Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153470 (Spleen)
 4,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hb M Akita disease is a cyanotic hemoglobinopathy found in Akita Prefecture, Japan. The abnormal hemoglobin was found to be the same as Hb M Hyde Park (beta92 His replaced by Tyr) by chemical analysis in 1967. In this disease signs of accelerated hemolysis (serum bilirubin, 2.4 mg/dl; splenomegaly, 2 finger breadths; Hb, 10.7 g/dl; reticulocyte index, 2.7) were noted, but the causes of its slight anemia were revealed to be fairly complex by ferrokinetic study, RBC life-span measurement, and 99mTc myeloscintigram. The anemia in this disease is caused not only by shortened erythrocyte survival (T 1/2 = 11.5 days by 51Cr-tagging method) and sequestration of red cells in the spleen (Spleen: liver ratio = 2.5 approximately 3.0 by 51Cr-surface counting), but also by slow supply of erythrocytes to the peripheral blood from the bone marrow, presumably, related to the existence of unstable Hb M Akita and its derivative (Hb Akita) in the erythroid cells. Both Carrell's isopropanol test and Heinz body formation test were positive. In spite of maximally increased total erythropoiesis (8 times as high as the normal level; M:E ratio = 0.22:1.0), supply of red cells from the bone marrow to the peripheral blood was significantly decreased. The distribution of hematopoietic sites throughout the body was reasonably uniform.
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PMID:Altered erythropoiesis and increased hemolysis in hemoglobin M Akita (M Hyde Park beta92 His replaced by Tyr) disease. 105 75

Dose levels for these studies were selected mainly on the basis of subchronic studies, although consideration was also given to workplace exposure levels and proposed mechanism of tumor formation with structurally similar compounds. For the chronic study, groups of 60 male and 60 female Sprague-Dawley CD (Registered Trademark of Charles River Breeding Laboratories, Portage, MI) rats were given 0, 0.25, 1.5, or 9.0 mg/kg/day paranitroaniline (PNA) by gavage in corn oil for a period of 2 years. Parameters monitored included clinical observations, ophthalmoscopic exams, body weights, food consumption, hematology, clinical chemistry, and urinalysis at regular intervals throughout the study. All gross lesions and over 40 tissues were examined histologically for all control and high-dosage-level animals. Gross lesions, spleens, and livers of low- and mid-dosage groups were also examined histologically. For the reproduction study, groups of 15 male and 30 female rats, designated as F0 generation, were given PNA at the same levels as the chronic study for 14 weeks prior to mating and during mating, gestation, and lactation. Selected groups of 15 male and 30 female rats of the F1 generation received the same dose of PNA for 18 weeks prior to mating and during mating, gestation, and lactation. F2 pups were observed through weaning at which time they were euthanized. Observations made during the study included body weights, food consumption, mating and fertility indices, pup and litter survival indices, and histopathology of selected tissues. In the chronic study, except for a slight decrease in survival of high-dose male rats late in the study, survival in all treated groups was comparable to controls. Blood methemoglobin levels were elevated in the mid- and high-dosage groups, while slight anemia was observed in the high-dosage group also. Spleen weights were significantly increased in the high-dosage groups. An accumulation of brown pigment was observed in the cytoplasm of the sinusoidal macrophages or littoral cells of the liver and in the reticuloendothelial cells of the spleen. No treatment-related increase in tumor incidence was observed. In the reproduction study, no consistent pattern of effect from treatment between the F0 and F1 generation was seen in mating, pregnancy, or fertility indices. Thus, administration of PNA at levels which produced significant methemoglobinemia and low-level anemia in the rat and histological changes in the spleen produced no tumors or reproducible effects on reproductive performance.
