Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the immunotoxicity of benzene, the effects of benzene inhalation on T and B lymphocytes and immune responses in mice were examined. BALB/c male mice were exposed to 50 or 200 ppm benzene vapor, 6 hr/day for 7 or 14 consecutive days. T and B lymphocytes, in blood and spleen, were detected by the cytotoxicity assay with anti-Thy-1.2 monoclonal antibody and the membrane immunofluorescence test with anti-immunoglobulin antibody, respectively. Humoral immune response to sheep red blood cells was determined by the hemolytic plaque-forming cell assay. Cell-mediated immune response was measured by contact sensitivity (CS) to picryl chloride. The activity of suppressor cells was evaluated in spleen by the suppressive effect on passive transfer of CS. The ratio and absolute number of T and B lymphocytes in blood and spleen were depressed after a 7-day exposure at 50 ppm benzene. The depression of B lymphocytes was dose dependent and more intense than that of T lymphocytes. The ability to form antibodies was suppressed by benzene at all exposure levels, but the CS response was resistant to benzene inhalation and rather enhanced at 200 ppm exposure for 14 days. The activity of suppressor cells could not be detected at this dose level. These data show that benzene inhalation effects on humoral and cell-mediated immune responses are a result of the selective toxicity of benzene to B lymphocytes and suppressor T cells.
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PMID:Effects of benzene inhalation on lymphocyte subpopulations and immune response in mice. 294

Acute administration of Aroclor-1254 (500 mg/kg) or 3,4,5,3',4',5'-hexabromobiphenyl (HBB) (2-6 mg/kg) IP, profoundly inhibited the plaque forming response to subsequent challenge with sheep erythrocytes in Ah locus positive (C57Bl/6N or B6C3F1N) mice. These studies showed: the immunotoxicity results paralleled enzyme induction results insofar as HBB was approximately 100 times more potent than Aroclor 1254; neither Aroclor nor HBB treatment caused significant induction in the Ah locus negative DBA/2N mice; when B6C3F1 mice were challenged with sheep red blood cells (SRBC) 6 or 16 weeks post Aroclor 1254 treatment, substantial recovery of a PFC response was observed; when these compounds were administered to older (76-week-old) (B6C3F1 mice, severe depression of a PFC response was observed. In contrast to its profound depression of a PFC response, Aroclor-1254 (up to 1250 mg/kg) caused slight increases in lymphocyte proliferation induced by either T or B cell mitogens. A single 500 mg/kg dose of Aroclor-1254 also suppressed the ability of recipient B6C3F1 animals to reject a challenge with either the syngenic fibrosarcoma (PYB6) or the gram negative pathogen (Listeria monocytogenes).
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PMID:Induction of immunotoxicity in mice by polyhalogenated biphenyls. 309 83

Previous studies have clearly established that physiologic and pharmacologic levels of estrogens modulate immunologic responses that result in simultaneous activation of the reticuloendothelial system and depression of cell-mediated immunity. The mechanisms of estrogen immunoregulation were examined in adult female mice administered pharmacologic levels of exogenous estrogens. Evaluation of steroidal and nonsteroidal compounds with varying degrees of estrogenicity (i.e., uterotrophic activity) provided evidence that their immunotoxicity, for the most part, correlates with estrogenicity. The mechanisms responsible for these effects appear to be complex, mediated through a direct chemical interaction with lymphoid target cells, as well as with nonlymphoid tissue, resulting in the release of soluble immunoregulatory factors. The latter phenomenon was examined in detail and it appears to constitute a regulatory factor(s) produced by thymic epithelium in response to an estrogen stimulus. This response is not only estrogen specific but may involve specific binding to estrogen receptors or receptor-like structures present in cytosol preparations from thymic epithelial cells.
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PMID:Estrogen immunosuppression is regulated through estrogenic responses in the thymus. 672 53

