32 results on '"TESTAI, EMANUELA"'
Search Results
2. Contributors
- Author
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Austin, Christopher P., primary, Balls, Michael, additional, Blaauboer, Bas J., additional, Botham, Philip, additional, Burt, Tal, additional, Casey, Warren, additional, Červinka, Miroslav, additional, Cheng, Shujun, additional, Combes, Robert D., additional, Corvi, Raffaella, additional, Cronin, Mark T.D., additional, Curren, Rodger D., additional, De Angelis, Isabella, additional, Dehne, Eva-Maria, additional, Doe, John, additional, Eskes, Chantra, additional, Feigenbaum, Alexandre, additional, Forgacs, Zsolt, additional, Forsby, Anna, additional, France, Malcolm P., additional, Freeman Bain, Simon A., additional, Goldberg, Alan, additional, Gruber, Franz P., additional, Guillouzo, André, additional, Hartung, Thomas, additional, Heinonen, Tuula, additional, Hickman, James, additional, Hill, Erin H., additional, Imai, Koichi, additional, Kandarova, Helena, additional, Kavlock, Robert J., additional, Kenna, J Gerry, additional, Knudsen, Lisbeth E., additional, Kojima, Hajime, additional, Kolar, Roman, additional, Leist, Marcel, additional, Lidbury, Brett A., additional, Lowit, Anna, additional, Minor, Philip, additional, Pfaller, Walter, additional, Prieto, Pilar, additional, Ram, Rebecca, additional, Repetto, Guillermo, additional, Rogiers, Vera, additional, Roi, Annett J., additional, Rowan, Andrew, additional, Sakai, Yasuyuki, additional, Sesardic, Thea, additional, Shuler, Michael, additional, Śladowski, Dariusz, additional, Spielmann, Horst, additional, Stephens, Martin L., additional, Tähti, Hanna, additional, Tanaka, Noriho, additional, Testai, Emanuela, additional, Tice, Raymond R., additional, Trigwell, Susan, additional, Verfaillie, Catherine, additional, von Aulock, Sonja, additional, Worth, Andrew P., additional, Yoon, Miyoung, additional, and Zuang, Valérie, additional
- Published
- 2019
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3. Contributors
- Author
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Ajwa, Husein, primary, Ale, Iris S., additional, Allen, Sandra L., additional, Alsop, Judith, additional, Arce, Gail, additional, Ashworth, D.J., additional, Balakrishnan, Sharada, additional, Barnett, John B., additional, Barr, Dana B., additional, Barry, Terrell, additional, Baynes, Ronald E., additional, Beauvais, Sheryl, additional, Bentley, Karin S., additional, Bernard, Craig E., additional, Besbelli, Nida, additional, Billington, Richard, additional, Blacker, Ann M., additional, Blancazo, Jerry N., additional, Breckenridge, Charles B., additional, Brooks, Gerald T., additional, Bruckner, James, additional, Brundage, Kathleen M., additional, Bui, Quang, additional, Buratti, Franca M., additional, Bus, James S., additional, Calvert, Geoffrey M., additional, Carlock, Linda L., additional, Casida, John E., additional, Chambers, Howard W., additional, Chambers, Janice E., additional, Chan, Heidi P., additional, Chester, Graham, additional, Clark, J. Marshall, additional, Class, Thomas, additional, Clifton, M. Scott, additional, Cochran, Roger, additional, Consiglio, Emma Di, additional, Dary, Curtis C., additional, Dayan, Franck E., additional, De Vries, Allison L., additional, Dix, Kelly J., additional, Dong, Michael H., additional, Dotson, Timothy A., additional, Doull, John, additional, Driver, Jeffrey H., additional, Duke, Stephen O., additional, Dyk, M. Bigelow, additional, Eastmond, David A., additional, Eaton, David L., additional, Ehrich, Marion, additional, Eisenbrandt, David L., additional, Eldridge, J. Charles, additional, Evans, Jeffrey B., additional, Farmer, Donna, additional, Felsot, Allan S., additional, Fenner-Crisp, Penelope A., additional, Fletcher, Joan L., additional, Flores, Sara, additional, Fortmann, Roy, additional, Fujita, Toshio, additional, Gammon, Derek W., additional, Gao, Suduan, additional, Garry, V.F., additional, Gehen, Sean C., additional, Georgopoulos, Panos, additional, Gollapudi, B.B., additional, Gordon, Elliot B., additional, Guerino, F., additional, Hanley, Thomas R., additional, Hanson, Lindsay, additional, Harp, Paul R., additional, Harrass, Michael C., additional, Harris, Jane E., additional, Hayes, Wayland J., additional, Hertner, Thomas, additional, Hess, Frederick G., additional, Heydens, William F., additional, Hodgson, Ernest, additional, Holden, L., additional, Hotchkiss, Jon A., additional, Hurt, Susan, additional, Isukapalli, Sastry, additional, Iyengar, Seshadri, additional, Iyer, Poorni, additional, Jensen, Inge M., additional, Jones, Russell L., additional, Jortner, Bernard S., additional, Kaneko, Hideo, additional, Kavlock, Robert J., additional, Kelly, Iain D., additional, Kenna, Michael P., additional, Kennepohl, Elke, additional, Keum, Young Soo, additional, Kim, Jeong-Han, additional, Kleinschmidt, Loreen, additional, Klonne, Dennis R., additional, Knaak, James B., additional, Krolski, Mike E., additional, Lamb, Ian C., additional, Lampman, Richard L., additional, Langner, Mikael, additional, Lantz, Jennifer L., additional, Lasserre-Bigot, Dominique, additional, Levin, Edward D., additional, Li, Qing X., additional, Liu, Jing, additional, Lock, Edward A, additional, Lotti, Marcello, additional, Lunchick, Curt, additional, Lyubimov, A.V., additional, Maibach, Howard, additional, Maier, Lisa E., additional, Makris, Susan, additional, Manning, Mark J., additional, Marsh, Rex E., additional, Marty, Melanie, additional, May-Hertl, Ursula, additional, McCurdy, Thomas, additional, McKone, Tom, additional, Meek, Edward C., additional, Mehler, Louise N., additional, Mihlan, Gary J., additional, Moore, Thomas B., additional, Morgan, Marsha K., additional, Munro, Ian C., additional, Narahashi, Toshio, additional, Nishimura, Keiichiro, additional, Novak, Robert J., additional, Ntow, William J., additional, O’Malley, Michael A., additional, Oehme, Frederick W., additional, Ollinger, Janet, additional, Osimitz, Thomas G., additional, Pandian, Muhilan D., additional, Parsons, P.P., additional, Paule, Merle G., additional, Payraudeau, Virginie, additional, Peck, Erin C., additional, Pelfrène, Alain F., additional, Pendino, Kimberly, additional, Petersen, Barbara J., additional, Piccirillo, Amanda L., additional, Piccirillo, Vincent J., additional, Pleil, Joachim D., additional, Ponnock, Kathryn, additional, Pope, Carey, additional, Poppenga, Robert H., additional, Qi, Su-wei, additional, Qin, Ruijun, additional, Ramsingh, Deborah, additional, Reiter, Lawrence W., additional, Richardson, Rudy J., additional, Ritter, Leonard, additional, Riviere, Jim E., additional, Ross, John H., additional, Rozman, Karl K., additional, Rubin, Andrew L., additional, Rust, Michael K., additional, Ruzo, Luis O., additional, Salmon, Terrell P., additional, Sangha, G.K. (Ghona), additional, Seiber, James N., additional, Selman, Frank, additional, Sheets, Larry P., additional, Sheldon, Linda S., additional, Silva, Marilyn, additional, Simpkins, James W., additional, Slikker, William, additional, Slovic, Paul, additional, Smith, Andrew G., additional, Snodgrass, Wayne R., additional, Sobus, Jon R., additional, Soderlund, David M., additional, Solomon, Keith