Effect of carbon tetrachloride on gonadal physiology in male rats.

Carbon tetrachloride was administered to male albino rats for varied intervals. It was found to have no significant adverse effect on spermatogenesis after 10 and 15 days of treatment. Severe damage to the spermatogenic cycle was observed after 20 days of treatment, leading to exfoliation of the germinal epithelium, depletion of germ cells, and shrinkage of the tubules.     

Administration of gonadal steroids to neonatal rats affects beta-endorphin levels in the adult

Administration of gonadal steroids to neonatal rats has a profound effect on the function of the neuroendocrine system in the adult animal. Considering that gonadal steroids modulate hypothalamic and pituitary levels of beta-endorphin (BE) in adult male and female rats, the effects of neonatal gonadal steroid treatment on BE levels in the adult animal were investigated. Neonatal male rats were administered testosterone and neonatal female rats were treated with estrogen. Matched control littermates received vehicle. All animals were sacrificed at 90 days of age. Neonatal gonadal steroid treatment did not affect the level of immunoreactive beta-endorphin (IR-BE) in the anterior pituitary (AP) of male rats but did result in a significant increase in IR-BE in the AP of female rats. Neonatal administration of gonadal steroids produced a significant decrease in IR-BE in the neurointermediate lobe of the pituitary (NIL) of both male and female rats, with the magnitude of the decrease being greater in the NIL of the female rats. IR-BE levels in the hypothalamus of male or female rats were not altered by the treatments. Column chromatography indicated that the increase in IR-BE in the AP represented a proportional increase in BE and beta-lipotropin, while the reduction in IR-BE in the NIL of the treated rats represented a reduction in BE. These findings suggest that gonadal steroids may influence the development of the neurotransmitter systems which regulate BE levels in the adult pituitary, the development of the biosynthetic mechanisms of the adult pituitary, or both.     

Hepatoprotective effect of aqueous extract of Aframomum melegueta on ethanol-induced toxicity in rats

In recent years there have been remarkable developments in the prevention of diseases, especially with regards to the role of free radicals and antioxidants. Ethanol-induced oxidative stress appears to be one mechanism by which ethanol causes liver injury. The protective effect of aqueous plant extract of Aframomum melegueta on ethanol-induced toxicity was investigated in male Wistar rats. The rats were treated with 45 % ethanol (4.8 g/kg b.w.t.) for 16 days to induce alcoholic diseases in the liver. The activities of alanine aminotransferase, aspartate aminotransferase and triglyceride were monitored and the histological changes in liver examined in order to evaluate the protective effects of the plant extract. Hepatic malondialdehyde and reduced glutathione, as well as superoxide dismutase and glutathione-S-transferase activities were determined for the antioxidant status. Chronic ethanol administration resulted in a statistically significant elevation of serum alanine aminotransferases and triglyceride levels, as well as a decrease in reduced glutathione and superoxide dismutase which was dramatically attenuated by the co-administration of the plant extract. Histological changes were related to these indices. Co-administration of the plant extract suppressed the elevation of lipid peroxidation, restored the reduced glutathion, and enhanced the superoxide dismutase activity. These results highlight the ability of Aframomum melegueta to ameliorate oxidative damage in the liver and the observed effects are associated with its antioxidant activities.     

Gonadal toxicity of short term chronic endosulfan exposure to male rats

Endosulfan was studied for its effect on rat testicular toxicity in relation to the enzymes of androgen biosynthesis, viz. 3 beta-hydroxysteroid dehydrogenase (EC 1.1.1.145, 3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (EC 1.1.1.64, 17 beta-HSD); cytosolic conjugation enzyme, glutathione-S-transferase (EC 2.5.1.18); and testicular as well as serum testosterone levels at the dose levels of 2.5, 5.0, 7.5 and 10 mg/kg body weight fed orally for 7 and 15 days. Organ and body weights of the treated animals did not change significantly, however, the testicular protein contents were found to be increased appreciably after 7 days treatments. The activity profile of cytosolic conjugation enzyme showed much remained low during 7 days treatment, however, the two steroidogenic enzymes showed much individual variations in response to endosulfan treatments. An overall varied response with respect to testosterone biosynthesis and its secretion to serum was observed suggesting nevertheless, a profound hormonal imbalance caused by this insecticide to male gonads on short term chronic exposures.     