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PMID:Chronic toxicity, oncogenic potential, and reproductive toxicity of p-nitroaniline in rats. 225 23

o-Nitrochlorobenzene (ONCB) is a chemical intermediate used for the synthesis of various industrial chemicals. To evaluate the subchronic toxicity of this compound, three groups of 15 male and 15 female Sprague-Dawley rats were exposed to ONCB vapor 6 hr/day, 5 days/week for 4 weeks at target concentrations of 10, 30, or 60 mg/m3. A control group of 15 animals/sex was exposed to room air in a separate inhalation chamber. Concentrations of ONCB in the chambers were determined at least three times a day using a uv spectrophotometer. Parameters monitored in this study included observation for signs of toxicity, body weights, ophthalmoscopic exam, hematology, and clinical chemistry. At necropsy, selected organ weights were recorded and over 35 tissues/animal were examined microscopically for all control and high-exposure level animals. No mortality was observed in this study. Mean body weights of all groups were comparable to controls. Animals exposed to the mid and high concentrations of ONCB showed a significant increase in blood methemoglobin and a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen and liver weights (absolute and relative to body weight) were significantly increased for these two groups. Microscopic changes, observed only in the spleen, included increased degree of extramedullary hematopoiesis and hemosiderosis. These data suggest that the toxicity of ONCB is comparable to that of its structural analog, p-nitrochlorobenzene. Thus these two compounds should have similar work-place exposure limits.
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PMID:Assessment of toxicity of o-nitrochlorobenzene in rats following a 4-week inhalation exposure. 380 55

In this study, Sprague-Dawley rats were exposed in a TEM chamber to 20-MHz (HF-band) continuous-wave radiofrequency radiation (RFR) for 6 hr/day, 5 days/week up to 6 weeks. The average E-field intensity was 2686 +/- 164 V/m (mean +/- SD) and the calculated specific absorption rate was 0.3 W/kg. Randomly sampled rats killed on Days 8, 22, 39, and 42 after initiation of exposure showed no statistically significant differences from controls for body mass, spleen cell density, erythrocyte and leukocyte counts, hematocrit, hemoglobin, methemoglobin, erythrocyte fragility, bilirubin, creatinine, SGPT, alkaline phosphatase, calcium, sodium, potassium, and spleen cell chemiluminescence. Splenic mass differences were statistically significant (p less than 0.05) only on Day 22. Spleen to body mass ratios differed significantly between exposed and control groups on Days 22 and 39 (P less than 0.05 and P less than 0.025, respectively). Histologic examination of the rats revealed the successive accumulation of phagocytic cells, lymphoid proliferation, development of lesions, and tissue necrosis characteristic of respiratory mycoplasmosis. In a followup experiment, a separate set of rats was exposed for 6 weeks to identical levels of RFR. No significant differences were found in splenic parameters and spleen cell peroxidative activity. Histologic examination of these animals revealed no evidence of mycoplasma infection. The observed differences between exposed and control animals of the first experiment appear to have resulted from subclinical respiratory mycoplasmosis rather than exposure to RFR.
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PMID:Effects of 20-MHz radiofrequency radiation on rat hematology, splenic function, and serum chemistry. 402 74

In the present study, acute hematopoietic toxicity of aniline as a function of time was investigated in rats. The animals were given a single oral dose of aniline hydrochloride (2 mmol/kg) and euthanized at zero (control), 0.25, 0.5, 1, 3, 6, 12, 24 and 48 h following the treatment. The blood methemoglobin level increased dramatically and attained a peak level of 37% (31 fold greater than the controls) at 0.5 h. Thereafter, the increases were less pronounced and the level declined with time. Spleen weight to body weight ratio remained unchanged up to 24 h, but increased approximately 25% at 48 h. Lipid peroxidation (MDA content) in the spleen increased by 39% at 24 h and remained steady even at 48 h. MDA-protein adducts, as quantitated by a competitive ELISA, showed 94, 126 and 265% increases in the spleen homogenates at 12, 24 and 48 h, respectively, following the treatment. However, no changes were observed in the splenic protein oxidation. Morphological examination showed congestion of splenic blood vessels and marked expansion of red pulp at 24 and 48 h. These studies suggest that aniline related changes in the blood are reflected very early as evident from increases in the methemoglobin content, whereas changes in the spleen appear later and are characterized by splenic weight changes, increased lipid peroxidation, MDA-protein adduct formation and morphological changes after a single high dose exposure. The increased lipid peroxidation in the spleen also suggests that free radical-mediated reactions could be the potential mechanism of splenic toxicity of aniline and lipid peroxidation precedes protein oxidation.