Aflatoxin B1, the potent carcinogenic compound produced by the Aspergillus flavus group of fungi on food and feed, induces immunosuppressive effects in rodents. In this communication, we report an immunomodulatory approach to abrogate aflatoxin B1-induced immunotoxicity in rats using protein A of Staphylococcus aureus Cowan 1. We have earlier demonstrated that protein A can protect the animals from toxicities induced by a number of drugs, chemicals and toxins. In the present study various combinations of aflatoxin B1 exposure and protein A treatment in animals were used. It was observed that protein A could provide protection to animals from aflatoxin B1-induced immunotoxicity, as measured by a battery of tests assessing cell-mediated immunity (CMI) profile of the host. Various parameters showing suppression of CMI following aflatoxin B1 exposure were reverted back towards normalcy in protein A-treated animals. It is concluded that protein A may prove to be a useful agent to protect the host from aflatoxin immunotoxicity, in view of its stimulatory effects on various immune functions even after their initial depression due to aflatoxin B1.
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PMID:Immunostimulating effects of protein A in immunosuppressed aflatoxin-intoxicated rats. 770 70

The thymoma cell line EL4.IL-2 (EL-4) was used as a T-cell model to assess the immunotoxic effects of several mycotoxins produced by the Aspergillus-Penicillium and the Fusarium groups. EL-4 cells were stimulated with phorbol 12-myristate 12-acetate (PMA) in the presence of mycotoxins at various concentrations for 5 d and culture supernatants were analyzed for interleukins (IL) IL-2 and IL-5 by enzyme-linked immunosorbent assay (ELISA). The cytokine effects were further related to proliferation and cell viability using the MTT [3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay with absorbance at 570 nm (A570) as the endpoint indicator. IL-2 and IL-5 levels were dramatically increased by cyclopiazonic acid at 50-1000 ng/ml, whereas IL-2 was significantly decreased at 10 microgram/ml. Proliferation was slightly increased at 100-1000 ng/ml cyclopiazonic acid but markedly depressed at 5 and 10 microgram/ml. When EL-4 cells were exposed to 5 and 10 microgram/ml of ochratoxin A, IL-2 production was markedly increased while IL-5 production was significantly decreased. The A570 was significantly decreased by ochratoxin A at 10 microgram/ml. IL-2 and Il-5 production was almost totally suppressed by patulin at concentrations > or = 500 ng/ml and by T-2 toxin at > or = 5 ng/ml. These effects occurred concurrently with marked depression of A570 in the MTT assay. Although A570 was unaffected by either zearalenone or alpha-zearalenol exposure, both IL-2 and IL-5 levels were significantly elevated by these toxins at 5 or 10 microgram/ml. IL-2 and IL-5 production were not affected in EL-4 cells cultured with either the Aspergillus-Penicillium toxins aflatoxin B1 and secalonic acid or the Fusarium toxins wortmannin, fumonisin B1, or fusaric acid at concentrations up to 10 microgram/ml. In total, the EL-4 culture studies indicated that cyclopiazonic acid, ochratoxin A, zearalenone, and alpha-zearalenol could stimulate cytokine production whereas patulin and T-2 toxin were inhibitory. Cytokine dysregulation was not always related directly to perturbations in proliferation. The results suggest that the EL-4 thymoma cell line could be a simple and effective in vitro model for evaluating immunotoxicity of various classes of environmental chemicals.
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PMID:Effects of mycotoxins on cytokine production and proliferation in EL-4 thymoma cells. 869 8

Toxicology has two goals. The first is to identify and characterize the adverse effects that can be produced in biological systems by exposure to chemicals and the second is to use this information to predict the type and severity of responses in other species and exposure situations. The tools that the toxicologist uses to detect and describe the adverse effects of chemical exposure include the traditional acute, subchronic, and chronic studies in animals plus a variety of special studies designed to demonstrate specific organ damage, reproductive and teratogenic effects, neurotoxicity, immunotoxicity, genotoxicity, and other responses. These are often supplemented with studies of the kinetics and the mechanism of action and more recently with studies designed to elucidate the molecular basis for cancer and other effects. Theses studies together with the information on exposure provide the basis for subsequent toxicologic predictions. Although general effects such as weight loss and mortality are included in toxicity protocols, most of the toxicology tests are related to specific end-organ toxicity or to mechanism or behavioral studies. We do not have animal protocols to study individually the subjective symptoms described for multiple chemical sensitivity, such as depression, fatigue, headache, and memory loss, and our tests lack sufficient specificity to evaluate a syndrome which is composed primarily of such symptoms. Since all chemicals can produce adverse effects under some conditions of exposure, toxicologic predictions are most useful when they specify both the type of adverse effect anticipated and the dose required to produce the effect. Multiple chemical sensitivity does not appear to consistently involve specific chemicals or specific adverse effects and the effects observed are reported to lack evidence of a threshold and to occur at extremely low levels. It is difficult to include these parameters in any reasonable toxicologic prediction relating cause and response in multiple chemical sensitivity or similar conditions.
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PMID:Specificity and dosimetry of toxicologic responses. 892 57