Multiple treatments with SRIH-14 or octreotide affect adrenal zona glomerulosa in adult male rats

Somatostatin analogues are currently used to treat various disorders such as hypersecretion and different neuroendocrine tumors. In this study we examined the effects on the adrenal cortex of somatostatin (SRIH-14) and octreotide administered subcutaneously twice daily for 5 days to adult male rats. Control rats received saline under the same regime. After sacrifice, the adrenal glands were removed and examined morphometrically using the M(42) multipurpose test system. Blood samples were prepared for biochemical tests. Both SRIH-14 and octreotide induced morphofunctional changes in adrenal zona glomerulosa. We found significant decreases (p < 0.05) in the absolute cell and nuclear volumes of zona glomerulosa in both experimental groups in comparison to the control. The serum aldosterone level was 11% lower (p < 0.05) in the SRIH-14 and 13% (p < 0.05) lower in the octreotide-treated group in comparison with the control group. Morphometric parameters of zona fasciculata and zona reticulata and corticosterone levels were not altered significantly (p > 0.05) in either treated group. It may therefore be concluded that both SRIH-14 and octreotide affected zona glomerulosa in the same manner by decreasing morphofunctional characteristics.     

Prenatal testosterone exposure leads to hypertension that is gonadal hormone-dependent in adult rat male and female offspring

Prenatal testosterone exposure impacts postnatal reproductive and endocrine function, leading to alterations in sex steroid levels. Because gonadal steroids are key regulators of cardiovascular function, it is possible that alteration in sex steroid hormones may contribute to development of hypertension in prenatally testosterone-exposed adults. The objectives of this study were to evaluate whether prenatal testosterone exposure leads to development of hypertension in adult males and females and to assess the influence of gonadal hormones on arterial pressure in these animals. Offspring of pregnant rats treated with testosterone propionate or its vehicle (controls) were examined. Subsets of male and female offspring were gonadectomized at 7 wk of age, and some offspring from age 7 to 24 wk received hormone replacement, while others did not. Testosterone exposure during prenatal life significantly increased arterial pressure in both male and female adult offspring; however, the effect was greater in males. Prenatal androgen-exposed males and females had more circulating testosterone during adult life, with no change in estradiol levels. Gonadectomy prevented hyperandrogenism and also reversed hypertension in these rats. Testosterone replacement in orchiectomized males restored hypertension, while estradiol replacement in ovariectomized females was without effect. Steroidal changes were associated with defective expression of gonadal steroidogenic genes, with Star, Sf1, and Hsd17b1 upregulation in testes. In ovaries, Star and Cyp11a1 genes were upregulated, while Cyp19 was downregulated. This study showed that prenatal testosterone exposure led to development of gonad-dependent hypertension during adult life. Defective steroidogenesis may contribute in part to the observed steroidal changes.     

Ebselen as protection against ethanol-induced toxicity in rat stomach.

The mucosal protective effect of ebselen was examined in an ethanol-induced rat gastric lesion model. Examination of gastric tissue samples by light microscopy showed that i.g. exposure to 50% ethanol induced gastric injury, which was more prominent in female rats. Ethanol did not effect the gastric acid secretion examined by means of H(+)-K+ATPase, the increment of which might be harmful in the stomach. But ebselen with or without ethanol kept H(+)-K+ATPase below control levels. Gastric alcohol dehydrogenase (ADH) was mainly responsible for oxidation of ethanol in the stomach before it enters the bloodstream. I.g. ethanol exposure inhibited the ADH activity but ebselen eliminated the ethanol-induced inhibition of this enzyme. Therefore, ebselen exhibited a beneficial effect by increasing the gastric ethanol metabolism and by ameliorating the possible tissue toxicity of ethanol. Consistently, we also found that ebselen diminished the blood ethanol level. A gender difference in the blood ethanol levels existed following the same dose of ethanol but there was no difference in ADH activity. Histologically, mucosal injury following ebselen exposure together with ethanol was less severe compared with ethanol treatment alone. We concluded that the decrease in ethanol-induced mucosal injury following ebselen may have contributed to the inhibition of H(+)-K+ATPase and the activation of ADH by ebselen.     

Implication of free radical mechanisms in ethanol-induced cellular injury.

Numerous experimental data reviewed in the present article indicate that free radical mechanisms contribute to ethanol-induced liver injury. Increased generation of oxygen- and ethanol-derived free radicals has been observed at the microsomal level, especially through the intervention of the ethanol-inducible cytochrome P450 isoform (CYP2E1). Furthermore, an ethanol-linked enhancement in free radical generation can occur through the cytosolic xanthine and/or aldehyde oxidases, as well as through the mitochondrial respiratory chain. Ethanol administration also elicits hepatic disturbances in the availability of non-safely-sequestered iron derivatives and in the antioxidant defense. The resulting oxidative stress leads, in some experimental conditions, to enhanced lipid peroxidation and can also affect other important cellular components, such as proteins or DNA. The reported production of a chemoattractant for human neutrophils may be of special importance in the pathogenesis of alcoholic hepatitis. Free radical mechanisms also appear to be implicated in the toxicity of ethanol on various extrahepatic tissues. Most of the experimental data available concern the gastric mucosa, the central nervous system, the heart, and the testes. Clinical studies have not yet demonstrated the role of free radical mechanisms in the pathogenesis of ethanol-induced cellular injury in alcoholics. However, many data support the involvement of such mechanisms and suggest that dietary and/or pharmacological agents able to prevent an ethanol-induced oxidative stress may reduce the incidence of ethanol toxicity in humans.     