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PMID:Acute hematopoietic toxicity of aniline in rats. 924 55

To elucidate the mechanism(s) of splenic toxicity of aniline, studies were conducted with nitrosobenzene (NB), an N-oxidized metabolite of aniline. Male Sprague-Dawley rats were given 0.025, 0.05, 0.1, or 0.2 mmol/kg/d of NB in 0.5 ml of 0.25% agar by gavage for 4 d; control rats received the vehicle only. Animals were euthanized at 24 h following the last dose. NB treatment resulted in decreased erythrocyte counts, whereas methemoglobin content increased at 0.1- and 0.2-mmol/kg doses. Spleen weight to body weight ratios were greater by 55 and 81% at O.1- and 0.2-mmol/kg NB doses, respectively. Total iron content in the spleens of NB-treated rats showed dose-dependent significant increases, and the nonheme iron followed a similar pattern. Splenic lipid peroxidation showed a dose-dependent response and was greater by 19, 56, 74, and 85% at the 4 doses, respectively. Malondialdehyde (MDA)-protein adducts, as quantitated by a competitive enzyme-linked immunosorbent assay (ELISA), were markedly greater in all the NB-treated groups, with the highest increase of 248% at 0.2 mmol/kg. Furthermore, NB exposure also resulted in greater protein oxidation (carbonyl content) in the spleens at 0.1- and 0.2-mmol/kg doses. These results suggest that NB is a splenotoxin and therefore can contribute to the splenic toxicity of aniline. Results of this study further support our earlier findings that oxidative stress is a potential mechanism in the splenotoxicity of aniline.
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PMID:Contribution of nitrosobenzene to splenic toxicity of aniline. 1091 91

This article addresses results from a single 4-h and repeated 1- and 4-wk inhalation exposure studies in Wistar rats with vapor and/or aerosol atmospheres of 4-ethoxyaniline (p-phenetidine). Groups of 10 rats/sex were exposed nose-only to mean analytical concentrations of 11.1, 86.2, and 882.6 mg p-phenetidine/m(3) using an exposure regimen of 6 h/day, 5 days/wk for 4 wk. Concentrations were selected based on results from a pilot study in which rats were exposed under identical conditions on 5 consecutive days for 6 h/day to mean analytical concentrations of 38.2, 133.0, and 1247.6 mg/m(3). In repeated exposure studies, the focus of endpoints was on hematotoxicity. The LC50 was not determined, but no rats died following a single 4-h exposure to 5085 mg/m(3) as a mixture of vapor and aerosol. No mortality was observed either in the 1- or 4-wk studies. Rats exposed to 882.6 mg/m(3) and above evoked characteristic signs of toxicity that included cyanosis, with no apparent progression of findings during the exposure period. Animals exposed to 86.2 mg/m(3) and above exhibited a concentration-dependent, significant increase in blood methemoglobin and reticulocyte counts as well as a significant decrease in hemoglobin, hematocrit, and red blood cell counts. Spleen weights were significantly increased in groups exposed to 133.0 mg/m(3) and above. Microscopic changes demonstrated an increased hematopoiesis (bone marrow smears) and splenic hemosiderosis at 86.2 and 882.6 mg/m(3) and a hepatic hemosiderosis only at 882.6 mg/m(3). These data suggest that the toxicity of p-phenetidine is similar to that of its structural analog aniline. Based on the erythrocytotoxicity occurring at 86.2 mg/m(3) and above, including the apparent reactive changes in bone marrow (increased erythropoiesis) and spleen (increased erythroclasia), the no-observed-adverse-effect level (NOAEL) of the 4-wk study was 11.1 mg/m(3) air and that of the 1-wk study was 38.2 mg/m(3) air. This difference in NOAELs is considered to be related to the selection of exposure concentrations rather than cumulative toxicity.