R., additional, Spurlock, Frank, additional, Stevens, James T., additional, Stoker, Tammy E., additional, Stott, W.T., additional, Sudakin, Daniel L., additional, Takayama, Chiyozo, additional, Testai, Emanuela, additional, Thongsinthusak, Thomas, additional, Timchalk, Charles, additional, Timofeeva, Olga A., additional, Tobia, Abraham J., additional, Tornero-Velez, Rogelio, additional, Tulve, Nicolle S., additional, Uchida, Matazaemon, additional, Ujváry, István, additional, Vallero, Daniel, additional, van Ravenswaay, Bennard, additional, Waechter, Felix, additional, Weber, Edgar, additional, Wester, Ronald C., additional, Whatling, Paul, additional, Whitmyre, Gary K., additional, Wicke, Heinrich, additional, Wijeyesakere, Sanjeeva J., additional, Wilks, Martin F., additional, Wilson, Alan G.E., additional, Wilson, Barry W., additional, Woodward, Michael D., additional, Wright, Jayne, additional, Yates, S.R., additional, Yoshida, Masanori, additional, Young, Bruce M., additional, Zalom, Frank G., additional, Zartarian, Valerie, additional, Zhai, Hongbo, additional, and Zhang, Xiaofei, additional
- Published
- 2010
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4. Chlorpyrifos
- Author
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Testai, Emanuela, primary, Buratti, Franca M., additional, and Di Consiglio, Emma, additional
- Published
- 2010
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5. Contributors
- Author
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Absher, Marlene, primary, Akesson, Bengt, additional, Altenburger, Rolf, additional, Amiard, Jean-Claude, additional, Amiard-Triquet, Claude, additional, Andersen, Melvin E., additional, Babich, H., additional, Bej, Asim K., additional, Boedeker, Wolfgang, additional, Boethling, Robert S., additional, Böhm, György M., additional, Brown, David L., additional, Cadrin, Monique, additional, Cairns, John, additional, Carson, Johnny L., additional, Castranova, Vincent, additional, Collier, Clarence R., additional, Cory-Slechta, Deborah A., additional, Craighead, John E., additional, Cuccerini, Brenda, additional, Davis, Devra Lee, additional, Domingo, José L., additional, Ducatman, Alan M., additional, Dziedzic, Daniel, additional, Elsenhans, Bernd, additional, Englande,, A.J., additional, Fan, Anna M., additional, Faust, Michael, additional, Forth, Wolfgang, additional, Frakes, Robert A., additional, Galassi, Silvana, additional, Gamble, John F., additional, Gordon, Christopher J., additional, Grant, William F., additional, Griffin, G.D., additional, Grimme, L. Horst, additional, Gross, Kenneth B., additional, Hakkinen, P.J. (Bert), additional, Hawker, Darryl, additional, Herricks, Edwin E., additional, Hicks, Lebelle R., additional, Hogan, G. Richard, additional, Hunting, Katherine, additional, Isom, Gary E., additional, Jones, Troyce D., additional, Jones, William, additional, Jori, Armanda, additional, Kagamimori, Sadanobu, additional, Kang, Han K., additional, Katoh, Terutaka, additional, Krishnan, Kannan, additional, Lebowitz, Michael D., additional, Lehnert, Bruce E., additional, Lidén, Carola, additional, Lijinsky, William, additional, Lipfert, Frederick W., additional, Lison, Dominique, additional, Lundberg, Ingvar, additional, Ma, Jane Y.C., additional, Ma, Joseph K.H., additional, Mahbubani, Meena H., additional, Massad, Eduardo, additional, McCormick, Paul V., additional, Mohler, John G., additional, Naruse, Yuchi, additional, Natarajan, A.T., additional, Obe, Günter, additional, Prasad, M. Hema, additional, Provini, Alfredo, additional, Quackenboss, James J., additional, Reddy, P.P., additional, Reuhl, Kenneth R., additional, Rose, Noel R., additional, Roth, Sheldon H., additional, Saldiva, Paulo H.N., additional, Schaeffer, David J., additional, Scheunert, Irene, additional, Schümann, Klaus, additional, Sharma, Raghubir P., additional, Shaw, Glen, additional, Simpson, Lance L., additional, Smith, Frank A., additional, Snow, Elizabeth T., additional, Sparks, Donald L., additional, Squibb, Katherine S., additional, Steinberger, Anna, additional, Stott, William T., additional, Swift, David L., additional, Testai, Emanuela, additional, Torstensson, Lennart, additional, Vittozzi, Luciano, additional, Wallace, Lance A., additional, Watson, A.P., additional, Webber, James S., additional, Welch, Laura S., additional, Wheeler, Candace S., additional, Witschi, Hanspeter, additional, and Wyzga, Ronald E., additional
- Published
- 1993
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6. Chloroform
- Author
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Vittozzi, Luciano, primary and Testai, Emanuela, additional
- Published
- 1993
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7. OpenCYP: An open source database exploring human variability in activities and frequencies of polymophisms for major cytochrome P-450 isoforms across world populations.
- Author
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Vichi S, Buratti FM, Di Consiglio E, Turco L, S Lautz L, Darney K, Dorne JCM, and Testai E
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Population Surveillance, Proteomics, Cytochrome P-450 Enzyme System genetics, Cytochrome P-450 Enzyme System metabolism, Databases, Genetic, Polymorphism, Genetic, Protein Isoforms genetics, Protein Isoforms metabolism
- Abstract
The open source database "OpenCYP database" has been developed based on the results of extensive literature searches from the peer-reviewed literature. OpenCYP provides data on human variability on baseline of activities and polymophism frequencies for selected cytochrome P-450 isoforms (CYP1A2, CYP2A6, CYP2D6, CYP3A4/3A5 and CYP3A7) in healthy adult populations from world populations. CYP enzymatic activities were generally expressed as the metabolic ratio (MR) between an unchanged probe drug and its metabolite(s) in urine or plasma measured in healthy adults. Data on other age groups were very limited and fragmented, constituting an important data gap. Quantitative comparisons were often hampered by the different experimental conditions used. However, variability was quite limited for CYP1A2, using caffeine as a probe substrate, with a symmetrical distribution of metabolic activity values. For CYP3A4, human variability was dependent on the probe substrate itself with low variability when data considering the dextromethorphan/demethilathed metabolite MR were used and large variability when the urinary 6β-hydroxycortisol/cortisol ratio was used. The largest variability in CYP activity was shown for CYP2D6 activity, after oral dosing of dextromethorphan, for which genetic polymorphisms are well characterised and constitute a significant source of variability. It is foreseen that the OpenCYP database can contribute to promising tools to support the further development of QIVIVE and PBK models for human risk assessment of chemicals particularly when combined with information on isoform-specific content in cells using proteomic approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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8. Human variability in glutathione-S-transferase activities, tissue distribution and major polymorphic variants: Meta-analysis and implication for chemical risk assessment.