Role of selenium against lead toxicity in male rats

Male albino rats were intramuscularly administered a single dose of lead acetate (100 μmol/kg b.wt). Another group of rats were injected with sodium selenite (10 μmol/kg b.wt) before lead intoxication. After 3 and 24 hours, lead treatment resulted in significant increases in acid and alkaline phosphatases, GOT and GPT, total proteins, and cholesterol in serum. The total triglycerides in serum was decreased after 24 hours of intoxication. Lead treatment also produced significant elevation of lipid peroxidation in liver and kidney. The antioxidant capacity of hepatic and renal cells in terms of the activities of superoxide dismutase, glutathione reductase, and glutathione content was diminished. It appears from these results that lead may exert its toxic effect via peroxidative damage to renal and hepatic cell membranes after 24 hours. Selenium administration prior to lead injection produced pronounced prophylactic action against lead effects, and it is observed that selenium enhances the endogenous antioxidant capacity of the cells by increasing the activities of the superoxide dismutase and glutathione reductase and the glutathione content. As a result, the lipid peroxidation was decreased in both liver and kidney. © 1998 John Wiley & Sons, Inc. J Biochem Mol Toxicol 12: 345–349, 1998     

Effect of bromocriptine on the hypothalamo-pituitary function in adult male rats.

Daily oral administration of bromocriptine (50 μg/kg) to adult male rats, suppressed serum prolactin levels. The pituitary prolactin levels remained unaltered. Serum FSH levels as well as pituitary FSH levels showed no significant change as compared to the controls. Serum LH levels were significantly decreased in spite of the high pituitary LH levels, in bromocriptine treated rats. In the drug treated rats, $\text{in vitro}$ sensitivity of the pituitary to the exogenous LH-RH was not altered; whereas hypothalamic LH-RH content was considerably lowered. These observations suggest the possible effect of bromocriptine on the synthesis of LH-RH in the hypothalamus which leads to the accumulation of LH in the pituitary and decline of serum LH.     

Ethanol potentiates in vivo hepatotoxicity of endosulfan in adult male rats.

In an attempt to evaluate the effect and interaction of ethanol on endosulfan-induced hepatotoxicity in vivo to adult male rats, both, endosulfan (7.5 mg/kg body wt) and ethanol (1.5 g/kg body wt) were studied separately as well as in combination after a chronic oral exposure of 30 days. When fed separately, both the agents were found to induce microsomal mixed function oxidase (MFO) system in treated animals. A simultaneous induction in the activity of cytosolic GSH-s-transferase was found to be associated with significantly induced ascorbate-induced microsomal lipid peroxidation. Both endosulfan and ethanol showed increasing trends in the activities of reducing equivalent (NADPH)-generating enzymes in liver. The activity of hepatic alcohol dehydrogenase was, however, found to be relatively unaffected. When ethanol was administered in combination with endosulfan, the observed effects on the activities of major drug metabolizing enzymes, microsomal lipid peroxidation and NADPH generation were further pronounced. Findings demonstrated the MFO inducing capability of both endosulfan and ethanol, and showed further that chronic ethanol ingestion might potentiate the in vivo hepatotoxicity of endosulfan if administered in combination.     

Melatonin-induced suppression of gonadotropin titers in male golden hamsters: Effect on gonadal feedback mechanisms

Daily subcutaneous injections of melatonin cause testicular regression and a decline in circulating gonadotropin levels in male hamsters maintained on long photoperiods. We examine here if a reduction in gonadotropin levels also occurs in castrates administered melatonin and if melatonin-regressed hamsters respond to castration with an increased release of pituitary gonadotropins — a typical “castration response.” Groups of intact and castrated male hamsters maintained on a photoperiod of LD 14:10 received subcutaneous injections of 15 ug melatonin/day. Controls received vehicle only. After 7 weeks of injections the intact males were castrated. All animals were sacrificed a few days later and serum was assayed for gonadotropin titers. Melatonin injections caused a marked decline in serum gonadotropins in castrates and in intact males also caused testicular regression. In the latter, no “castration response” was observed upon removal of the testes. Thus, daily injections of melatonin depress serum gonadotropins in castrate and intact males and block the castration-associated rise in circulating gonadotropins in the latter.     

