We tested whether mechanistically based screening assays can rapidly provide information on the potential for compounds to affect key enzymes and receptor targets, thus identifying those compounds requiring further in-depth analysis. METHODS: A library of 176 synthetic chemicals was prepared and examined in a high-throughput screening (HTS) manner using nine enzyme-based and five receptor-based bioassays. RESULTS: All the assays have high Z' values, indicating good discrimination among compounds in a reliable fashion, and thus are suitable for HTS assays. On average, three positive hits were obtained per assay. Although we identified compounds that were previously shown to inhibit a particular enzyme class or receptor, we surprisingly discovered that triclosan, a microbiocide present in personal care products, inhibits carboxylesterases and that dichlone, a fungicide, strongly inhibits the ryanodine receptors. CONCLUSIONS: Considering the need to rapidly screen tens of thousands of anthropogenic compounds, our study shows the feasibility of using combined HTS assays as a novel approach toward obtaining toxicologic data on numerous biological end points. The HTS assay approach is very useful to quickly identify potentially hazardous compounds and to prioritize them for further in-depth studies.
Keywords: Receptors, Aryl Hydrocarbon -- drug effects
Keywords: Receptors, Estrogen -- drug effects
Keywords: Receptors, Androgen -- drug effects
Keywords: Naphthoquinones -- pharmacology
Keywords: High-Throughput Screening Assays -- methods
Keywords: Triclosan -- toxicity
Keywords: Environmental Studies
Keywords: Receptors, Androgen
Keywords: Receptors, Aryl Hydrocarbon
Keywords: Ryanodine Receptor Calcium Release Channel
Keywords: Toxicology -- methods
Keywords: Carboxylesterase -- antagonists & inhibitors
Keywords: Ryanodine Receptor Calcium Release Channel -- drug effects
Keywords: Receptors, Estrogen
Copyright - Copyright National Institute of Environmental Health Sciences Dec 2009
Language of summary - English
Pages - 1867-72
ProQuest ID - 222639093
Last updated - 2012-10-17
Place of publication - Research Triangle Park
Corporate institution author - Morisseau, Christophe; Merzlikin, Oleg; Lin, Amy; He, Guochun; Feng, Wei; Padilla, Isela; Denison, Michael S; Pessah, Isaac N; Hammock, Bruce D
DOI - 1943895271; 50348501; 67001; ENHP; 20049205; INODENHP0006174681
Ahn KC, Zhao B, Chen J, Cherednichenko G, Sanmerti E, Denison MS, et al. 2008. In vitro biologic activities of the antimicrobials triclocarban, its analogs, and triclosan in bioassay screens: receptor-based bioassay screens. Environ Health Perspect 16:1203-1210.
Beetham JK, Tian T, Hammock BD. 1993. cDNA cloning and expression of a soluble epoxide hydrolase from human liver. Arch Biochem Blophys 305:197-201.
Bellinger AM, Mongillo M, Marks AR. 2008. Stressed out the skeletal muscle ryanodine receptor as a target of stress. J Clin Invest 118:445-453.
Berridge MJ. 2006. Calcium microdomains: organization and function. Cell Calcium 40:405-412.
Bonefeld-Jergensen EC, Long M, Hofmeister MV, Vinggaard AM. 2007. Endocrine-disrupting potential of bisphenol A, bispneno) A dimethacrylate, 4-n-nonylphenol, and 4-noctylphenol in vitro, new data and a brief review. Environ Health Perspect 115|suppl 1):69-76.
Cali JJ, Ma D, Sobol M, Simpson DJ, Frackman S, Good TD, et al. 2006. Luminogenic cytochrome P450 assays. Expert Opin Drug Metab Toxicol 2:629-845.
California Department of Toxic Substances Control. 2008. California Green Chemistry Initiative Final Report. Available: http://www.dtsc.ca.gov/PollutionPrevention/ Green Chemistry Initiative/upload/GREEN_Chem.pdf [accessed 8 June 2009].
Casida JE, Quistad GB. 2005. Serine hydrolase targets of organophosphorus toxicants. Chem Biol Interact 157-158:277-7283.
Chen CW, Hurd C, Vorojeikina DP, Arnold SF, Notides AC. 1997. Transcriptional activitation of the human estrogen receptor by DDT isomers and metabolites in yeast and MCF-7 cells. Biochem Pharmacol 53:1161-1172.
Denison MS, Heath-Pagliuso S, 1998. The Ah receptor a regulator of the biochemical and toxicological actions of structurally diverse chemicals. Bull Environ Contam Toxicol 61:557-568.
Denison MS, Nagy SR. 2003. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals, Annu Rev Pharmacol Toxicol 43:309-334.
Dixon M. 1972. Graphical determination of Km and Ki. Biochem J 129:197-202.
