The Immunological and Neurochemical Toxicity of Benzene and its Interaction with Toluene in Mice

Benzene and toluene are known groundwater contaminants . Male CD-I mice were continuously exposed to 0, 31, 166, and 790 mg/ L benzene and 0, 17, 80, and 405 mg/L toluene, respectively, in drinking water for four weeks. Benzene caused a reduction of leukocytes, lymphocytes and erythrocytes, and resulted in a macrocytic anemia. Lymphocyte response to both B- and T-cell mitogens, mixed lymphocyte response to alloantigens, and the ability of cytotoxic lymphocytes to lyse tumor cells were enhanced at the lowest dose of benzene and depressed in the higher dosage animals. Benzene at doses of 166 and 790 mg/L decreased the number of sheep red blood cell (SRBC) -specific plaque-forming cells, the level of serum anti-SRBC antibody, and the activity of interleukin-2 (IL -2). Benzene treatment increased endogenous concentrations of the brain biogenic amines norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and concomitantly, elevated the levels of their respective major metabolites vanillymandelic acid (VMA), 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in several brain regions . In most cases, the changes were dose related; in several instances, maximum effects occurred at the 166 mg/L benzene dose. Toluene did not adversely affect the hematological parameters. Depression of immune function was evident at the highest dose (405 mg/L), except for mitogeneses. Increased neurochemical concentrations caused by toluene displayed a dose-dependent biphasic manner which began at a dose of 17 mg/L, peaked at 80 mg/L, and decreased at 405 mg/L. Toluene treatment had more selective effects on NE, 5-HT ,VMA and 5-HIAA, than DA, DOPAC and HVA. Both compounds, by increasing concentrations of the hypothalamic NE and its major metabolite VMA, stimulated the hypothalamic-pituitary-adrenocortical axis activity, resulting in an elevated plasma adrenocorticotropic hormone and serum corticosterone which had an additive adverse effect on IL-2 synthesis. Toluene, 325 mg/ L, completely inhibited benzene-induced cytopenia and immunosuppression when it was coadministered with benzene (166 mg/L). The low dose of toluene (80 mg/L ) did not antagonize benzene immunotoxicity. Mice given the combined exposures exhibited raised levels of regional neurochemicals when compared to the untreated controls. Increased levels of monoamine metabolites in several brain regions were greater in the combined treatments of benzene and toluene than when either chemical was used alone. The results of the interaction studies support the known metabolic interaction mechanisms of benzene and toluene

Toxicity and Environmental Health Hazards of Petroleum Products in Wells Used for Drinking Water in the Intermountain West

Introduction: Groundwater is aprimary source of drinking water for about 50 percent of the population in the U.S. This source of drinking water has been generally regarded as safe from contamination. Several papers indicate that numerous underground storage tanks containing petroleum products may be leaking and contaminating public water supply wells across the U.S. (Matis, 1971; Ferguson, 1979; Woodhull, 1981; Burmaster and Harris, 1982; Lehman, 1984; Dowd, 1984; OTA, 1984). A study conducted by the Utah Cureau of Solid and Hazardous Wastes in 1985 concluded that there are at least 2,314 underground steel tanks, most of which are used to store gasoline and diesel fuel, in Utah which are more than 20 years old and may be leaking. Contamination of well water by petrolium products from leaking underground storage tanks (LUST) is a matter of increasing concern. LUST pose a serious threat to the groundwater and public health. Leaks of petroleum products from LUST at industrial plants, commercial establishments (e.g., automobile service stations), and other operations could be expected to increase the types and concentrations of petroleum products in groundwater used for drinking and exposure of humans to the toxic effects of these chemical compounds. Petroleum products are persistent and highly mobile contaminatns which are difficult to remove from groundwater. In addition, many of these chemicals are known or suspected carcinogens or mutagens which can pose undesireable human health risks (e.g., cancer, birth defects, and other chronic conditions) at 10 ppb and below (Council on Environmental Quality, 1980). There is a need for more research on the types and concentrations of petroleum products (e.g., benzene, toluene, ethylbenzene) found in public water supply wells used for drinking water and the immunotoxic and neurotoxic effects of these organic compounds. The objectives of this research project were: 1. To characterize petroleum products in raw water from wells used for drinking water in selected areas (industrial, commercial, and other) of Utah. 2. To evaluate the toxicity of selected petroleum products in experimental animals, with emphasis on the following: a. Immunotoxic and hypersensitivity effects. b. Neurotoxic and behavioral effects

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

Immunological and Neurobiochemical Alterations Induced by Repeated Oral Exposure of Phenol in Mice