Pregnant Wistar rats were exposed to 2,4,6-Tribromophenol (TBP) by whole body inhalation (0, 0.03, 0.1, 0.3, 1.0 mg/m3, 24 hr/day, 7 days/weeks, from day 1 to 21 of gestation). Significant decreases in orientation reactions were noted at concentrations of 1.0 mg/m3 (p < 0.05) in the open field test. Nonsignificant trends (p > 0.05) toward decreased horizontal movement and emotionality in the open field and increased electrical impulse skin pain threshold (SPT) were observed. No significant exposure-related differences in the nonspecific immunological status (phagocytosis and blood anti-microbe activity) of pregnant rats were seen after the exposure. Preimplantation and postimplantation embryo losses were significantly increased in a dose-dependent manner and were seen in all treated groups except the lowest concentration (0.03 mg/m3) group. Signs of retarded fetal skeletal development and increased frequencies of visceral abnormalities were found at concentrations of 0.1 and 1.0 mg/m3. Significant effects were found for lower incisor eruption and ear unfolding at a concentration of 0.3 mg/m3. The grooming behavior of 30-day old male progeny was significantly less than control in all experimental groups. Grooming behavior in female subjects exposed to a concentration of 0.3 mg/m3 and emotionality in subjects exposed to a concentration of 1 mg/m3 were decreased significantly. At 60 days of age emotional reactions were significantly decreased in female subjects from the 0.03, 0.3 and 1.0 mg/m3 groups. SPT was significantly increased in the 1 mg/m3 group for both male and female pups. Thus, evidence of CNS depression influence of TBP both in maternal and offspring groups was found. The NOEL (No Observed Effect Level) for developmental neurotoxicity is thus < 0.03 mg/m3, and the NOEL for maternal neurotoxicity is 0.3 mg/m3. These results suggest that exposure to TBP for 24 hr/day throughout gestation may cause developmental neurotoxicity, embryotoxicity and fetotoxicity, but not immunotoxicity.
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PMID:Developmental neurotoxicity and immunotoxicity of 2,4,6-tribromophenol in Wistar rats. 955 67

The aim of this study was to compare the effect of cyclosporin A (CsA) in inbred Lewis rats with published assessment of immunotoxicity in 'classical' outbred Wistar rats. A second purpose was to consider the contribution of a panel of in vitro assays in cell cultures when added to an immunotoxicity study in vivo. The in vivo effect of CsA was investigated in a 28-day subacute immunotoxicity study in male Lewis rats at three different concentrations: 1.25, 5 and 20 mg kg(-1). The highest dose of CsA exceeded the maximum tolerated dose. A drop in body, spleen and popliteal lymph node weight of exposed animals displayed symptoms of toxicity. At a high toxic dose, haematological changes showed a decrease in the leucocyte count and in the percentage of lymphocytes, and an increase in the percentage of polymorphonuclear leucocytes. The haematocrit was significantly dose-dependently suppressed in all rats exposed to CsA. A similar dose-dependent depression of the mean cell volume of erythrocytes was found in rats given high and middle doses of CsA. The phagocytic activity of polymorphonuclear leucocytes and monocytes also was significantly dose-dependently suppressed. No significant changes in primary antibody response to sheep erythrocytes or in vitro proliferative response of spleen lymphocytes to mitogens were found in those rats.A battery of in vitro cytotoxicity methods was selected for the evaluation of metabolic and functional activity of subcellular organelles (mitochondria, lysosomes) and for the detection of drug-induced superoxide-mediated damage in HeLa cells. This cell line was chosen because it has a lower activity of superoxide dismutase (SOD) than normal cells and is sufficiently sensitive for the detection of the induction of oxygen radicals. The in vitro results indicated a direct relationship between CsA cytotoxicity and a change in the mitochondrial enzyme activity, as well as an induction of superoxide production. The results of the study indicated that a combination of selected in vivo and in vitro methods is an inexpensive way to obtain more complex information on cell status affected by xenobiotics.
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PMID:Effect of cyclosporin A in Lewis rats in vivo and HeLa cells in vitro. 1201 94