Dutton DR, Parkinson A. 1989, Reduction of 7-alkoxyresorufins by NADPH-cytochrame P450 reductase and its differential effects on their O-dealkylation by rat liver microsomal cytochrome P450. Arch Biochem Biophys 268:617-629.
European Chemicals Agency. 2007. REACH: Registration, Evaluation, Authorisation and Restriction of Chemicals. Available: http://echa.europa.eu/reach_en.asp [accessed 8 June 2009].
Feng W, Liu G, Xia R, Abramson JJ, Pessah IN. 1999. Site-selective modification of hyperreactive cysteines of ryanodine receptor complex by quinones. Mol Pharmacol 55:821-831.
Gad SC. 2D0B. Introduction, In: Animal Models in Toxicology, 2nd ed (Gad SC. edl. New York:Informa Healthcare, 1-18.
Garrison PM, Tullis K, Aarts JM, Brouwer A, Giesy JP, Denison MS. 1896. Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8tetrachlorodibenzo-p-dioxin-like chemicals. Fundam Appl Toxicol 30:194-203.
Gihb S, 2008. Toxicity testing in the 21st century: a vision and a strategy. Reprod Toxicol 25:136-138.
Habig WH, Pabst MJ, Jakoby WB. 1974. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130-7139.
Han D, Nagy SR, Denison MS. 2004. Comparison of recombinant cell bioassays for the detection of Ah receptor agonists. Biofactors 20:11-22.
Harada T, Nakagawa Y. Wadkins RM, Potter PM, Wheelock CE. 2009. Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure-activity relationship analysis. Bioorg Med Chem 17:149-164.
Huang H, Nishi K, Tsai H-J, Hammock BD. 2007. Development of highly sensitive fluorescent assays for fatty acid amide hydrolase. Anal Biochem 363:12-21.
James RW. 2006. A long and winding road: defining the biological role and clinical importance of paraoxonases. Clin Chem Lab Med 44:1052-1059.
Jones PD, Wolf NM, Morisseau C, Whetstone P, Hock B, Hammock BD. 2005. Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies. Anal Biochem 343:66-75.
KĂ¤renlampi SO. Tuomi K, Korkalainen M, Raunio H. 1989. 2-(4-Chlorophenyl)benzothiazole is a potent Inducer of cytochrome P450IA1 in a human and a mouse cell line. Anomalous correlation between protein and mRNA induction. Eur J Biochem 181:143-148.
Kenet T, Froemcke R, Schreiner C, Pessah IN, Merzenich MM. 2007. Abnormal auditory cortex, development in PCB exposed rats. Proc Natl Acad Sci USA 104:7646-7651.
Kim KH, Inan SY, Berman RF, Pessah IN. 2009. Differential patterns of excrtotoxicity and ryanodine receptor modulation in the hippocampus by two ortho-substituted polychlorinated biphenyls. Toxicol Appi Pharmacol 237:168-177.
Marenghi F, Rescia M, Macri C, Di Consiglio E, De Angelis G, Testai E, et al. 2007. Lindane may modulate the female reproductive development through the interaction with ER-Ăź: an in vivo-in vitro approach. Chem Biol Interact 169:1-14.
McGovern SL, Caselli E, Grigorieff N, Shoichet BK. 2002. A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 45:1712-1722.
Morisseau C, Goodrow MH, Dowdy D, Zheng J, Greene JF, Sanborn JR, et al. 1999. Potent urea and carbamate inhibitors of soluble epoxide hydrolases. Proc Natl Acad Sci USA 96:8849-8854.
Morisseau C, Hammock BD. 2008. Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical. Pest Manag Sci 64:594-609.
Nagy SR, Sanborn JR, Hammock BD1 Denison MS. 2002. Development of a green fluorescent protein based cell bioassay for the rapid and inexpensive detection and characterization of AhR agonists. Toxicol Sci 65:200-210.
National Center for Biotechnology Information. 2009. PubChem. Available: http://pubchem.ncbi.nlm.nih.gov/assay/ assay.cgi?aid=707 iaccessed 3 November 2009].
Nishi K, Huang H, Karnrta SG, Kim I-H, Morisseau C, Hammock BD. 2006. Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2. Arch Biochem Biophys 445:115-123.
Owens CV Jr, Lambright C, Bobseine K, Ryan B, Gray LE Jr, Gullett BK, et al. 2007. Identification of estrogenic compounds emitted from the combustion of computer printed circuit boards in electronic waste. Environ Sci Technol 41:8506-8511.
Pessah IN, Durie EL, Schiedt MJ,Zimani I. 1990. Anthraquinonesensitized Ca^sup 2+^ release channel from rat cardiac sarcoplasmic reticulum: possible receptor-mediated mechanism of doxorubicin cardiomyopathy. MoI Pharmacol 37:503-514.