- Author
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Buratti FM, Darney K, Vichi S, Turco L, Di Consiglio E, Lautz LS, Béchaux C, Dorne JCM, and Testai E
- Subjects
- Algorithms, Animals, Bayes Theorem, Cytosol enzymology, Humans, Isoenzymes genetics, Polymorphism, Genetic, Tissue Distribution, Toxicokinetics, Uncertainty, Glutathione Transferase genetics, Glutathione Transferase metabolism, Risk Assessment methods
- Abstract
The input into the QIVIVE and Physiologically-Based kinetic and dynamic models of drug metabolising enzymes performance and their inter-individual differences significantly improve the modelling performance, supporting the development and integration of alternative approaches to animal testing. Bayesian meta-analyses allow generating and integrating statistical distributions with human in vitro metabolism data for quantitative in vitro-in vivo extrapolation. Such data are lacking on glutathione-S-transferases (GSTs). This paper reports for the first time results on the human variability of GST activities in healthy individuals, their tissue localisation and the frequencies of their major polymorphic variants by means of extensive literature search, data collection, data base creation and meta-analysis. A limited number of papers focussed on in vivo GST inter-individual differences in humans. Ex-vivo total GST activity without discriminating amongst isozymes is generally reported, resulting in a high inter-individual variability. The highest levels of cytosolic GSTs in humans are measured in the kidney, liver, adrenal glands and blood. The frequencies of GST polymorphisms for cytosolic isozymes in populations of different geographical ancestry were also presented. Bayesian meta-analyses to derive GST-related uncertainty factors provided uncertain estimates, due to the limited database. Considering the relevance of GST activities and their pivotal role in cellular adaptive response mechanisms to chemical stressors, further studies are needed to identify GST probe substrates for specific isozymes and quantify inter-individual differences., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2021
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9. Minimization of spreading of SARS-CoV-2 via household waste produced by subjects affected by COVID-19 or in quarantine.
- Author
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Di Maria F, Beccaloni E, Bonadonna L, Cini C, Confalonieri E, La Rosa G, Milana MR, Testai E, and Scaini F
- Subjects
- COVID-19, Humans, Italy, SARS-CoV-2, Betacoronavirus, Coronavirus Infections, Household Products, Pandemics, Pneumonia, Viral, Quarantine, Solid Waste
- Abstract
Currently available evidence supports that the predominant route of human-to-human transmission of the SARS-CoV-2 is through respiratory droplets. Indirect hands contact with surfaces contaminated by infectious droplets subsequently touching the mouth, nose or eyes seems to be another route of an indirect contact transmission. Persistence of the virus on different surfaces and other materials has been reported in recent studies: SARS-CoV-2 was more stable on plastic and stainless steel than on copper and cardboard. Viable virus was detected up to 72 h after application to different surfaces, although infectivity decay was also observed. This evidence suggests the likelihood that waste generated from patients affected by COVID-19 or subjects in quarantine treated in private houses or in areas different from hospitals and medical centres could be contaminated by SARS-CoV-2. Consequently, waste streams may represent a route for viral spreading being a potential risk also for the operators directly involved in the different phases of waste management. To address this concern, a specific multidisciplinary working group was settled by the Italian National Institute of Health (ISS) during the COVID-19 emergency, in order to establish guidelines related to solid waste collection, delivering, withdrawal, transport, treatment and disposal. Temporary stop of waste sorting, instructions for the population on how to package waste, instructions for Companies and operators for the adoption of adequate personal protection equipment (PPE), the use and sanitation of proper vehicles were among the main recommendations provided to the community by publications of freely downloadable reports and infographics in layman language. Incineration, sterilization and properly managed landfills were identified as the facilities to be preferentially adopted for the treatment of this kind of waste, considering the main inactivation strategies of SARS-CoV-2 (e.g. treatment length > 9 days and temperature > 70 °C for more than 5 min)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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10. In vitro detoxication of microcystins in human samples: variability among variants with different hydrophilicity and structure.
- Author
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Santori N, Buratti FM, Scardala S, Dorne JCM, and Testai E
- Subjects
- Dose-Response Relationship, Drug, Female, Glutathione metabolism, Glutathione Transferase genetics, Humans, Hydrophobic and Hydrophilic Interactions, Inactivation, Metabolic, Isoenzymes, Male, Microcystins chemistry, Microcystins toxicity, Molecular Structure, Polymorphism, Genetic, Recombinant Proteins metabolism, Risk Assessment, Substrate Specificity, Toxicokinetics, Glutathione Transferase metabolism, Liver enzymology, Microcystins metabolism
- Abstract
Cyanotoxins, among which >200 variants of Microcystins (MC), constitute an emerging issue in food safety. Microcystins (MC) toxicity is congener-specific; however, the in vitro inhibition of PP1/PP2A (the key molecular event of MC toxicity) by single MC variants is comparable and MC toxicokinetics seems to be the critical point. Here, the variability in GSH conjugation catalysed by human recombinant enzymes and human hepatic cytosol has been compared between hydrophilic (MC-LR and MC-RR) and hydrophobic (MC-LW, MC-YR and MC-LF) variants, according to measured logPow. In vitro detoxication reaction (spontaneous plus enzymatic) is favored by the variant hydrophilicity, with MC-LF very poorly detoxified. With MC-YR and -LW the spontaneous reaction always gave the major contribution, whereas with MC-LR and -RR the enzymatic reaction became by far predominant when GSH was depleted. Consequently, the well-known GST polymorphisms seems not to be the major driver for potential human variability in susceptibility towards the MC-toxicity, except for MC-RR and -LR when GSH is depleted. Looking at these results and literature data, MC-RR (the least cytotoxic and acutely toxic in rodents) is the more hydrophilic, has the lowest OATP-mediated hepatic uptake and the highest detoxication efficiency. The opposite is true for the most lipophilic MC-LF: once entered in the cells with the highest uptake, it is very poorly detoxified, and resulted as the most toxic in various cell types. MC-dependent TK should be considered in order to estimate the variability in toxicity and to support the use of quantitative in vitro-in vivo extrapolation models of single toxins and their mixtures co-occurring in the environment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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11. Metabolism of triflumuron in the human liver: Contribution of cytochrome P450 isoforms and esterases.
