Nucleic acid and protein content in various cellular fractions of different regions of the brain were investigated in male albino rats following aluminum (Al) exposure (at the dose of 15% of LD50 i.p. for 28 days) on either an adequate or inadequate protein diet. It was observed that there was a decrease in homogenate DNA content in the thalamic area (Th), midbrain-hippocampal region (MH)and cerebellum (CL), but not in the cerebrum (CC) of the protein-restricted group of animals. Increased RNA content was recorded in the ribosomal and soluble fractions of CL of the adequately protein-fed animals compared to pair-fed controls. In the low-protein-fed animals, on the other hand, a decrease in RNA content was observed in the whole homogenate and nuclear fractions of CC, MH and CL, the ribosomal and soluble fractions of MH and CL, and in the mitochondrial fraction of TH. Ribonucleolytic activity was found to be increased only in the Th and CL of the adequately protein-fed group. Protein contents in the subcellular fractions of these four regions remain almost unaltered with the present dose and duration of Al-exposure; only the soluble fraction of CC and microsomal fraction of Th of the low-protein-fed group showed a dignificant decrease. The results of the present investigation confirm that Al has generally depressive effects on the nucleic acid metabolism of the brain and suggest that these effects are region-specific as well as dependent on dietary protein level. It is further suggested that alterations in the cellular microenvironment, caused by protein malnutrition, may play a significant role in the modification of the effects of Al in the brain.
Six-week old SD-Slc male rats were treated for 4 weeks with compounds known to induce toxicological changes in male reproductive organs (pyridoxine in saline, 500 mg/kg/day, i.p.) or sperm (trimethylphosphate in distilled water, 100 mg/kg/day, p.o.). Each sperm sample taken from the cauda epididymis was analyzed with flow cytometry for the evaluation of sperm viability and counts. Sperm motility and morphology by microscopical observation, and histopathological examination of reproductive organs were also performed for estimating the adverse effects of each compound on spermatogenesis and sperm. While a decrease in sperm motility was noted for the trimethylphosphate group, the low motile sperm was evaluated as being viable sperm, not moribund, with flow cytometry. In the pyridoxine group, microscopical observation revealed morphological changes of sperm and a decrease of motility. The present sperm analysis with flow cytometry also suggested morphological changes reflected by dot plot as well as decrease of sperm viability and counts. These results indicated that this procedure led to profound findings in the compound-treated animals, with evaluation as viable sperm, not moribund, in a low motile sperm sample, and suggesting morphological changes in the dot plot of flow cytometry.
We compared the tissue concentration of dipterex and the inhibition of the neuropathy target esterase (NTE) activity among groups of hens (n = 8 each) which were intravenously (IV), subcutaneously (SC) or orally (PO) administered the insecticide dipterex. The tissue concentrations of dipterex in the SC group were higher than those in the IV and PO groups. When dosed subcutaneously, the tissue concentration of dipterex was high in the brain, spinal cord and muscle at 3 hr after dosing and then concentrated in the spinal cord and muscle for the subsequent 3 hr. When dosed intravenously or orally, dipterex was evenly dispersed in various tissues. All hens treated with dipterex showed acute neurotoxic signs within 15 min after dosing. The hend dosed intravenously recovered from this acute poisoning within 3 hr, and the hens dosed orally recovered within 6 hr, while the hens dosed subcutaneously redovered within 24 hr after dosing. One hen in the SC group exhibited acute neurological sequelae following the acute poisoning. In addition, the loss of body weight was the largest in the SC group (157 ± 49 g), moderate in the IV group (133 ± 91 g), small in the PO group (96 ± 54 g) and the smallest in the PMSF (phenylmethanesulfonyl fluoride, which was dosed to promote delayed neuropathy) grourp (80 ± 49g). In the untreated hens, the activity of NTE in both the cerebrum and cerebellum was higher than that in the midbrain (p < 0.01). There was no difference in NTE activity between the cerebrum and cerebellum. In both the cerebrum and midbrain, the inhibition of NTE activity in the PO group was less than that in the IV and SC groups, and no difference was found between the IV and SC groups. In the cerebellum, the inhibition of NTE activity in the SC group was larger than that in the IV and PO groups. These results indicate that the SC dosing of dipterex results in a stronger neurotoxicity compared to IV and PO dosing. However it was difficult to induce the clinical signs of delayed neuropathy with any administration of dipterex in hens, even when the promotion of delayed neurotoxicity of dipterex was attempted with PMSF or double doses of dipterex itself.