Sodium vanadate toxicity in adult and developing rats

The toxic effect of vanadium (sodium metavanadate) during pregnancy and lactation was studied by feeding vanadium to pregnant, Sprague-Dawley rats at levels of 1 (control) or 75 μg V/g diet through d 21 postpartum, at which time they were killed. Vanadium-fed dams had lower food intakes and weight gains than controls during pregnancy. Survival until d 21 postpartum was significantly lower in the vanadium pups compared to controls. In addition, the surviving pups gained less weight than control pups, despite similar birth weights. On a relative body weight basis, vanadium pups had larger livers, brains, and testes than controls, suggesting that these animals were developmentally delayed. Vanadium dams and pups had higher concentrations of hepatic vanadium than controls. Vanadium pups also had higher concentrations of hepatic zinc than control pups. Maternal hepatic zinc concentrations were not affected by diet. Also, no significant differences in hepatic iron, copper, or manganese concentrations were observed for either dams or pups. Hepatic thiobarbituric acid reactivity was higher in whole cell and isolated mitochondria for vanadium dams and pups than for control dams and pups, indicating that these animals may have had higher levels of lipid peroxidation. This idea was supported by the observation of lower concentrations of reduced glutathione in the livers of vanadium pups compared to controls. In contrast, kidney and brain glutathione levels were not affected by diet. In conclusion, animals during periods of rapid growth are susceptible to vanadium toxicity, and increased lipid peroxidation may be one factor underlying this toxicity.     

Newly proliferated cells in the adult male amygdala are affected by gonadal steroid hormones

Gonadal steroid hormones play an important role in the proliferation, survival, and activation of neurons. The present study was performed to examine the effects of testosterone and its metabolites on newly proliferated cells in the amygdala of adult male meadow voles (Microtus pennsylvanicus). Treatment with testosterone propionate (TP) in castrated males resulted in plasma testosterone levels similar to males following mating. TP-treated males displayed a significant increase in the density of cells labeled with a cell proliferation marker (BrdU) in the amygdala. Treatment with estradiol benzoate (EB) exerted a similar effect as TP on the density of BrdU-labeled cells, whereas 5alpha-dihydrotestosterone (DHT) was ineffective. A larger proportion (approximately 44%) of the BrdU-labeled cells in the amygdala displayed a neuronal phenotype, and a lesser percentage (approximately 35%) displayed a glial progenitor phenotype; however, treatment effects were not found in either population of cells. Hormonal effects appeared to be site-specific as no group differences were found in the dentate gyrus of the hippocampus or ventromedial hypothalamus. Finally, a time course study indicated that BrdU-labeled cells in the amygdala are present as early as 30 min following an acute injection of BrdU. Together, these data suggest that gonadal steroid hormones influence the number of newly proliferated cells in the amygdala, most likely by acting through an estrogenic mechanism, and these effects may be exerted on locally proliferating progenitors within the amygdala.     

Perseverative responding in male and female Wistar rats: effects of gonadal hormones

Response perseveration was investigated in an experimental procedure which has previously been shown to be sensitive to pharmacologically induced behavioral perseveration and response stereotypy. Different groups of intact, gonadectomized, and gonadectomized plus chronically testosterone-treated male and female Wistar rats were exposed to this procedure in which reinforcers were randomly assigned to one of two levers in an operant chamber. One response on the lever to which the reinforcer was assigned was sufficient to produce a food pellet. Response perseveration, defined as the percentage of trials on which more than one response on the lever not selected for reinforcement was made prior to switching to the selected lever was highest in testosterone-treated subjects. Females made more responses on the lever which had been selected for food on the preceding trial, suggesting that females may be more sensitive than males to the consequences of their behavior. This behavioral difference between the sexes may be mediated by the male hormone testosterone.     

Response of adult male rats to LH-RH after neonatal immunization with antiserum to LH-RH

Male rats were passively immunized at Day 5 of age with LH-RH antiserum. Their response to LH-RH at 100 days of age was examined. Serum FSH and LH concentrations increased more than in control rats, although basal plasma levels were similar. The pituitary content of LH, but not FSH, was significantly increased, and hypothalamic content of LH-RH was similar in both groups. The testes and seminal vesicles were smaller in experimental animals than in controls. It is suggested that transient blockade of LH-RH secretion during the neonatal period produces abnormalities in pituitary-testicular functon in the adult rat.