Key Scientific Issues in the Health Risk Assessment of Trichloroethylene

Trichloroethylene (TCE) is a common environmental contaminant at hazardous waste sites and in ambient and indoor air. Assessing the human health risks of TCE is challenging because of its inherently complex metabolism and toxicity and the widely varying perspectives on a number of critical scientific issues. Because of this complexity, the U.S. Environmental Protection Agency (EPA) drew upon scientific input and expertise from a wide range of groups and individuals in developing its 2001 draft health risk assessment of TCE. This scientific outreach, which was aimed at engaging a diversity of perspectives rather than developing consensus, culminated in 2000 with 16 state-of-the-science articles published together as an Environmental Health Perspectives supplement. Since that time, a substantial amount of new scientific research has been published that is relevant to assessing TCE health risks. Moreover, a number of difficult or controversial scientific issues remain unresolved and are the subject of a scientific consultation with the National Academy of Sciences coordinated by the White House Office of Science and Technology Policy and co-sponsored by a number of federal agencies, including the U.S. EPA. The articles included in this mini-monograph provide a scientific update on the most prominent of these issues: the pharmacokinetics of TCE and its metabolites, mode(s) of action and effects of TCE metabolites, the role of peroxisome proliferator–activated receptor in TCE toxicity, and TCE cancer epidemiology

Mechanism of haematotoxicity induced by phenylhydrazine: a review

This work was carried out to show the effects of phenylhydrazine (PHZ) induced anaemic condition. Anaemic condition is defined as reduction in red blood cells (RBC) than normal number of red blood cells. The anti-anaemic activity can be studied using the changes in haematological parameters (PCV, RBC & Haemoglobin) influenced by PHZ [(40mg/kg p.o.)] in rats. PHZ, a potent chemical that causes different effects on different tissues at several levels. Administration of PHZ causes haemolytic anaemia, genotoxic effects and rose in iron absorption in spleen, liver and duodenum & causes change in iron metabolism. PHZ acts by activating immune response which triggers phagocytosis and also interfere with the binding of erythropoietin (EPO) receptors and further JAK-STAT pathway. PHZ also causes genotoxic effect by forming single strand DNA damage. In view of lipid peroxidation along with the formation of Thiobarbituric acid (TBA)-reactive malonyldialdehyde, it is recommend that PHZ induces anaemia as an outcome of peroxidation of  RBC membrane lipids and this effect may be a upshot of the autoxidation of the drug and the interaction of membrane lipids and oxygen radical

Key Issues in the Modes of Action and Effects of Trichloroethylene Metabolites for Liver and Kidney Tumorigenesis

Trichloroethylene (TCE) exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to determine which TCE metabolites may be responsible for these effects, the key events involved in their modes of action (MOAs), and the relevance of these MOAs to humans. In this article, which is part of a mini-monograph on key issues in the health risk assessment of TCE, we present a review of recently published scientific literature examining the effects of TCE metabolites in the context of the preceding questions. Studies of the TCE metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA), and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver tumorigenesis and that many DCA effects are consistent with conditions that increase the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl)-l-cysteine have revealed a number of different possible cell signaling effects that may be related to kidney tumorigenesis at lower concentrations than those leading to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis for kidney tumorigenesis have failed to establish the formation of formate as a key event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced liver and kidney tumors have yet to be definitively established, these results support the likelihood that toxicity is due to multiple metabolites through several MOAs, none of which appear to be irrelevant to humans

Synthesis, spectral characterization and bioactivity evaluation of sulfonamide derivatives of p-nitrobenzene sulfonylchloride

1375-1383A simple and convenient method for the synthesis of biologically active sulfonamide derivatives of p-nitrobenzene sulfonylchloride has been achieved. All the title compounds have been characterized by spectral and elemental analysis. They have been further screened in vitro for their antibacterial and antifungal activities. All the compounds show good to moderate activity against both bacteria and fungi when compared with standard bactericide, Streptomycin and fungicide, Nystatin

Differential expression analysis for sequence count data

*Motivation:* High-throughput nucleotide sequencing provides quantitative readouts in assays for RNA expression (RNA-Seq), protein-DNA binding (ChIP-Seq) or cell counting (barcode sequencing). Statistical inference of differential signal in such data requires estimation of their variability throughout the dynamic range. When the number of replicates is small, error modelling is needed to achieve statistical power.