Pessah IN, Stambuk RA, Casida JE. 1987. Ca^sup 2+^-activated ryanodine binding: mechanisms of sensitivity and intensity modulation by Mg^sup 2+^, caffeine, and adenine nucleotides. MoI Pharmacol 31:232-238.
Roegge CS, Morris JR, Villareal S, Wang VC, Powers BE, Klintsova AY, et al. 2006. Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg. Neurotoxicol Teratol 28:74-85.
Rogers JM, Denison MS. 2000. Recombinent cell bioassay for endocrine disrupters: development of stably transfected human ovarian cell line for the detection of estrogenic and anti-estrogenic chemicals. In Vitr Mol Toxicol 3:67-82.
Saito A, Seiler S, Chu A. Fleischer S. 1984. Preparation and morphology of sarcoplasmic reticulum terminal cisternae from rabbit skeletal muscle. J Cell Biol 99:875-885.
Satoh T, Hosokawe M. 2006. Structure, function and regulation of carboxylesterases. Chem Biol Interact 162:195-211.
Scialli AR. 2008. The challenge of reproductive and developmental toxicology under REACH. Regul Toxicol Pharmacol 51:244-250.
Shan G, Hammock BD. 2QQ1. Development of sensitive esterase assays based on alpha-cyano-containlng esters. Anal Biochem 299:54-62.
Silliman CC, Wang M. 2006. The merits of in vitro versus in vivo modeling in investigation of the immune system. Environ Toxicol Pharmacol 21:123-134.
Steinmetz R, Young PC, Caperell-Grant A, Gize EA, Madhukar BV, Ben-Jonathan N, et al. 1998. Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells. Cancer Res 56:5403-5409.
Tingle MD, Helsby NA. 2006. Can in vitro drug metabolism studies with human tissue replace in vivo animal studies? Environ Toxicol Pharmacol 21:184-190.
U.S. Environmental Protection Agency. 1998. High Production Volume (HPV) Challenge Program. Available: http://www. epa.gov/HPV/ [accessed 8 June 2009).
Vandenberg LN, Mattini MV, Sonnenschein C, Rubin BS, Soto AM. 2009. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption, Endocr Rev 30:75-95.
Wixtrom RN, Silva MH, Hammock BD. 1988. Affinity purification of cytosolic epoxide hydrolase using derivatized epoxyactivated Sepharose gels. Anal Biochem 169:71-80.
Yang D, Kim KH, Phimister A, Bachstetter A, Ward T, Stackman R, et al. 2009. Developmental exposure to polychlcrmated biphenyls IPCBsI interferes with experiencedependent dendritic plasticity and ryanodine receptor expression in weanling rats. Environ Health Perspect 117:426-435.
Zhang J, Chung TDY, Oldenburg KR. 1999. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 4:67-73.
Ahn, Ki Chang, Gee, Shirley J. 2008 "In vitro biologic activities of the antimicrobials triclocarban, its analogs, and triclosan in bioassay screens: Receptor-based bioassay screens" Environmental Health Perspectives (EHP) 116 9 1203-1210
Beetham, Jeffrey K, Tian, Tongyan 1993 "CDNA cloning and expression of a soluble epoxide hydrolase from human liver" Archives of Biochemistry and Biophysics 305 1 197-201
Bellinger, Andrew M., Mongillo, Marco 2008 "Stressed out: the skeletal muscle ryanodine receptor as a target of stress" Journal of Clinical Investigation 118 2 445-453
58. Berridge, MJ. 2006. Calcium microdomains: organization and function. Cell Calcium. 40:405-412.
Bonefeld-Jorgensen EC, Long M. Hofmeister MV, Vinggaard AM. 2007. Endocrine-disrupting potential of bisphenol A, bisphenol A dimethacrylate, 4-n-nonylphenol, and 4-n-octylphenol in vitro: new data and a brief review. Environ Health Perspect 115(suppl 1):69-76.
Cali, James J., Ma, Dongping 2006 "Luminogenic cytochrome P450 assays" Expert opinion on drug metabolism & toxicology 2 4 629-645
California Department of Toxic Substances Control. 2008. California Green Chemistry Initiative Final Report. Available: http://www.dtsc.ca.gov/PollutionPrevention/GreenChemistryInitiative/upload/GREEN_Chem.pdf [accessed 8 June 2009].