- Author
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Timoumi R, Buratti FM, Abid-Essefi S, Dorne JCM, and Testai E
- Subjects
- Humans, Benzamides metabolism, Cytochrome P-450 Enzyme System metabolism, Insecticides metabolism, Isoenzymes metabolism, Microsomes, Liver metabolism
- Abstract
Triflumuron (TFM) is a benzoylurea insecticide commonly used in Tunisian agriculture and around the world to control crop pests and flies as a promising alternative to conventional insecticides for its arthropod specificity and low toxicity. From the evidence available in animal models, it can be expected that the metabolism of TFM is catalyzed by cytochrome P450 (CYP) and esterases. However, no data are available on human metabolism of TFM with regards to phase I metabolism and CYP isoform specificity. Hence, this manuscript describes experimental investigations to underpin in vitro phase I TFM metabolism in human samples for the first time. TFM biotransformation by recombinant human CYPs was characterized, then human liver microsomes (HLM) and chemical specific inhibitors have been used to identify the relative contribution of CYPs and esterases. Our results showed that all CYP isoforms were able to metabolize TFM with different affinity and efficiency. The relative contribution based both on the kinetic parameters and the CYP hepatic content was 3A4 > >2C9 > 2C8 > 2A6 > 1A2 > 2B6 > 2D6 > 2C19 > 2C18 > 1A1 at low TFM concentration, whilst at high TFM concentration it was 1A2 > >2C9 = 3A4 = 2A6 > 2C19 > 2B6 = 2C8 > 2D6 > 1A1 > 2C18. Experiments with HLMs confirmed the involvement of the most relevant CYPs in the presence of specific chemical inhibitors with a catalytic efficiency (Cliapp) lower by an order of magnitude compared with recombinant enzymes. Esterases were also relevant to the overall TFM kinetics and metabolism, with catalytic efficiency higher than that of CYPs. It is foreseen that such isoform-specific information in humans will further support in silico models for the refinement of the human risk assessment of single pesticides or mixtures., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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12. Cyanobacteria blooms in water: Italian guidelines to assess and manage the risk associated to bathing and recreational activities.
- Author
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Funari E, Manganelli M, Buratti FM, and Testai E
- Subjects
- Environmental Monitoring, Humans, Italy, Microcystins, Recreation, Bathing Beaches, Cyanobacteria, Eutrophication, Lakes microbiology
- Abstract
Cyanobacteria thrive in many aquatic environments, where they can produce cyanotoxins with different toxicological profile. Anthropic pressure and climate changes are causing the expansion in terms of time and space of their blooms, increasing the concerns for human health in several exposure scenarios. Here the update of the Italian guidelines for the management of cyanobacterial blooms in bathing water is presented. A risk-based approach has been developed according to the current scientific knowledge on cyanobacteria distribution in the Italian Lakes and on chemical, toxicological and epidemiological aspects of different cyanotoxins, summarized in the first part of the paper. Oral, dermal and inhalation exposure to cyanotoxins, during recreational activities, are individually examined, to develop a framework of thresholds and actions aimed at preventing harmful effects for bathers. Guidelines, also by comparing international guidance values and/or guidelines, provide criteria to plan environmental monitoring activities, health surveillance and public communication systems. Finally the still important scientific gaps and research needs are highlighted., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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13. The safety of the use of bisphenol A in medical devices.
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Testai E, Hartemann P, Rodríguez-Farre E, Rastogi SC, Bustos J, Gundert-Remy U, Hensten A, Kopperud HM, Olea N, Piersma A, and De Jong W
- Subjects
- Animals, Benzhydryl Compounds pharmacokinetics, Dose-Response Relationship, Drug, Equipment Design, Humans, Phenols pharmacokinetics, Risk Assessment, Benzhydryl Compounds adverse effects, Equipment Safety, Equipment and Supplies adverse effects, Patient Safety, Phenols adverse effects
- Published
- 2016
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14. The safety of dental amalgam and alternative dental restoration materials for patients and users.
- Author
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Rodríguez-Farre E, Testai E, Bruzell E, De Jong W, Schmalz G, Thomsen M, and Hensten A
- Subjects
- Animals, Body Burden, Humans, Risk Assessment, Dental Amalgam adverse effects, Dental Hygienists, Dental Restoration, Permanent adverse effects, Dentists, Mercury Compounds adverse effects, Occupational Exposure adverse effects, Occupational Health, Patient Safety
- Published
- 2016
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15. The safety of medical devices containing DEHP plasticized PVC or other plasticizers on neonates and other groups possibly at risk (2015 update).
- Author
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Testai E, Hartemann P, Rastogi SC, Bernauer U, Piersma A, De Jong W, Gulliksson H, Sharpe R, Schubert D, and Rodríguez-Farre E
- Subjects
- Age Factors, Animals, Diethylhexyl Phthalate standards, Equipment Design, Equipment and Supplies standards, Humans, Infant, Newborn, Plasticizers standards, Polyvinyl Chloride standards, Risk Assessment, Risk Factors, Toxicity Tests, Diethylhexyl Phthalate adverse effects, Equipment Safety standards, Equipment and Supplies adverse effects, Patient Safety, Plasticizers adverse effects, Polyvinyl Chloride adverse effects
- Published
- 2016
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16. Opinion on environmental risks and indirect health effects of mercury from dental amalgam.
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Linders J, Janssen C, Testai E, Vighi M, Dekant W, Munth J, Pirrone N, and Richardson M
- Subjects
- Humans, Public Health, Dental Amalgam adverse effects, Environmental Pollution adverse effects, Mercury adverse effects
- Published
- 2015
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17. Understanding the biokinetics of ibuprofen after single and repeated treatments in rat and human in vitro liver cell systems.
- Author
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Truisi GL, Consiglio ED, Parmentier C, Savary CC, Pomponio G, Bois F, Lauer B, Jossé R, Hewitt PG, Mueller SO, Richert L, Guillouzo A, and Testai E
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal toxicity, Cell Line, Cell Survival drug effects, Cytochrome P-450 Enzyme System metabolism, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Ibuprofen chemistry, Ibuprofen toxicity, Liver cytology, Male, Models, Statistical, Primary Cell Culture, Rats, Rats, Wistar, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Ibuprofen pharmacokinetics, Liver metabolism
- Abstract
Common in vitro toxicity testing often neglects the fate and intracellular concentration of tested compounds, potentially limiting the predictability of in vitro results for in vivo extrapolation. We used in vitro long-term cultures of primary rat (PRH) and human hepatocytes (PHH) and HepaRG cells to characterise and model the biokinetic profile of ibuprofen (IBU) after single and daily repeated exposure (14 days) to two concentrations. A cross-model comparison was carried out at 100μM, roughly corresponding to the human therapeutic plasma concentration. Our results showed that IBU uptake was rapid and a dynamic equilibrium was reached within 1 or 2 days. All three cell systems efficiently metabolised IBU. In terms of species-differences, our data mirrored known in vivo results. Although no bioaccumulation was observed, IBU intracellular concentration was higher in PRH due to a 10-fold lower metabolic clearance compared to the human-derived cells. In HepaRG cells, IBU metabolism increased over time, but was not related to the treatment. In PHH, a low CYP2C9 activity, the major IBU-metabolising CYP, led to an increased cytotoxicity. A high inter-individual variability was seen in PHH, whereas HepaRG cells and PRH were more reproducible models. Although the concentrations of IBU in PRH over time differed from the concentrations found in human cells under similar exposure conditions., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
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18. Species- and congener-differences in microcystin-LR and -RR GSH conjugation in human, rat, and mouse hepatic cytosol.