Dimethylvinyl chloride is a clear colorless liquid, which, because of its volatility and flammability at room temperature, is a significant fire hazard. It has a boiling point of 68.1 degrees C (155 degrees F) and a density at 20 degrees C of 0.919 g/ml. Dimethylvinyl chloride is a byproduct in the production of 3-chloro-2-methylpropene by the chlorination of isobutene. It is not known to be produced in the United States for other than laboratory purposes. This chemical was nominated for toxicologic studies because of its reported presence in ambient air in the Baltimore area and was selected for toxicologic characterization because of its structural similarity to the known animal and human carcinogen, vinyl chloride monomer. Toxicology and carcinogenesis studies of dimethylvinyl chloride (96%-98% pure), a structural analog of vinyl chloride monomer, a known human carcinogen, by administered dimethylvinyl chloride in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 0, 100, or 200 mg/kg body weight 5 days per week for 102 or 103 weeks. The selection of these doses was based on results of 13-week studies, which included depression of body weight at doses of 500 mg/kg or above in rats as well as histopathologic changes intestinal epithelium, bone marrow, hepatocytes, and the testes at doses of 250 mg/kg and above; doses in mice were selected on the basis of histopathologic changes in lymphopoietic cells, liver, pancreatic islets, ovary, testis, and spleen, with changes being most prominent at doses of 500 mg/kg and above. In the 2-year studies, body weights of rats and mice given 100 mg/kg were comparable to those of the vehicle controls except for the last few weeks in mice when body weights were markedly lower than those for the vehicle controls. At 200 mg/kg, the mean body weights of rats and mice were progressively decreased relative to those of vehicle controls, with the significant departure from vehicle controls occurring somewhat earlier in males than in females. Survival of vehicle control rats and mice was comparable to historical values; however, survival of dosed male and female rats was significantly lower than that of vehicle controls, with the incidence of mortality being more severe at the high dose than at the low dose. There were no survivors in the high dose group of male rats after week 85 or in the high dose group of female rats after week 97. Survival was significantly lower among dosed male and female mice compared with vehicle controls. In the absence of toxicological findings that would explain the early deaths, it is assumed that the high incidence of tumors and chemical-related toxicity contributed to the decreased survival of dosed rats and mice. In rats, the severity and incidence of nonneoplastic lesions were minimal; these lesions included necrosis of the duodenum and epithelial hyperplasia at the sites of tumor formation--the nasal cavity, esophagus, and forestomach. In mice, the severity of nonneoplastic lesions was also minimal; the lesions included necrosis of the liver, bone marrow granulocytic hyperplasia, and inflammation of the nasal cavity (small number, females only.) Several types of neoplastic lesions occurred with significantly increased incidences in dosed animals as shown in the following table (see page 11 of Technical Report). Among rats, these lesions included malignant epithelial tumors of the nasal cavity and squamous cell tumors of the oral cavity, esophagus, and forestomach in males and females. The increased number of fibroadenomas of the mammary gland in female rats may have been related to dimethylvinyl chloride administration. The lack of a clear dose-response relationship for certain tumors in rats is considered to be related to the increased number of early deaths observed in the high dose groups. Among dosed mice, there were significantly increased incidences of squamous cell carcinomas of the forestomach (both sexes), squamous cell papillomas of the forestomach (males), and squamous cell carcinomas of the preputial gla preputial gland (males). The increased incidence of papillary adenomas of the harderian gland and alveolar/bronchiolar adenomas or carcinomas in female mice may have been related to administration of dimethylvinyl chloride. Limited metabolism studies of 14C-labeled dimethylvinyl chloride were conducted in male F344/N rats and B6C3F1 mice. Single doses of 150 mg/kg were administered to rats for 1, 2, or 4 consecutive days. About 25&percnt; of the administered doses was exhaled as carbon dioxide; this amount was independent of the number of doses administered. Another 25&percnt;-35&percnt; of the administered dose was exhaled; 96&percnt; of this parent was material. Approximately 35&percnt; and 6&percnt; were excreted in the urine and feces, respectively. The elimination half-life of radioactive label was 3-4 days for the liver and kidney, the two organs containing the greatest amounts of the administered dose. In mice, a much smaller fraction of the dose was exhaled and a larger proportion was excreted in urine compared with rats. Dimethylvinyl chloride was not mutagenic in four strains ofSalmonella typhimurium with or without metabolic activation, but it was mutagenic in the mouse lymphoma L5178Y/TK&plusmn; assay in the absence of metabolic activation. Sister-chromatid exchanges were induced in Chinese hamster ovary cells with and without metabolic activation, but there was no increase in chromosomal aberrations. When fed to Drosophila, dimethylvinyl chloride induced significant increases in the frequencies of both sex-linked recessive lethal mutations and reciprocal translocations. Studies of the immunotoxicity of dimethylvinyl chloride were conducted in which female B6C3F1 mice received daily oral doses of 0, 50, 100, 200, or 400 mg dimethylvinyl chloride per kilogram body weight. Compound-related increases in susceptibility to bacterial infection and decreases in macrophage cytostasis were observed at all doses. At the highest dose, the decreased resistance to bacterial and viral challenge could be related to alterations in specific immune function. However, the increased mortality in rats and mice in the 2-year studies was not relatable to infectious processes. An audit of the experimental data was conducted for these2-year toxicology and carcinogenesis studies on dimethylvinyl chloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of dimethylvinyl chloride for both sexes of F344/N rats and B6C3F1 mice. This was based on increased incidences of neoplasms of the nasal cavity, oral cavity, esophagus, and forestomach of male and female F344/N rats. B6C3F1 mice showed increased incidences of squamous cell neoplasms of the forestomach in males and females and squamous cell carcinomas of the preputial gland in males. Synonym: 1-chloro-2-methylpropene
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PMID:NTP Toxicology and Carcinogenesis Studies of Dimethylvinyl Chloride (1-Chloro-2-Methylpropene) (CAS No. 513-37-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 37