Casida, JE, Quistad, GB 2005 "Serine hydrolase targets of organophosphorus toxicants" Chemico-Biological Interactions 157-158 C (Special Issue) 277-283
CHEN, C. W., HURD, C. 1997 "Transcriptional activation of the human estrogen receptor by DDT isomers and metabolites in yeast and MCF-7 cells" Biochemical Pharmacology 53 8 1161-1172
DENISON, M. S., HEATH-PAGLIUSO, S. 1998 "The ah receptor : A regulator of the biochemical and toxicological actions of structurally diverse chemicals" Bulletin of Environmental Contamination and Toxicology 61 5 557-568
DENISON, Michael S., NAGY, Scott R. 2003 "Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals" Annual Review of Pharmacology and Toxicology 43 309-334
Dixon M (1972) The graphical determination of Km and Ki. Biochem J 129: 197-202
Dutton, D.R., Parkinson, A. 1989 "Reduction of 7-alkoxyresorufins by NADPH-cytochrome P450 reductase and its differential effects on their O-dealkylation by rat liver microsomal cytochrome P450" Archives of Biochemistry and Biophysics 268 2 617-629
Feng, Wei, Liu, Guohua 1999 "Site-selective modification of hyperreactive cysteines of ryanodine receptor complex by quinones" Molecular Pharmacology 55 5 821-831
Gad SC. 2006. Introduction, In: Animal Models in Toxicology, 2nd ed (Gad SC. ed). New York:Informa Healthcare, 1-18.
Garrison PM, Tullis K, Aarts JM, Brouwer A, Giesy JP, Denison MS. 1996. Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8tetrachlorodibenzo-p-dioxin-like chemicals. Fundam Appl Toxicol 30:194-203.
Gibb, S, Gibb, S 2008 "Toxicity testing in the 21st century: A vision and a strategy" Reproductive Toxicology 25 1 136-138
Habig, W.H., Pabst, M.J. 1974 "Glutathione S transferases. The first enzymatic step in mercapturic acid formation" Journal of Biological Chemistry 249 22 7130-7139
Han, Dalho, Nagy, Scott R. 2004 "Comparison of recombinant cell bioassays for the detection of Ah receptor agonists" Biofactors 20 1 11-22
Harada, Toshiyuki, Nakagawa, Yoshiaki 2009 "Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure-activity relationship analysis" Bioorganic & Medicinal Chemistry 17 1 149-164
Huang, Huazhang, Nishi, Kosuke 2007 "Development of highly sensitive fluorescent assays for fatty acid amide hydrolase" Analytical Biochemistry 363 1 12-21
JAMES, Richard W. 2006 "A long and winding road : defining the biological role and clinical importance of paraoxonases" Clinical Chemistry and Laboratory Medicine 44 9 1052-1059
Jones, P D, Wolf, N M 2005 "Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies" Analytical Biochemistry 343 1 66-75
Karenlampi, S.O., Tuomi, K. 1989 "2-(4'-Chlorophenyl)benzothiazole is a potent inducer of cytochrome P450IA1 in a human and a mouse cell line. Anomalous correlation between protein and mRNA induction" European Journal of Biochemistry 181 1 143-148
Maranghi, Francesca, Rescia, Michele 2007 "Lindane may modulate the female reproductive development through the interaction with ER-beta: an in vivo-in vitro approach" Chemico-Biological Interactions 169 1 1-14
MCGOVERN, Susan L., CASELLI, Emilia 2002 "A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening" Journal of medicinal chemistry (Print) 45 8 1712-1722
49. Morisseau C, Goodrow MH, Dowdy D, Zheng J, Greene JF, Sanborn JR, Hammock BD. Potent urea and carbamate inhibitors of soluble epoxide hydrolases. Proc Natl Acad Sci U S A. 1999;96(16):8849-8854.
Morisseau, Christophe, Hammock, Bruce D. 2008 "Gerry Brooks and epoxide hydrolases: four decades to a pharmaceutical" Pest Management Science 64 6 594-609
Nagy, Scott R., Sanborn, James R. 2002 "Development of a green fluorescent protein-based cell bioassay for the rapid and inexpensive detection and characterization of Ah receptor agonists" Toxicological Sciences 65 2 200-210
National Center for Biotechnology Information. 2009. PubChem. Available: http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=707 iaccessed 3 November 2009].
Nishi, K, Huang, H Z 2006 "Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2" Archives of Biochemistry and Biophysics 445 1 115-123
Owens Jr CV, Lambright C, Bobseine K, Ryan B, Gray Jr. LE, Gullett BK, Wilson VS. (2007). Identification of estrogenic compounds emitted from the combustion of computer printed circuit boards in electronic waste. Environ Sci Technol 41: 8506-8511.
Pessah IN, Stambuk RA, Casida JE. 1987. Ca^sup 2+^-activated ryanodine binding: mechanism of sensitivity and intensity modulation by Mg^sup 2+^, caffeine, and adenine nucleotides. Mol Pharmacol 31:232-238.