Long-term (78 weeks) administration of lacidipine, a dihydropyridine calcium antagonist, increased the incidence of Leydig cell tumors (LCTs) in Sprague-Dawley rats. Lacidipine also increased and decreased the plasma luteinizing hormone (LH) and testosterone levels, respectively. Leydig cells from lacidipine-treated rats showed increases in luteinizing hormone-releasing hormone (LHRH) receptor expression, protein kinase C (PKC) activity, expression of proto-oncogenes, and 5-bromodeoxyuridine uptake; whereas their calcium level, LH receptors, and testosterone content decreased. These data suggest that LHRH receptors play an important role in the development of rat LCTs induced by lacidipine, which activates a cascade of dell cycle-regulatory genes via PKC. When isolated Leydig clells were cultured with lacidipine or nicardipine, these changes in rat Leydig cells were not demonstrable in mice and monkeys, species having many fewer testicular LHRH receptors than rats. Thus, lacidipine may pharmacologically induce LCTs in rats but not in mice, with the difference depending on the presence or absence of testicular LHRH receptors. The induction of LCTs by lacidipine in rats is unlikely to occur in humans, since their Leydig cells lack LHRH receptors.
The chemical structure of 2-mercaptobenzimidazole (2-MBI), which is widely used as a rubber antioxidant, is partially similar to those of thiourea (TU) and ethylenethiourea (ETU), both potent thyrotoxic compounds. In order to determine the oral toxicity of 2-MBI, a 28-day repeated dose toxicity study in Wistar rats followed by observation over a 14-day recovery period was conducted at dose levels of 2, 10 and 50 mg/kg 2-MBI administered by gavage. No toxic deaths occurred due to 2-MBI treatment. Decreases of body weight gain and food consumption in the 50 mg/kg dose group were observed during the second half of the treatment period. In addition, hematological examination and serum biochemical tests revealed decreased white blood cells and hemoglobin and increased serum urea nitrogen, cholesterol, phospholipid, γ-glutamyl transpeptidase and the Na+ /K+ ratio in the 50 mg/kg dose group. Marked thyroid enlargement (to 10 fold the control weight), histopathologically associated with diffuse hyperplasia of follicles with decreased colloid and thickening of the fibrous capsule, was found. Reduction in thymus weight was also observed in a dose-dependent manner without significant histopathological alteration. The non-observed effect level (NOEL) of 2-MBI in this gavage study was found to be less than 2 mg/kg/day based on the significant decrease in thymus weight in the 2 mg/kg 2-MBI treatment group. In an ancillary study, measurement of serum levels of T3, T4 and TSH, and thyroid weight after gavage treatment with 0.15 and 0.3 mmol/kg of three antithyroid compounds for 14 days revealed a more potent antithyroid effect for 2-MBI than for TU or ETU.
To establish an animal model of asthma, fully sensitized guinea pigs inhaled aerosolized ovalbumin after booster treatments. At 0, 1, 3, 6, 24 and 48 hr after provocation (hap), histopathological and immunohistochemical changes in the airways of guinea pigs were examined. From 1 to 6 hap, anaphylactic changes such as perivascular edema and bronchoconstriction were detected. After that, intensive infiltration of eosinophils appeared and lasted until 48 hap. Temporal increases in the number of apoptotic cells and proliferating cell nuclear antigen positive cells were detected in the alveoli after the provocation. These findings suggest that this animal model showing both immediate and late asthmatic responses may be useful as an asthmatic model.
In this study, we investigated the phlebitic potentials of several infusion solutions for peripheral parenteral nutrition to clarify the effects of pH and osmolality on the development of infusion phlebitis. A 10% glucose solution with electrolytes (GE, pH 4.93, 727 mOsm/kg), a 10% amino acid solution (AA, pH 6.95, 929 mOsm/kg), or a 5:2 admixture of GE and AA (GEAA, pH 6.46, 779 mOsm/kg) was infused into the rabbit ear vein for 6 hr at 10 mL/kg/hr, and the infused veins were examined histopathologically. Both GE and AA caused phlebitic changes, such as loss of venous endothelial cells, inflammatory bell infiltration, and perivascular edema. However, their admixture, GEAA, caused scant phlebitic changes. These results were as follows: 1) rabbit peripheral veins could tolerate the pH (6.46) and the osmolality (779 mOsm/kg) of GEAA under the conditions of this study;2) GE caused phlebitis due to its acidity (PH 4.93); 3) AA caused phlebitis due to its hyperosmolslity (929 mOsm/kg); and 4) mixing GE and AA eliminated the factors causing phlebitis in each solution. The admixture of GE and another 10% amino acid solution (AB, pH 6.04) at the ratio of 5:2 (GEAB, pH 5.76, 758 mOsm/kg) caused phlebitic changes. Since its osmolality was lower than that of GEAA, it was considered that GEAB caused phlebitic changes due to its acidity (pH 5.76), which was attributed to the acidic amino acid solution used as a component.
Guinea pigs of two strains, outbred Hartley and inbred Strain 2, were immunized sub-cutaneously with cephalothin (CET, 20 mg/body) alone, without adjuvant. Immune responses to the antibiotic were assessed by guinea-pig passive cutaneous anaphylaxis (GP-PCA) and active systemic anaphylaxis (GP-ASA) reactions. The immune response to CET in the female Hartley guinea pigs was higher than that in the males. In contrast, no difference in response to CET in Strain 2 guinea pigs was observed between males and females. These results suggested that female Hartley guinea pigs possessing a higher response should be employed in antigenicity studies involving the β-lactam antibiotics.