- Author
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Buratti FM and Testai E
- Subjects
- Animals, Biotransformation, Catalysis, Female, Glutathione metabolism, Humans, Kinetics, Male, Marine Toxins, Mice, Rats, Sprague-Dawley, Species Specificity, Substrate Specificity, Cytosol enzymology, Glutathione Transferase metabolism, Liver enzymology, Microcystins metabolism
- Abstract
The accepted pathway for MC biotransformation is GSH conjugation, occurring either spontaneously or catalyzed by GST. In the present work, the already available information on human MC metabolism have been expanded and the capacity of human GST to conjugate MC-LR has been confirmed in human liver cytosol. At physiological GSH content the spontaneous reaction predominated on the enzymatic one; the prevalence of the enzymatic reaction occurred following GSH depletion, and the shift was detectable at higher GSH levels, the lower was MC concentration. However, at low MC-LR concentrations (≤10μM), representative of repeated oral exposure, the relevance of the enzymatic reaction became predominant at GSH concentration between 1 and 2mM. MC-LR conjugate was detectable at ≥0.5mM GSH, whereas, with 10μM MC-RR detectable levels of conjugate were observed at 0.05mM GSH, a 10-fold lower concentration. Overall, our data indicate that MC-RR is more efficiently conjugated than MC-LR, especially at low concentrations. Cytosol samples from rat and mouse were used to characterize GSH conjugation of MC-LR and MC-RR, and to check for possible species differences. At physiological GSH content, in both rodent species the enzymatic reaction accounted for half of the total conjugate formation, reducing the impact of spontaneous reaction with respect to human. Rat and mouse GST showed similar MC-LR and-RR GSH conjugation, but a two-fold higher catalytic efficiency than human sample. This is mainly due to higher affinity for the substrate, with Kmapp values being an order of magnitude lower in the animal models than in human liver cytosol. More pronounced differences in the metabolism of the two variants were evidenced in rodents than in humans., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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19. Metals in cosmetics: an a posteriori safety evaluation.
- Author
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Marinovich M, Boraso MS, Testai E, and Galli CL
- Subjects
- Consumer Product Safety, Humans, Risk Assessment, Safety, Skin drug effects, Cosmetics analysis, Cosmetics chemistry, Metals adverse effects, Metals chemistry
- Abstract
According to EU Regulation No. 1223/2009/CE cosmetic products for daily use can contain 'technically unavoidable traces' of metals. This definition is too vague. Authorities should set well-defined limits, considering the risks associated with metal contamination of personal care products (PCPs). This paper characterizes the risk arising from a number of metals (antimony, arsenic, cadmium, cobalt, chromium, mercury, nickel, lead) that may occur in 'unavoidable traces" in raw materials and, consequently, in PCPs. A 'worst case scenario' was adopted, based on the following assumptions: (i) the individual ingredients contained the maximum amount in traces allowed for each metal; (ii) the hypothetical PCP was produced exclusively with that single ingredient; (iii) when absorption through the skin was not known, data related to oral absorption were used. Risk characterization was performed calculating the Systemic Exposure Dosage (SED) and the Margin of Safety (MoS=NOAEL or BMDL10/SED). Exposure to the allegedly 'technically unavoidable' maximum amounts of metals in cosmetic ingredients resulted in MoSs exceeding 100 (safety threshold) with one exception. This suggests that the availability of experimental dermal absorption rates could enable significant improvement in MoS, thus increasing safety levels. Although results are reassuring, the authors recommend minimization of contamination, according to the state of the art of manufacturing methods., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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20. Survival, growth and toxicity of Microcystis aeruginosa PCC 7806 in experimental conditions mimicking some features of the human gastro-intestinal environment.
- Author
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Stefanelli M, Vichi S, Stipa G, Funari E, Testai E, Scardala S, and Manganelli M
- Subjects
- Culture Media chemistry, Darkness, Humans, Hydrogen-Ion Concentration, Leucine metabolism, Microcystis metabolism, Microcystis physiology, Microcystis radiation effects, Survival Analysis, Temperature, Gastrointestinal Tract microbiology, Microcystis growth & development, Toxins, Biological metabolism
- Abstract
Cyanotoxins (CTX) are widely produced by several cyanobacteria (CB), increasingly spreading in most water bodies and terrestrial habitats, and represent a risk for human health. CB are prokaryotes, and although mostly autotrophic, several examples of heterotrophy in symbiotic relationship with different organisms have been described. In addition to the known routes of exposure, it has been hypothesized that CB might 'colonize' human intestine with relevant implications for human health. Colonization is a complex process and requires specific features of the possible invaders. Still, a short-term persistence as living and toxin-producing organisms within the intestinal lumen of the host could represent an 'internal' source of exposure to CTX. In this work we ran microcosm experiments (4-18days), looking at Microcystis aeruginosa PCC7806 resistance and cyanotoxin-producing capabilities in darkness, 37°C, pH 2, and subsequent recovery in a rich medium, in darkness, 37°C, in the presence of enteric bacteria, mimicking few important features of the gastrointestinal environment. We measured cyanobacterial populations and growth, microcystin (MC) production and the presence of mcyB gene. M. aeruginosa could grow in the dark at 37°C up to 17days, and survive at pH 2 at a rate between 30% and 70%, depending on the age and toxicity of the starting culture. Cell lysis resulted in a substantial amounts of MC released, not degraded at gastric pH. Following the acidic passage, still in the dark at 37°C, M. aeruginosa restarted to grow within 24h for the next 3-4days, independently on the presence of intestinal bacteria, maintaining the MC cell quota and mcyB gene. Our results show new features of CB: a significant resistance of M. aeruginosa in conditions far from its optimal one, that is an environment mimicking some of the important characteristics of human gastrointestinal tract, suggesting the possibility of an internal source of exposure to CTX, with implications for the risk assessment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
21. PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: recommendations from a joint EPAA--EURL ECVAM ADME workshop.
- Author
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Bessems JG, Loizou G, Krishnan K, Clewell HJ 3rd, Bernasconi C, Bois F, Coecke S, Collnot EM, Diembeck W, Farcal LR, Geraets L, Gundert-Remy U, Kramer N, Küsters G, Leite SB, Pelkonen OR, Schröder K, Testai E, Wilk-Zasadna I, and Zaldívar-Comenges JM
- Subjects
- Animal Testing Alternatives, Drug-Related Side Effects and Adverse Reactions, Environmental Exposure adverse effects, Humans, Pharmacokinetics, Risk Assessment, Environmental Pollutants pharmacokinetics, Environmental Pollutants toxicity, Models, Biological
- Abstract
Information on toxicokinetics is critical for animal-free human risk assessment. Human external exposure must be translated into human tissue doses and compared with in vitro actual cell exposure associated to effects (in vitro-in vivo comparison). Data on absorption, distribution, metabolism and excretion in humans (ADME) could be generated using in vitro and QSAR tools. Physiologically-based toxicokinetic (PBTK) computer modelling could serve to integrate disparate in vitro and in silico findings. However, there are only few freely-available PBTK platforms currently available. And although some ADME parameters can be reasonably estimated in vitro or in silico, important gaps exist. Examples include unknown or limited applicability domains and lack of (high-throughput) tools to measure penetration of barriers, partitioning between blood and tissues and metabolic clearance. This paper is based on a joint EPAA--EURL ECVAM expert meeting. It provides a state-of-the-art overview of the availability of PBTK platforms as well as the in vitro and in silico methods to parameterise basic (Tier 1) PBTK models. Five high-priority issues are presented that provide the prerequisites for wider use of non-animal based PBTK modelling for animal-free chemical risk assessment., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