Roegge, Cindy S., Morris, John R. 2006 "Purkinje cell and cerebellar effects following developmental exposure to PCBs and/or MeHg." Neurotoxicology and Teratology 28 1 74-85
SAITO, A., SEILER, S. 1984 "Preparation and morphology of sarcoplasmic reticulum terminal cisternae from rabbit skeletal muscle" The Journal of Cell Biology 99 3 875-885
Satoh, Tetsuo, Hosokawa, Masakiyo 2006 "Structure, function and regulation of carboxylesterases" Chemico-Biological Interactions 162 3 195-211
Scialli, Anthony R. 2008 "The challenge of reproductive and developmental toxicology under REACH" Regulatory Toxicology and Pharmacology 51 2 244-250
Shan, G M, Hammock, B D 2001 "Development of sensitive esterase assays based on alpha-cyano-containing esters" Analytical Biochemistry 299 1 54-62
Silliman, C C, Wang, M 2006 "The merits of in vitro versus in vivo modeling in investigation of the immune system" Environmental Toxicology and Pharmacology 21 2 123-134
Steinmetz, Rosemary, Young, Peter C M 1996 "Novel estrogenic action of the pesticide residue beta-hexachlorocyclohexane in human breast cancer cells" Cancer Research 56 23 5403-5409
Tingle, MD, Helsby, NA 2006 "Can in vitro drug metabolism studies with human tissue replace in vivo animal studies?" Environmental Toxicology and Pharmacology 21 2 184-190
2. U.S. Environmental Protection Agency (U.S. EPA). High Production Volume (HPV) Challenge Program. 2004. [displayed 21 May 2007]. Available at http://www.epa.gov/chemrtk/index.htm
VANDENBERG, Laura N., MAFFINI, Maricel V. 2009 "Bisphenol-A and the Great Divide : A Review of Controversies in the Field of Endocrine Disruption" Endocrine Reviews 30 1 75-95
WIXTROM, R. N., SILVA, M. H. 1988 "Affinity purification of cytosolic epoxide hydrolase using derivatized epoxy-activated Sepharose gels" Analytical Biochemistry 169 1 71-80
Yang, Dongren, Kim, Kyung Ho 2009 "Developmental Exposure to Polychlorinated Biphenyls Interferes with Experience-Dependent Dendritic Plasticity and Ryanodine Receptor Expression in Weanling Rats" Environmental Health Perspectives (EHP) 117 3 426-435
Zhang, Ji-Hu, Chung, Thomas D.Y. 1999 "A simple statistical parameter for use in evaluation and validation of high throughput screening assays" Journal of Biomolecular Screening 4 2 67-73 English
928. Moser, V C; Padilla, S, and Moser, V C. Esterase Metabolism of Cholinesterase Inhibitors Using Rat Liver in Vitro. 2011 Mar 15; 281, (1-3): 56-62.
Rec #: 43489
Keywords: IN VITRO
Notes: Chemical of Concern: CPY
Abstract: Abstract: A variety of chemicals, such as organophosphate (OP) and carbamate pesticides, nerve agents, and industrial chemicals, inhibit acetylcholinesterase (AChE) leading to overstimulation of the cholinergic nervous system. The resultant neurotoxicity is similar across mammalian species; however, the relative potencies of the chemicals across and within species depend in part on chemical-specific metabolic and detoxification processes. Carboxylesterases and A-esterases (paraoxonases, PON) are two enzymatic detoxification pathways that have been widely studied. We used an in vitro system to measure esterase-dependent detoxification of 15 AChE inhibitors.The target enzyme AChE served as a bioassay of inhibitor concentration following incubation with detoxifying tissue. Concentration-inhibition curves were determined for the inhibitor in the presence of buffer (no liver), rat liver plus calcium (to stimulate PONs and thereby measure both PON and carboxylesterase), and rat liver plus EGTA (to inhibit calcium-dependent PONs, measuring carboxylesterase activity). Point estimates (concentrations calculated to produce 20, 50, and 80% inhibition) were compared across conditions and served as a measure of esterase-mediated detoxification. Results with well-known inhibitors (chlorpyrifos oxon, paraoxon, methyl paraoxon, malaoxon) were in agreement with the literature, serving to support the use of this assay. Only a few other inhibitors showed slight or a trend towards detoxification via carboxylesterases or PONs (mevinphos, aldicarb, oxamyl). There was no apparent PON- or carboxylesterase-mediated detoxification of the remaining inhibitors (carbofuran, chlorfenvinphos, dicrotophos, fenamiphos, methamidophos, methomyl, monocrotophos, phosphamidon), suggesting that the influence of esterases on these chemicals is minimal. Thus, generalizations regarding these metabolic pathways may not be appropriate. As with other aspects of AChE inhibitors, their metabolic patterns appear to be chemical-specific.
