An epidemiologic study of early biologic effects of benzene in Chinese workers.

Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans

Benzene Metabolite 1,2,4-Benzenetriol Induces Halogenated DNA and Tyrosines Representing Halogenative Stress in the HL-60 Human Myeloid Cell Line

Background: Although benzene is known to be myelotoxic and to cause myeloid leukemia in humans, the mechanism has not been elucidated

Global Gene Expression Profiling of a Population Exposed to a Range of Benzene Levels

BackgroundBenzene, an established cause of acute myeloid leukemia (AML), may also cause one or more lymphoid malignancies in humans. Previously, we identified genes and pathways associated with exposure to high (> 10 ppm) levels of benzene through transcriptomic analyses of blood cells from a small number of occupationally exposed workers.ObjectivesThe goals of this study were to identify potential biomarkers of benzene exposure and/or early effects and to elucidate mechanisms relevant to risk of hematotoxicity, leukemia, and lymphoid malignancy in occupationally exposed individuals, many of whom were exposed to benzene levels < 1 ppm, the current U.S. occupational standard.MethodsWe analyzed global gene expression in the peripheral blood mononuclear cells of 125 workers exposed to benzene levels ranging from < 1 ppm to > 10 ppm. Study design and analysis with a mixed-effects model minimized potential confounding and experimental variability.ResultsWe observed highly significant widespread perturbation of gene expression at all exposure levels. The AML pathway was among the pathways most significantly associated with benzene exposure. Immune response pathways were associated with most exposure levels, potentially providing biological plausibility for an association between lymphoma and benzene exposure. We identified a 16-gene expression signature associated with all levels of benzene exposure.ConclusionsOur findings suggest that chronic benzene exposure, even at levels below the current U.S. occupational standard, perturbs many genes, biological processes, and pathways. These findings expand our understanding of the mechanisms by which benzene may induce hematotoxicity, leukemia, and lymphoma and reveal relevant potential biomarkers associated with a range of exposures

Model-based parametric study of frontostriatal abnormalities in schizophrenia patients

<p>Abstract</p> <p>Background</p> <p>Several studies have suggested that the activity of the prefrontal cortex (PFC) and the dopamine (DA) release in the striatum has an inverse relationship. One would attribute this relationship primarily to the circuitry comprised of the glutamatergic projection from the PFC to the striatum and the GABAergic projection from the striatum to the midbrain DA nucleus. However, this circuitry has not characterized satisfactorily yet, so that no quantitative analysis has ever been made on the activities of the PFC and the striatum and also the DA release in the striatum.</p> <p>Methods</p> <p>In this study, a system dynamics model of the corticostriatal system with dopaminergic innervations is constructed to describe the relationships between the activities of the PFC and the striatum and the DA release in the striatum. By taking published receptor imaging data from schizophrenia patients and healthy subjects into this model, this article analyzes the effects of striatal D2 receptor activation on the balance of the activity and neurotransmission in the frontostriatal system of schizophrenic patients in comparison with healthy controls.</p> <p>Results</p> <p>The model predicts that the suppressive effect by D2 receptors at the terminals of the glutamatergic afferents to the striatum from the PFC enhances the hypofrontality-induced elevation of striatal DA release by at most 83%. The occupancy-based estimation of the 'optimum' D2 receptor occupancy by antipsychotic drugs is 52%. This study further predicts that patients with lower PFC activity tend to have greater improvement of positive symptoms following antipsychotic medication.</p> <p>Conclusion</p> <p>This model-based parametric study would be useful for system-level analysis of the brains with psychiatric diseases. It will be able to make reliable prediction of clinical outcome when sufficient data will be available.</p

Marine Drugs from Sponge-Microbe Association—A Review

The subject of this review is the biodiversity of marine sponges and associated microbes which have been reported to produce therapeutically important compounds, along with the contextual information on their geographic distribution. Class Demospongiae and the orders Halichondrida, Poecilosclerida and Dictyoceratida are the richest sources of these compounds. Among the microbial associates, members of the bacterial phylum Actinobacteria and fungal division Ascomycota have been identified to be the dominant producers of therapeutics. Though the number of bacterial associates outnumber the fungal associates, the documented potential of fungi to produce clinically active compounds is currently more important than that of bacteria. Interestingly, production of a few identical compounds by entirely different host-microbial associations has been detected in both terrestrial and marine environments. In the Demospongiae, microbial association is highly specific and so to the production of compounds. Besides, persistent production of bioactive compounds has also been encountered in highly specific host-symbiont associations. Though spatial and temporal variations are known to have a marked effect on the quality and quantity of bioactive compounds, only a few studies have covered these dimensions. The need to augment production of these compounds through tissue culture and mariculture has also been stressed. The reviewed database of these compounds is available at www.niobioinformatics.in/drug.php

The Candrarki of Dinakara: A Text Related to Solar and Lunar Tables

A set of tables devoted to the sun and the moon, titled the Candrarki ("Related to the moon and sun"), was compiled in Sanskrit by Indian astronomer Dinakara along with a short accompanying text, intended to give guidance on how to construct a calendar (pancanga) for any desired year and geographical circumstances. The epoch of this table-text is 9 April 1578. We present here an edition of the text, a literal translation, and detailed technical commentary