The cytochrome P450 (CYP1A1) enzyme metabolically activates many polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), to DNA- and protein-binding intermediates that are associated with toxicity, mutagenesis, and carcinogenesis. As a result, it is widely accepted that CYP1A1 potentiates the toxicity of this class of chemicals. In distinct contrast, we show here that CYP1A1 inducibility is essential in the detoxication of oral BaP. We compared Cyp1a1(-/-) knockout mice, having the genetic absence of the CYP1A1 enzyme, with Cyp1a1(+/+) wild-type mice. At an oral BaP dose of 125 mg/kg/day, Cyp1a1(-/-) mice died within 30 days whereas Cyp1a1(+/+) mice displayed no outward signs of toxicity. The rate of BaP clearance was 4-fold slower in Cyp1a1(-/-) than Cyp1a1(+/+) mice. The cause of death in Cyp1a1(-/-) mice receiving oral BaP seemed to be immunotoxicity, including toxic chemical depression of the bone marrow; some toxic effects in Cyp1a1(-/-) mice were noted at a BaP dose as low as 1.25 mg/kg/day. DNA post-labeling studies demonstrated dramatically higher BaP-DNA adduct levels in all Cyp1a1(-/-) tissues assayed, with the exception of the small intestine, which is probably a major site of BaP metabolism in Cyp1a1(+/+) mice. Different BaP-DNA adduct patterns were also observed between the two genotypes receiving oral BaP. Despite previous studies in vitro and in cell culture that have shown a participatory role for CYP1A1 in BaP toxicity, the present data indicate that, in the intact animal, inducible CYP1A1 is extremely important in detoxication and protection against oral BaP toxicity.
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PMID:Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation. 1510 51


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