Keywords: nerve agents
Keywords: Cholinergic nerves
Keywords: Metabolic pathways
Keywords: X 24330:Agrochemicals
Keywords: Pharmacy And Pharmacology
Keywords: Pesticides (carbamates)
Keywords: Toxicology Abstracts
Date revised - 2011-10-01
Language of summary - English
Pages - 56-62
ProQuest ID - 886635749
SubjectsTermNotLitGenreText - Detoxification; nerve agents; Calcium; Acetylcholinesterase; esterase; monocrotophos; Cholinergic nerves; Aryldialkylphosphatase; Chlorfenvinphos; Paraoxon; Cholinesterase; Metabolic pathways; methamidophos; Carbofuran; Enzymes; Carboxylesterase; Aldicarb; organophosphates; Pesticides (carbamates); Chlorpyrifos; fenamiphos; Pesticides; Neurotoxicity; Liver; Phosphamidon; Pons; Metabolism
Last updated - 2011-12-13
Corporate institution author - Moser, V C; Padilla, S
DOI - OB-da29cd6d-c467-4928-bf77csamfg201; 14515423; 0300-483X English
929. Mosquin, Paul L; Licata, Amy Collins; Liu, Bing; Sumner, Susan C J, and Okino, Miles S. Reconstructing Exposures From Small Samples Using Physiologically Based Pharmacokinetic Models and Multiple Biomarkers. 2009 Mar; 19, (3): 284-97.
Rec #: 44989
Keywords: HUMAN HEALTH
Notes: Chemical of Concern: CPY
Abstract: Abstract: This study examines the use of physiologically based pharmacokinetic (PBPK) models for inferring exposure when the number of biomarker observations per individual is limited, as commonly occurs in population exposure surveys. The trade-off between sampling multiple biomarkers at a specific time versus fewer biomarkers at multiple time points was investigated, using a simulation-based approach based on a revised and updated chlorpyrifos PBPK model originally published. Two routes of exposure, oral and dermal, were studied as were varying levels of analytic measurement error. It is found that adding an additional biomarker at a given time point adds substantial additional information to the analysis, although not as much as the addition of another sampling time. Furthermore, the precision of the estimates of exposed dose scaled approximately with the analytic precision of the biomarker measurement. For acute exposure scenarios such as those considered here, the results of this study suggest that the number of biomarkers can be balanced against the number of sampling times to obtain the most efficient estimator after consideration of cost, intrusiveness, and other relevant factors.
Keywords: Reproducibility of Results
Keywords: Chlorpyrifos -- blood
Keywords: Insecticides -- urine
Keywords: Likelihood Functions
Keywords: Environmental Studies
Keywords: Biological Markers -- blood
Keywords: Insecticides -- pharmacokinetics
Keywords: Biological Markers
Keywords: Biological Markers -- urine
Keywords: Biological Markers -- metabolism
Keywords: Chlorpyrifos -- pharmacokinetics
Keywords: Models, Theoretical
Keywords: Insecticides -- blood
Keywords: Chlorpyrifos -- urine
Copyright - Copyright Nature Publishing Group Mar 2009
Language of summary - English
Pages - 284-97
ProQuest ID - 219569528
Last updated - 2012-11-20
Place of publication - Tuxedo
Corporate institution author - Mosquin, Paul L; Licata, Amy Collins; Liu, Bing; Sumner, Susan C J; Okino, Miles S
DOI - 1646259551; 41927201; 68909; ENNP; 18461092; NTPGENNPjes200817 English
930. Mouslim, C. ; Aittaleb, M.; Hume, R. I., and Akaaboune, M. A Role for the Calmodulin Kinase Ii-Related Anchoring Protein (ΑKap) in Maintaining the Stability of Nicotinic Acetylcholine Receptors.