*Results:* We propose an error model that uses the negative binomial distribution, with variance and mean linked by local regression, to model the null distribution of the count data. The method controls type-I error and provides good detection power. 

*Availability:* A free open-source R software package, _DESeq_, is available from the Bioconductor project and from "http://www-huber.embl.de/users/anders/DESeq":http://www-huber.embl.de/users/anders/DESeq

Efficient Genome-Wide Detection and Cataloging of EMS-Induced Mutations Using Exome Capture and Next-Generation Sequencing

Chemical mutagenesis efficiently generates phenotypic variation in otherwise homogeneous genetic backgrounds, enabling functional analysis of genes. Advances in mutation detection have brought the utility of induced mutant populations on par with those produced by insertional mutagenesis, but systematic cataloguing of mutations would further increase their utility. We examined the suitability of multiplexed global exome capture and sequencing coupled with custom-developed bioinformatics tools to identify mutations in well-characterized mutant populations of rice (Oryza sativa) and wheat (Triticum aestivum). In rice, we identified ∼18,000 induced mutations from 72 independent M2 individuals. Functional evaluation indicated the recovery of potentially deleterious mutations for >2600 genes. We further observed that specific sequence and cytosine methylation patterns surrounding the targeted guanine residues strongly affect their probability to be alkylated by ethyl methanesulfonate. Application of these methods to six independent M2 lines of tetraploid wheat demonstrated that our bioinformatics pipeline is applicable to polyploids. In conclusion, we provide a method for developing large-scale induced mutation resources with relatively small investments that is applicable to resource-poor organisms. Furthermore, our results demonstrate that large libraries of sequenced mutations can be readily generated, providing enhanced opportunities to study gene function and assess the effect of sequence and chromatin context on mutations

Discovering Regulatory Overlapping RNA Transcripts

STEREO is a novel algorithm that discovers cis-regulatory RNA interactions by assembling complete and potentially overlapping same-strand RNA transcripts from tiling expression data. STEREO first identifies coherent segments of transcription and then discovers individual transcripts that are consistent with the observed segments given intensity and shape constraints. We used STEREO to identify 1446 regions of overlapping transcription in two strains of yeast, including transcripts that comprise a new form of molecular toggle switch that controls gene variegation

Growth performance and carcass characteristics of growing ram lambs fed sweet sorghum bagasse-based complete rations varying in roughage-to-concentrate ratios

Different roughage-to-concentrate ratios of sweet sorghum bagasse (SSB) (a by-product of the biofuel industry)-based complete diets were assessed. Twenty four growing Nellore × Deccani ram lambs aged about 3 months (average body wt., 10.62 ± 0.25 kg) were randomly allotted to four complete rations (CR) varying in roughage-to-concentrate ratios viz. 60:40 (CR-I), 50:50 (CR-II), 40:60 (CR-III) and 30:70(CR-IV) for a period of 180 days. The feed intake was comparable among the lambs fed different experimental complete diets. Average daily weight gain (in grams) was 77.31 ± 4.90, 81.76 ± 5.16, 85.83 ± 2.83 and 86.30 ± 3.25, and feed conversion ratio (in kilograms of feed per kilogram gain) averaged 11.42 ± 0.68, 10.57 ± 0.64, 10.17 ± 0.37 and 9.96 ± 0.38 in ram lambs fed CR-I, CR-II, CR-III and CR-IV rations, respectively. Statistically, differences in daily weight gain and feed conversion ratio among the lambs fed four experimental rations were not significant (P > 0.05). The cost per kilogram gain was significantly (P < 0.01) higher in ram lambs fed CR-IV and CR-III rations compared to CR-I ration, and it was comparable between CR-I and CR-II rations. Dressing percentage averaged 44.90 ± 0.15, 42.57 ± 0.72, 43.67 ± 0.16 and 44.42 ± 0.76 for the respective diets. No significant difference and trend was observed in preslaughter weight, empty body weight, carcass weights, dressing percentage, wholesale cuts and edible and non-edible portions of experimental animals. Similarly, no significant variation could be seen in bone and meat yield (in per cent) and their ratios in various wholesale cuts among the dietary treatments. The roughage-to-concentrate ratio did not affect the chemical composition of meat; however, the fat content of meat was linearly increased with increase in the proportion of concentrate in the diets. The results of the experiment indicated that SSB can be included at 60 % level in the complete diet for economical mutton production from growing Nellore × Deccani ram lambs