22. A plea for risk assessment of endocrine disrupting chemicals.
- Author
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Testai E, Galli CL, Dekant W, Marinovich M, Piersma AH, and Sharpe RM
- Subjects
- Animals, Dose-Response Relationship, Drug, Endocrine Disruptors adverse effects, Humans, Toxicity Tests, Endocrine Disruptors toxicity, Risk Assessment
- Abstract
Some recent EU Regulations have focused on the potential risks posed by the presence of endocrine disrupters (ED) into the environment. However there are conflicting opinions on how to assess the risk from exposure to these molecules that can reversibly modulate hormonal activity, endocrine active substances (EAS) rather than causing irreversible damage (ED). The present paper attempts to discuss that perturbation of normal endocrine homeostasis in itself may not be an adverse effect, since the endocrine system is naturally dynamic and responsive to various stimuli as part of its normal function and it is modulated according to the characteristic trend of the dose-response curve. EDs should be evaluated using a weight-of-evidence (WoE) approach. If a chemical meets the criteria to be defined as an ED in experimental animals, the relevance of observed effects to the human then needs to be addressed. Hazard-based risk management is therefore not justified since does not meet the criteria for a sound scientifically based assessment., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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23. The conjugation of microcystin-RR by human recombinant GSTs and hepatic cytosol.
- Author
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Buratti FM, Scardala S, Funari E, and Testai E
- Subjects
- Cytosol enzymology, Cytosol metabolism, Female, Humans, Liver enzymology, Male, Recombinant Proteins metabolism, Glutathione Transferase metabolism, Liver metabolism, Marine Toxins metabolism, Microcystins metabolism
- Abstract
Many cyanobacterial species can produce cyanotoxins, among which mycrocistins (MC) are a group of ≈100 congeners of hepatotoxic cyclic heptapeptides. MC-RR differs from MC-LR, the most studied congener only for one residue (arginine vs leucine), resulting in a ten-fold difference in the acute toxicity in mice. Although humans may be exposed to MC through several routes and kinetics appeared to be the major factor affecting congener-specific toxicity, little is known on MC metabolism. The accepted pathway for MC detoxication is GSH conjugation: here the MC-RR conjugation with GSH catalyzed by 5 recombinant human GSTs and human liver cytosol (HLC) has been characterized and appeared to be more efficient than MC-LR conjugation. The catalytic efficiency score is T1-1>A1-1≈P1-1>M1-1>A3-3 (0.161-0.056pmol GSMC-RR (μgproteinminμM)(-1)). In HLC the spontaneous reaction is favored vs the enzymatic one (ratio 3:1) at physiological GSH content. However, at low MC-RR concentrations, representative of repeated oral exposure, and low GSH content (down to 0.05mM), possibly associated to exposure to drugs or in patients affected by several pathologies, the relevance of the enzymatic reaction progressively increases, providing the predominant contribution to MC-RR detoxication., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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24. Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress.
- Author
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Wilmes A, Limonciel A, Aschauer L, Moenks K, Bielow C, Leonard MO, Hamon J, Carpi D, Ruzek S, Handler A, Schmal O, Herrgen K, Bellwon P, Burek C, Truisi GL, Hewitt P, Di Consiglio E, Testai E, Blaauboer BJ, Guillou C, Huber CG, Lukas A, Pfaller W, Mueller SO, Bois FY, Dekant W, and Jennings P
- Subjects
- Cyclophilins metabolism, Epithelial Cells metabolism, Humans, Kidney Tubules, Proximal cytology, Metabolomics, NF-E2-Related Factor 2 metabolism, Oxidative Stress drug effects, Proteomics, Signal Transduction drug effects, Tandem Mass Spectrometry, Toxicology methods, Cyclosporine pharmacokinetics
- Abstract
High content omic techniques in combination with stable human in vitro cell culture systems have the potential to improve on current pre-clinical safety regimes by providing detailed mechanistic information of altered cellular processes. Here we investigated the added benefit of integrating transcriptomics, proteomics and metabolomics together with pharmacokinetics for drug testing regimes. Cultured human renal epithelial cells (RPTEC/TERT1) were exposed to the nephrotoxin Cyclosporine A (CsA) at therapeutic and supratherapeutic concentrations for 14days. CsA was quantified in supernatants and cellular lysates by LC-MS/MS for kinetic modeling. There was a rapid cellular uptake and accumulation of CsA, with a non-linear relationship between intracellular and applied concentrations. CsA at 15μM induced mitochondrial disturbances and activation of the Nrf2-oxidative-damage and the unfolded protein-response pathways. All three omic streams provided complementary information, especially pertaining to Nrf2 and ATF4 activation. No stress induction was detected with 5μM CsA; however, both concentrations resulted in a maximal secretion of cyclophilin B. The study demonstrates for the first time that CsA-induced stress is not directly linked to its primary pharmacology. In addition we demonstrate the power of integrated omics for the elucidation of signaling cascades brought about by compound induced cell stress., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
25. The contribution of human small intestine to chlorpyrifos biotransformation.
- Author
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Leoni C, Balduzzi M, Buratti FM, and Testai E
- Subjects
- Biotransformation, Blotting, Western, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System metabolism, Duodenum metabolism, Female, Humans, Hydroxylation, Ileum metabolism, Inactivation, Metabolic, Jejunum metabolism, Male, Microsomes metabolism, Regression Analysis, Testosterone metabolism, Chlorpyrifos pharmacokinetics, Insecticides pharmacokinetics, Intestine, Small metabolism
- Abstract
Despite the oral intake is the major route of exposure to chlorpyrifos for the general population, few data are available on human intestine biotransformation. In this study the contribution of chlorpyrifos (CPF) metabolism in human small intestine was investigated in microsomes from duodenum (HDM) and ileum/jejunum (HS2M) from 11 individual donors. Samples were characterized for testosterone hydroxylated metabolite formation and CYP content quantification by means of Western blotting. The two methods gave consistent results, evidencing the presence of CY3A4 and its-related activity in 10/11 samples, among which one showed also the presence of CYP2C9. Analogously, although with high interindividual variability (about 10 fold), CPF bioactivation to chlorpyrifos-oxon (CPFO) was observed in 10/11 HDM: intrinsic clearance highest value was 0.75 pmolCPFO/(mgproteinminμM). Detoxication to 3,5,6-trichloropyrin-2-ol formation was negligible. The comparison between HDM and HS2M indicates that most CPF bioactivation was confined in the duodenum, declining toward the distal ileum. Results suggest that following oral exposure, the small intestine CPF bioactivation, although much lower when compared to the total hepatic metabolism, could play a role in the pre-systemic CPF clearance, with CPFO transported into the lumen by the efflux P-glycoprotein and further metabolized by esterases., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
26. Foetal and neonatal exposure to chlorpyrifos: biochemical and metabolic alterations in the mouse liver at different developmental stages.