Rec #: 49989
Keywords: NO TOXICANT
Notes: Chemical of Concern: CPY
Abstract: COMMENTS: Cites: Front Biosci. 2002 Jul 1;7:d1697-711 (medline /12086924)
COMMENTS: Cites: EMBO J. 1998 Oct 1;17(19):5598-605 (medline /9755160)
COMMENTS: Cites: Cell. 2009 Jul 23;138(2):389-403 (medline /19615732)
COMMENTS: Cites: Nature. 1992 Oct 22;359(6397):739-41 (medline /1331805)
COMMENTS: Cites: Biochemistry. 1990 Jun 26;29(25):5899-905 (medline /2166564)
COMMENTS: Cites: J Cell Biol. 1990 Dec;111(6 Pt 1):2613-22 (medline /2277075)
COMMENTS: Cites: Science. 1997 Dec 19;278(5346):2075-80 (medline /9405336)
COMMENTS: Cites: Neuron. 2000 Feb;25(2):279-93 (medline /10719885)
COMMENTS: Cites: Neuron. 2000 May;26(2):313-29 (medline /10839352)
COMMENTS: Cites: Neuron. 2000 May;26(2):345-56 (medline /10839354)
COMMENTS: Cites: J Cell Biol. 2000 Sep 18;150(6):1385-98 (medline /10995443)
COMMENTS: Cites: Nat Rev Neurosci. 2001 Nov;2(11):791-805 (medline /11715056)
COMMENTS: Cites: Nature. 2002 Jan 10;415(6868):198-205 (medline /11805843)
COMMENTS: Cites: EMBO J. 2002 Jul 15;21(14):3590-7 (medline /12110572)
COMMENTS: Cites: Biochem J. 2003 Mar 15;370(Pt 3):873-80 (medline /12470297)
COMMENTS: Cites: Development. 2010 Apr;137(7):1017-33 (medline /20215342)
COMMENTS: Cites: Annu Rev Cell Dev Biol. 2010;26:179-210 (medline /20604708)
COMMENTS: Cites: J Neurosci. 2011 Oct 26;31(43):15586-96 (medline /22031904)
COMMENTS: Cites: J Neurosci. 2010 Sep 15;30(37):12455-65 (medline /20844140)
COMMENTS: Cites: J Cell Biol. 1989 Jun;108(6):2277-90 (medline /2472403)
COMMENTS: Cites: J Biol Chem. 1982 Feb 10;257(3):1238-46 (medline /6799504)
COMMENTS: Cites: Nature. 1995 Sep 21;377(6546):232-6 (medline /7675108)
COMMENTS: Cites: Biochem Biophys Res Commun. 1995 Apr 17;209(2):457-65 (medline /7733913)
COMMENTS: Cites: J Biol Chem. 1995 Feb 3;270(5):2074-81 (medline /7836435)
COMMENTS: Cites: Cell. 1994 Sep 9;78(5):761-71 (medline /8087844)
COMMENTS: Cites: J Biol Chem. 1993 Apr 25;268(12):8394-7 (medline /8386159)
COMMENTS: Cites: Mol Cell Biol. 1996 Jan;16(1):29-36 (medline /8524307)
COMMENTS: Cites: Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14782-7 (medline /15469925)
COMMENTS: Cites: Nat Neurosci. 2003 Mar;6(3):231-42 (medline /12577062)
COMMENTS: Cites: Cell. 1996 May 17;85(4):501-12 (medline /8653786)
COMMENTS: Cites: EMBO J. 2004 Oct 27;23(21):4156-65 (medline /15483627)
COMMENTS: Cites: Curr Biol. 2004 Nov 23;14(22):2057-62 (medline /15556870)
COMMENTS: Cites: Science. 2006 Jun 23;312(5781):1802-5 (medline /16794080)
COMMENTS: Cites: Development. 2006 Dec;133(24):4993-5000 (medline /17119023)
COMMENTS: Cites: J Cell Biol. 2007 Jun 18;177(6):1077-89 (medline /17576800)
COMMENTS: Cites: Cell. 2008 Oct 17;135(2):334-42 (medline /18848351)
COMMENTS: Cites: Neuron. 2008 Oct 23;60(2):285-97 (medline /18957220)
COMMENTS: Cites: EMBO Rep. 2009 Jul;10(7):755-61 (medline /19465887)
COMMENTS: Cites: J Biol Chem. 2009 Oct 9;284(41):28212-21 (medline /19671701)
COMMENTS: Cites: Proteins. 2010 Feb 1;78(2):365-80 (medline /19722269)
COMMENTS: Cites: Curr Biol. 2003 May 27;13(11):899-910 (medline /12781128)
ABSTRACT: αkap, a muscle specific anchoring protein encoded within the Camk2a gene, is thought to play a role in targeting multiple calcium/calmodulin kinase II isoforms to specific subcellular locations. Here we demonstrate a novel function of αkap in stabilizing nicotinic acetylcholine receptors (AChRs). Knockdown of αkap expression with shRNA significantly enhanced the degradation of AChR α-subunits (AChRα), leading to fewer and smaller AChR clusters on the surface of differentiated C2C12 myotubes. Mutagenesis and biochemical studies in HEK293T cells revealed that αkap promoted AChRα stability by a ubiquitin-dependent mechanism. In the absence of αkap, AChRα was heavily ubiquitinated, and the number of AChRα was increased by proteasome inhibitors. However, in the presence of αkap, AChRα was less ubiquitinated and proteasome inhibitors had almost no effect on AChRα accumulation. The major sites of AChRα ubiquitination reside within the large intracellular loop and mutations of critical lysine residues in this loop to arginine increased AChRα stability in the absence of αkap. These results provide an unexpected mechanism by which αkap controls receptor trafficking onto the surface of muscle cells and thus the maintenance of postsynaptic receptor density and synaptic function.