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PMID:Inhalation toxicity of 4-ethoxyaniline (p-phenetidine): critical analysis of results of subacute inhalation exposure studies in rats. 1169 70

2-Chloronitrobenzene and 4-chloronitrobenzene are oily yellow solids that are used primarily as chemical intermediates in the production of dyes, lumber preservatives, drugs, and photographic chemicals. Although these chemicals are solids at room temperature, the vapor pressures of these chemicals are sufficiently high to result in significant inhalation exposure. Toxicity studies of 2-chloronitrobenzene and 4-chloronitrobenzene were performed by exposing male and female F344/N rats and B6C3F1 mice to the chemicals by whole-body inhalation 6 hours per day, 5 days per week, for 2 weeks or 13 weeks. Animals were evaluated for histopathology, clinical chemistry (rats), hematology (rats), and reproductive system effects. In separate studies, the dermal absorption of the chemicals was compared, and the absorption, distribution, metabolism, and excretion were partially characterized following oral administration to male F344/N rats. 2-Chloronitrobenzene and 4-chloronitrobenzene were also administered orally to CD-1(R) Swiss mice for evaluation of reproductive and developmental toxicity. Genetic effects were evaluated in Salmonella typhimurium, in Chinese hamster ovary cells, and in Drosophila melanogaster. The highest exposure concentrations used in the 2 week and 13 week studies were limited by technical factors in vapor generation to 18 ppm (115.2 mg/m(3)) for 2-chloronitrobenzene and 24 ppm (153.6 mg/m(3)) for 4-chloronitrobenzene. Other concentrations were 0, 1.1, 2.3, 4.5, and 9 ppm (0, 7, 14.7, 28.8, and 57.6 mg/m(3)) for 2-chloronitrobenzene and 0, 1.5, 3, 6, and 12 ppm (0, 9.6, 19.2, 38.4, and 76.8 mg/m(3)) for 4-chloronitrobenzene. In 2-week studies with 2-chloronitrobenzene, all rats survived to the end of the study. One of five male mice exposed to 18 ppm died, but weight gains of exposed rats and mice were not affected. Exposed rats and mice had concentration-related increases in liver weights, and spleen weights were increased in rats and mice exposed to 18 ppm. Histopathologic findings in rats were limited to hemosiderin deposition in the liver and spleen at the highest exposure concentration. Exposed mice, primarily those in the 18 ppm groups, had coagulative necrosis, hepatocytomegaly, and granulomatous inflammation in the liver. Splenic changes including increased hematopoietic cell proliferation and hemosiderin deposition occurred at concentrations as low as 4.5 ppm. In 13-week studies with 2-chloronitrobenzene, all rats survived to the end of the study; 2 of 10 male mice exposed to 18 ppm died. Body weight gains of exposed rats and mice were similar to or somewhat higher than those of the respective controls. Methemoglobinemia occurred in rats and resulted in a normocytic, normochromic anemia that became responsive by the end of the study. Exposed rats and mice had increased liver weights, but these increases were not as great as those seen in the 2-week studies. Spleen weights were increased in exposed rats. Histopathologic changes in rats included increased basophilia of centrilobular hepatocytes, pigmentation and regeneration of the proximal convoluted tubules of the kidney, and hyperplasia of the nasal cavity respiratory epithelium. In mice, hepatocellular necrosis, cytomegaly, mineralization, and chronic inflammation occurred in the liver, primarily in mice in the 18 ppm group, and hematopoietic activity in the spleen was increased. In 2-week studies with 4-chloronitrobenzene, all rats and mice survived to the end of the studies. Body weight gains of exposed rats were similar to those of the controls; body weight gains of exposed mice were greater than those of the controls. Liver and spleen weights were increased in exposed rats and mice. In rats, histopathologic changes in the liver were limited to an increase in hemosiderin pigment in Kupffer cells. The spleens of exposed rats were congested and had increased hematopoietic activity and hemosiderin deposition. Kidneys of exposed male rats had lesions consistent with hyaline droplet nephropathy. The proximal convoluted