Phenol, a major metabolite of benzene, is a potentially immunotoxic and neurotoxic substance of environmental significance. Male CD-1 mice were continuously exposed to 0, 4.7, 19.5, and 95.2 mg phenol/l in drinking water for 4 weeks. Various immune functions were evaluated and levels of selected neurotransmitters and metabolites measured in discrete brain regions. The doses of phenol did not produce any overt clinical signs of toxicity; peripheral red blood cell counts and hematocrits decreased. A dose of 95.2 mg/l suppressed the stimulation of cultured splenic lymphocytes by lipopolysaccharide, pokeweed mitogen, and phytohemagglutinin and the response in mixed lymphocyte cultures. The two high doses suppressed antibody production response to the T cell-dependent antigen (sheep erythrocytes), as determined by plaque-forming cells, and serum antibody levels. Mice treated with phenol had lower levels of neurotransmitters in several brain regions. In the hypothalamus, a major norepinephrine-containing compartment, the concentrations of norepinephrine significantly decreased by 29 and 40% in groups dosed with 19.5 and 95.2 mg/l, while dopamine concentrations decreased in the corpus striatum by 21, 26, and 35% at 4.7, 19.5 and 95.2 mg/l, respectively. Phenol also decreased 5-hydroxytryptamine in the hypothalamus, medulla oblongata, midbrain and corpus striatum. Levels of monoamine metabolites decreased in the hypothalamus (5-hydroxyindoleacetic acid), midbrain (vanillylmandelic acid), corpus striatum (vanillylmandelic acid and dihydroxyphenylacetic acid), cortex (vanillylmandelic acid), and cerebellum (dihydroxyphenylacetic acid)

Evaluation of Toluene Exposure via Drinking Water On Levels of Regional Brain Biogenic Amines and Their Metabolites in CD-1 Mice

Toluene, a potentially neurotoxic substance, is found in trace amounts in groundwater. Adult male CD-1 mice were continuously fed drinking water ad libitum containing 0, 17, 80, and 405 mg/liter toluene. After a 28-day treatment, animals were tested for endogenous levels of the biogenic monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their respective metabolites, 3-methoxy-4-hydroxymandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in six discrete brain regions. The maximum toluene-induced increases of biogenic amines and their metabolites generally occurred at a toluene concentration of 80 mg/liter. In the hypothalamus, a major NE-containing compartment, the concentrations of NE significantly increased by 51, 63, and 34% in groups dosed with 17, 80, and 405 mg/liter, respectively. Significant increases of NE were also observed in the medulla oblongata and midbrain. Concomitantly, concentrations of VMA increased in various brain regions. Concentrations of DA were significantly higher in the corpus striatum and hypothalamus. Alterations in levels of DA metabolites, DOPAC and HVA, were marginal. Toluene significantly increased concentrations of 5-HT in all dissected brain regions, except cerebellum, and increased the 5-HIAA levels in the hypothalamus, corpus striatum, and cerebral cortex

Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms

Loss-of-function mutations in the gene encoding G proteincoupled receptor 56 (GPR56) lead to bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive disorder affecting brain development. The GPR56 receptor is a member of the adhesion-GPCR family characterized by the chimeric composition of a long ectodomain (ECD), a GPCR proteolysis site (GPS), and a sevenpass transmembrane (7TM) moiety. Interestingly, all identified BFPP-associated missense mutations are located within the extracellular region of GPR56 including the ECD, GPS, and the extracellular loops of 7TM. In the present study, a detailed molecular and functional analysis of the wild-type GPR56 and BFPP-associated point mutants shows that individual GPR56 mutants most likely cause BFPP via different combination of multiple mechanisms. These include reduced surface receptor expression, loss of GPS proteolysis, reduced receptor shedding, inability to interact with a novel protein ligand, and differential distribution of the 7TM moiety in lipid rafts. These results provide novel insights into the cellular functions of GPR56 receptor and reveal molecular mechanisms whereby GPR56 mutations induce BFPP

Genetic analysis and molecular mapping of QTLs associated with resistance to bacterial blight in a rice mutant, SA0423

Bacterial blight disease, caused by Xanthomonas oryzae pv. oryzae (Xoo), is one of the most serious diseases in rice producing areas. SA0423 is a broad-range resistance mutant selected from a popular japonica-type variety, TNG67, using sodium azide mutagenesis. Genetic analysis and QTL mapping of SA0423 were performed using the descendants obtained from crossing with Taichung Native 1, a susceptible and well-known indica variety, by challenging with a Taiwanese Xoo isolate, XF89b. Genetic analysis displayed that the resistance of SA0423 is regulated by quantitative trait loci (QTLs) with incomplete dominance. A linkage map covering 12 chromosomes and consisting of 148 SSR as well as 3 InDel markers was constructed. Three QTLs are identified on chromosomes 11, 8 and 6 and account for 21.1, 11 and 9.6 % of the observed phenotypic variance, respectively. Three QTLs are localized to 6, 7 and 14 confidence intervals, respectively. These QTLs contribute to approximately 47 % of the total phenotypic variation of the F-2 population. No epistatic effect could be detected among the three QTLs. Our results provide a suitable source of potential disease resistance genes and establish a system for improving rice bacterial blight resistance through marker-assisted selection