MESH HEADINGS: Animals
MESH HEADINGS: Blotting, Western
MESH HEADINGS: Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism
MESH HEADINGS: Cell Line
MESH HEADINGS: Cysteine Proteinase Inhibitors/pharmacology
MESH HEADINGS: DNA, Complementary/biosynthesis/genetics
MESH HEADINGS: Fluorescent Antibody Technique
MESH HEADINGS: Humans
MESH HEADINGS: Immunoprecipitation
MESH HEADINGS: Leupeptins/pharmacology
MESH HEADINGS: Mice
MESH HEADINGS: Microscopy, Confocal
MESH HEADINGS: Muscle Cells/physiology
MESH HEADINGS: Muscle Fibers, Skeletal/metabolism
MESH HEADINGS: Mutagenesis, Site-Directed
MESH HEADINGS: Patch-Clamp Techniques
MESH HEADINGS: Plasmids/genetics
MESH HEADINGS: RNA, Small Interfering/pharmacology
MESH HEADINGS: Real-Time Polymerase Chain Reaction
MESH HEADINGS: Receptors, Nicotinic/genetics/metabolism/*physiology
MESH HEADINGS: Transfection eng
931. Moussaoui, Yacine; Tuduri, Ludovic; Kerchich, Yacine; Meklati, B Y; Eppe, Gauthier, and Moussaoui, Yacine. Atmospheric Concentrations of Pcdd/Fs, Dl-Pcbs and Some Pesticides in Northern Algeria Using Passive Air Sampling. 2012 Jul; 88, (3): 270-277.
Rec #: 42679
Notes: Chemical of Concern: CPY
Abstract: Abstract: Two monitoring campaigns were conducted in northern Algeria to assess the contamination level of pesticides and persistent organic pollutants (POPs) in ambient air. Six pesticides ( alpha - and gamma -hexachlorocyclohexane, fenitrothion, malathion, chlorpyrifos and lambda -cyhalothrin) were monitored at two different sampling locations during the first campaign. The passive sampling was performed at a semi urban/industrial site but also in a rural area between July to September 2008. The pesticides levels, analyzed by GC/MS/MS, ranged from 16pgm-3 to 11ngm-3. The second campaign was carried out from May to November 2009. The polychlorodibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) concentrations were evaluated at an urban/industrial and at an industrial site. The PCDD/Fs and dl-PCBs, analyzed by HRGC/HRMS, ranged from 249 to 923fg TEQ m-3. In addition to passive sampling, active sampling using an isokinetic sampler was also performed at an industrial waste incinerator. The PCDD/Fs and dl-PCBs found was 268pg TEQ m-3. This paper presents the first measurements of PCDD/Fs, dl-PCBs and pesticides in rural, urban and industrial areas of northern Algeria.
Keywords: Industrial wastes
Keywords: Agricultural Chemicals
Keywords: M2 551.510.42:Air Pollution (551.510.42)
Keywords: Environment Abstracts; Meteorological & Geoastrophysical Abstracts; Aqualine Abstracts; Water Resources Abstracts; Pollution Abstracts
Keywords: Industrial Wastes
Keywords: Air sampling
Keywords: Atmospheric pollution
Keywords: SW 3050:Ultimate disposal of wastes
Keywords: persistent organic pollutants
Keywords: P 0000:AIR POLLUTION
Keywords: AQ 00007:Industrial Effluents
Keywords: Persistent organic pollutants
Keywords: ENA 01:Air Pollution
Keywords: Rural areas
Date revised - 2012-05-01
Language of summary - English
Location - Algeria
Pages - 270-277
ProQuest ID - 1017977408
SubjectsTermNotLitGenreText - Atmospheric pollution; Rural areas; Chlorpyrifos; Industrial wastes; persistent organic pollutants; Pesticides; Air sampling; Persistent organic pollutants; Incinerators; Dioxins; Malathion; PCDD; Agricultural Chemicals; Contamination; Pollutants; Industrial Wastes; Sampling; Monitoring; Samplers; Algeria
Last updated - 2012-09-10
British nursing index edition - Chemosphere [Chemosphere]. Vol. 88, no. 3, pp. 270-277. Jul 2012.
Corporate institution author - Moussaoui, Yacine; Tuduri, Ludovic; Kerchich, Yacine; Meklati, B Y; Eppe, Gauthier
DOI - 7bdd568a-4484-4597-b497csamfg201; 16730500; 0045-6535 English
932. Mu, Yusong and Carroll, Mark J. Thatch and Soil Pesticide Degradation and Microbial Activity as Influenced by Turf Cultivation Practices. 2009: (UMI# 1465512 ).
Rec #: 51809
Notes: Chemical of Concern: CPY
Abstract: Abstract: Pesticide degradation in turf is complicated by presence of an organic matter enriched layer called thatch. It is not well understood how the extensive pesticide sorption capacity of thatch may affect the aerobic degradation of pesticides in thatch. Hollow tine cultivation and vertical mowing are two commonly used cultivation practices used to control thatch.