic function along with elevated testosterone levels. Inhibition of estradiol synthesis in the brain might be the mechanism by which aromatase inhibitor induce the above effects in males.
2. In females, the effects of aromatase inhibition include lowering plasma estradiol levels. In pregnant females placental weight was increased in Fadrozole treated dams as compared to control pregnant females. Also, it improved testes architecture of male feti which may influence the postnatal testicular function in these males after puberty. This point deserves more investigation due its vital importance.
3. Exposure of pregnant females to air polluted with diesel exhaust or chemical aromatase inhibitor, Fadrozole has negative effects on pregnancy.