- Author
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Buratti FM, De Angelis G, Ricceri L, Venerosi A, Calamandrei G, and Testai E
- Subjects
- Age Factors, Animals, Animals, Newborn embryology, Female, Liver embryology, Liver growth & development, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Microsomes, Liver pathology, Pregnancy, Prenatal Exposure Delayed Effects pathology, Animals, Newborn metabolism, Chlorpyrifos toxicity, Liver drug effects, Liver metabolism, Prenatal Exposure Delayed Effects chemically induced, Prenatal Exposure Delayed Effects metabolism
- Abstract
The mechanisms implicated in the age-related toxicity, including its neurobehavioral effects after subtoxic developmental exposure to chlorpyrifos (CPF), a widely used insecticide, have not been fully elucidated yet. With the aim of investigating whether metabolic differences during ontogeny could account for the age-related susceptibility to CPF, we examined the developmental time-course of hepatic metabolizing enzymes and CPF metabolism in a cohort of mice exposed either prenatally (gestational day 15-18) and/or postnatally (postnatal day (PND) 11-14) to CPF at doses which were previously reported to induce neurobehavioural alterations, in the absence of brain acetyl-cholinesterase inhibition. Testosterone hydroxylase activity, CPF ex vivo biotransformation, glutathione content, as well as aromatase activity were determined in the liver of control and treated male and female mice at PND0, 9, 15 and 150. In control mice most Cyp activities were detectable and progressively increased up to PND15. In newborn control mice CPF bioactivation was much higher than the Cyp-catalysed detoxication, negligible at birth, indicating a possible increased susceptibility to CPF-induced effects in newborn mice. Detoxication rapidly increased with age, so that Cyp-related metabolic features cannot explain the higher susceptibility of juvenile mice. The observed age-dependent metabolic picture was partially altered by CPF prenatal treatment. Following in utero exposure CPF detoxifying capability was enhanced at birth and reduced at PND15, when CPF-oxon formation was slightly increased. No effects were evident at adulthood. Prenatal dosing was more effective in causing metabolic alterations than CPF postnatal treatment; no potentiation was observed in mice experiencing pre- plus post-natal CPF administration. Both in utero and postnatal CPF exposure decreased aromatase activity by 50% at PND9 and 15; this effect together with the presence of higher levels of the sex-specific Cyp2c activity at adulthood in male mice may suggest the occurrence of long-lasting impairment in the expression of hepatic Cyps under hormonal regulation. Altogether, the alterations in CPF Cyp-mediated biotransformation caused by perinatal CPF exposure seem not sufficient per se to explain the reported vulnerability of developing central nervous system to this insecticide, which can be due also to the parent compound itself or to the activation of different toxicological pathways. The hypothesis that observed effects on aromatase and sex-specific Cyp activity may be associated with a possible interference with the long-term alterations in sex-specific behavioural pattern deserves further investigation., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2011
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27. Early exposure to low doses of atrazine affects behavior in juvenile and adult CD1 mice.
- Author
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Belloni V, Dessì-Fulgheri F, Zaccaroni M, Di Consiglio E, De Angelis G, Testai E, Santochirico M, Alleva E, and Santucci D
- Subjects
- Age Factors, Animals, Atrazine administration & dosage, Cognition drug effects, Dose-Response Relationship, Drug, Endocrine Disruptors administration & dosage, Environmental Exposure adverse effects, Exploratory Behavior drug effects, Female, Herbicides administration & dosage, Learning drug effects, Male, Mice, Motor Activity drug effects, Pregnancy, Prenatal Exposure Delayed Effects, Social Behavior, Testosterone metabolism, Time Factors, Atrazine toxicity, Behavior, Animal drug effects, Endocrine Disruptors toxicity, Herbicides toxicity
- Abstract
Environmental exposure to endocrine disrupting chemicals is receiving increasing attention, with particular regard to distinct periods of development where neuroendocrine circuitries are critical for shaping the mammalian brain. Atrazine (ATZ), a widely used herbicide, has been reported to affect steroid hormones and interfere with pathways critical for sex-specific physiological and behavioral development. Aim of the present study was to evaluate effects of perinatal exposure to environmentally relevant subtoxic doses of ATZ, on neurobehavioral development in mice and investigate possible alterations in steroid hormone metabolism. Neurobehavioral development of female and male mice delivered from CD1 dams, and daily exposed from Gestational Day 14 until Postnatal Day 21 (PND 21) to 1 or 100 μg/kg bw ATZ, was investigated. Specifically, locomotor and exploratory activity, social interactions and cognitive performance were evaluated at PND 16, 31 and 60, respectively. Moreover, general toxicity clinical signs, testicular parameters, rate of testosterone metabolism and aromatase activity in F1 male liver were analyzed at adulthood. Changes in exploratory profile and in affiliative/investigative behavior were observed, revealing a feminization of behavioral profile in ATZ-exposed males. Alteration in learning performance at adulthood was also evident. A limited decreased sperm count and concentration, as well as some slight impairment in hepatic testosterone metabolism and in aromatase activity (slightly but not significantly decreased) were observed in both low and high dose exposed animals. In conclusion developmental exposure to non-toxic, environmentally relevant doses of ATZ can produce subtle functional alterations, detectable in juvenile rodents by a detailed behavioral analysis. Behavioral disturbances appeared mainly related with neurodevelopmental disorder affecting the social domain and the emotional/affective repertoire, although further research is needed to elucidate the mechanism through which the effects are induced., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
28. The food contaminant semicarbazide acts as an endocrine disrupter: Evidence from an integrated in vivo/in vitro approach.