tubules of exposed female rats c contained hemosiderin. Microscopic changes in exposed mice primarily involved increased hematopoietic activity in the spleen and hemosiderin pigmentation in the spleen, liver, and proximal convoluted tubules in the kidney. In 13-week studies with 4-chloronitrobenzene, there were no deaths that were clearly related to exposure to 4-chloronitrobenzene. Body weight gains of exposed rats and mice were either equal to or greater than those of the controls. A more severe methemoglobinemia developed in rats exposed to 4-chloronitrobenzene than occurred in rats exposed to 2-chloronitrobenzene, and this methemoglobinemia resulted in a responsive macrocytic, hyperchromic anemia. Spleen weights were markedly greater in exposed rats and mice than in controls. In exposed rats, lesions in the spleen, liver, and kidney were similar to those described for the 2-week study. Additionally, increased hematopoietic cell proliferation in bone marrow, histiocytic hyperplasia in mediastinal lymph nodes, testicular atrophy, and chronic inflammation of the harderian gland occurred in exposed rats. In exposed mice, microscopic changes in the spleen and liver were similar to those noted in the 2-week study. Additional lesions included increased hematopoiesis and hemosiderin deposition in the bone marrow of exposed males and females and squamous cell hyperplasia of the forestomach epithelium in female mice. In reproductive system assessments, there was evidence of decreased spermatogenesis in rats exposed to either 2- or 4-chloronitrobenzene. In mice, effects were limited to a decrease in sperm motility in males exposed to 2-chloronitrobenzene and an increase in estrous cycle length in females exposed to 4-chloronitrobenzene. In continuous breeding studies, a progressive decrease in fertility was noted in CD-1® Swiss mice receiving 4-chloronitrobenzene by oral gavage; fertility was not affected in mice administered 2-chloronitrobenzene by oral gavage. Percutaneous absorption of [14C]-2-chloronitrobenzene and [14C]-4-chloronitrobenzene was demonstrated in rats. For doses ranging from 0.65 to 65 mg/kg of either chemical, 33% to 40% of 2-chloronitrobenzene and 51% to 62% of 4-chloronitrobenzene were absorbed under nonocclusive conditions. Oral absorption was somewhat higher than dermal absorption for both chemicals, and metabolism was complicated, with over 20 unidentified metabolites isolated from urine of rats given either 2- or 4-chloronitrobenzene. 2-Chloronitrobenzene and 4-chloronitrobenzene were mutagenic in Salmonella typhimurium with S9 activation. In addition, both compounds induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells; requirements for S9 activation varied among testing laboratories. Neither compound induced sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated as adults or as larvae. In summary, inhalation exposure of rats and mice to 2- or 4-chloronitrobenzene resulted in methemoglobin formation and oxidative damage to red blood cells, leading to a regenerative anemia and a recognized spectrum of tissue damage and changes secondary to erythrocyte injury. In addition, numerous other lesions that were considered primary toxic effects occurred following exposure. These included renal hyaline droplet accumulation and testicular atrophy in male rats exposed to 4-chloronitrobenzene and hyperplasia of the respiratory epithelium in rats exposed to 2-chloronitrobenzene. A no-observed-adverse-effect-level (NOAEL) for rats was not achieved, as increases in methemoglobin and histopathologic changes occurred at exposure concentrations as low as 1.1 ppm for 2-chloronitrobenzene and 1.5 ppm for 4-chloronitrobenzene in the 13-week studies. The NOAEL for histopathologic injury in mice was 4.5 ppm for 2-chloronitrobenzene and 6 ppm for 4-chloronitrobenzene. 2-Chloronitrobenzene Synonyms: o-Cloronitrobenzene; 2-chloro-1-nitrobenzene; ONCB. 4-chloronitrobenzene Synonyms: p-Chloronitrobenzene; 4-chloro-1-nitrobenzene; PNCB.
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PMID:NTP technical report on the toxicity studies of 2-Chloronitrobenzene (CAS No. 88-73-3) and 4-Chloronitrobenzene (CAS No. 100-00-5) Administered by Inhalation to F344/N Rats and B6C3F1 Mice. 1220 91