- Author
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Maranghi F, Tassinari R, Marcoccia D, Altieri I, Catone T, De Angelis G, Testai E, Mastrangelo S, Evandri MG, Bolle P, and Lorenzetti S
- Subjects
- Administration, Oral, Animals, Aromatase metabolism, Cell Line, Dose-Response Relationship, Drug, Estrogens blood, Female, Gonadal Steroid Hormones blood, Humans, Male, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate metabolism, Testosterone metabolism, Vagina drug effects, Vagina pathology, Endocrine Disruptors toxicity, Food Contamination analysis, Semicarbazides toxicity
- Abstract
Semicarbazide (SEM) is a by-product of the blowing agent azodicarbonamide, present in glass jar-sealed foodstuffs mainly baby foods. The pleiotropic in vivo SEM toxicological effects suggested to explore its possible role as endocrine modulator. Endocrine effects of SEM were assessed in vivo in male and female rats after oral administration for 28 days at 0, 40, 75, 140mg/kg bw pro die during the juvenile period. Vaginal opening and preputial separation were recorded. Concentration of sex steroid in blood, the ex vivo hepatic aromatase activity and testosterone catabolism were detected. The in vitro approach to test SEM role as (anti)estrogen or N-methyl-d-aspartate receptors (NMDARs)-(anti)agonist included different assays: yeast estrogenicity, MCF-7 proliferation, stimulation of the alkaline phosphatase activity in Ishikawa cells and LNCaP-based NMDAR interference assay. In vivo SEM-treated female rats showed delayed vaginal opening at all tested doses, whereas in males preputial separation was anticipated at SEM 40 and 75mg/kg and delayed at 140mg/kg, the latter effect probably due to the significantly decreased body weight gain seen at the higher dose in both sexes. Serum estrogen levels were dose-dependently reduced in treated females, whereas dehydrotestosterone serum levels were also decreased but a clear dose-response was not evidenced. Testosterone catabolism was altered in a gender-related way, aromatase activity was increased in treated males at 75 and 140mg/kg and in females in all dose groups. In the three estradiol-competitive assays, SEM showed a weak anti-estrogenic activity, whereas in the LNCaP-based NMDAR interference assay SEM activity resembled MK-801 antagonist effect. SEM appeared to act as an endocrine disrupter showing multiple and gender specific mechanisms of action(s). A possible cascade-mechanism of SEM on reproductive signalling pathways may be hypothesized. Such in vivo-in vitro approach appeared to be an useful tool to highlight SEM activity on endocrine homeostasis.
- Published
- 2010
- Full Text
- View/download PDF
29. Evidences for CYP3A4 autoactivation in the desulfuration of dimethoate by the human liver.
- Author
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Buratti FM and Testai E
- Subjects
- Acetylcholinesterase metabolism, Animals, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System biosynthesis, DNA, Complementary biosynthesis, DNA, Complementary genetics, Data Interpretation, Statistical, Enzyme Activation physiology, Enzyme Inhibitors pharmacology, Humans, Kinetics, Male, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Recombinant Proteins metabolism, Sulfur metabolism, Cytochrome P-450 Enzyme System metabolism, Dimethoate pharmacokinetics, Insecticides pharmacokinetics, Liver enzymology, Liver metabolism
- Abstract
Dimethoate (DIM) is an organophosphorothionate (OPT) pesticide used worldwide as a systemic insecticide and acaricide. It is characterized by low-to-moderate acute mammalian toxicity; similarly to the other OPT pesticides, its mode of action is mediated by the inhibition of acetylcholinesterase (AChE), exerted by its toxic metabolite dimethoate-oxon or omethoate (OME), which is also used as a direct acting pesticide. Human hepatic DIM bioactivation to the toxic metabolite OME has been characterized by using c-DNA expressed human CYPs and human liver microsomes (HLM) also in the presence of CYP-specific chemical inhibitors, with a method based on AChE inhibition. The obtained kinetic parameters and AChE IC(50) have been compared with those previously obtained with other OPTs, indicating a lower efficiency in DIM desulfuration reaction and a lower potency in inhibiting AChE. Results showed that, similarly to the other OPTs tested so far, at low DIM concentration OME formation is mainly catalysed by CYP1A2, while the role of 3A4 is relevant at high DIM levels. Differently from the other OPTs, DIM desulfuration reaction showed an atypical kinetic profile, likely due to CYP3A4 autoactivation. The sigmoidicity degree of the activity curve increased with the level of CYP3A4 in HLM or disappeared in the presence of a CYP3A4 chemical inhibitor. This atypical kinetic behaviour can be considered one of the possible explanations for the recent findings that among patients hospitalized following OPT intoxication, DIM ingestion gave different symptoms and more severe poisoning (23.1% of fatal cases versus total) than chlorpyrifos (8% of deaths), which has a lower LD(50) value. Since DIM-poisoned patients poorly responded to pralidoxime, the possibility to use CYP3A4 inhibitors could be considered as a complementary treatment.
- Published
- 2007
- Full Text
- View/download PDF
30. Lindane may modulate the female reproductive development through the interaction with ER-beta: an in vivo-in vitro approach.
- Author
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Maranghi F, Rescia M, Macrì C, Di Consiglio E, De Angelis G, Testai E, Farini D, De Felici M, Lorenzetti S, and Mantovani A
- Subjects
- Animals, Aromatase metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Chromatography, High Pressure Liquid, Estrogen Receptor beta genetics, Female, Gene Expression Regulation, Gonadal Steroid Hormones metabolism, Humans, Liver metabolism, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Sexual Maturation drug effects, Testosterone metabolism, Estrogen Receptor beta metabolism, Hexachlorocyclohexane pharmacology, Sexual Development drug effects
- Abstract
Lindane (gamma-HCH) is a persistent environmental pollutant that may act as endocrine disrupter, affecting the nervous, immune and reproductive system, possibly through endocrine-mediated mechanisms. Since both estrogen receptors (ER-alpha and -beta) have shown to be target for endocrine disruption, we investigated the role of gamma-HCH on the development of female reproductive system. For an in vivo evaluation of gamma-HCH effects during prenatal period, pregnant CD1 mice were treated p.o. on gestational days 9-16 with 15 mg/kg bw/day of gamma-HCH and vehicle. The in vivo findings in treated F1 pups - in the absence of signs of systemic toxicity - included increase in the absolute and relative and absolute uterus weight revealed on post-natal day 22, earlier vaginal patency and reduced diameters of primary oocytes at fully sexual maturity. No effects on steroid hormone metabolism (aromatase, testosterone catabolism) were observed. Thus, gamma-HCH elicited subtle effects on female reproductive development likely mediated by ER-beta-mediated pathway(s), without a concurrent impairment of steroid hormone metabolism. Furthermore, to verify whether the endocrine interference of gamma-HCH is attributable to stimulation of ER-beta-mediated pathway(s), its effect has been evaluated in vitro on a cell line, LNCaP, expressing only functional ER-beta. In vitro treatments revealed a concentration-related effect on LNCaP cell viability and proliferation. Significantly, the contemporary addition of a pure anti-estrogen, the ER antagonist ICI 182,780, completely reversed gamma-HCH effects indicating an ER-beta-mediated action. Our findings indicate that gamma-HCH may act as endocrine disruptor during the female reproductive system development and ER-beta as a potential target for this compound and other endocrine disrupting chemicals as well.
- Published
- 2007
- Full Text
- View/download PDF
31. Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice.
- Author
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Cometa MF, Buratti FM, Fortuna S, Lorenzini P, Volpe MT, Parisi L, Testai E, and Meneguz A
- Subjects
- Acetylcholinesterase blood, Acetylcholinesterase metabolism, Administration, Oral, Animals, Brain drug effects, Brain enzymology, Chlorpyrifos administration & dosage, Chlorpyrifos analogs & derivatives, Chlorpyrifos chemistry, Chlorpyrifos metabolism, Cholinesterase Inhibitors administration & dosage, Cholinesterase Inhibitors chemistry, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Glutathione metabolism, Hydroxylation drug effects, Liver metabolism, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver enzymology, Microsomes, Liver metabolism, Molecular Structure, Pyridones metabolism, Testosterone metabolism, Weight Loss drug effects, Chlorpyrifos toxicity, Cholinesterase Inhibitors toxicity, Liver drug effects
- Abstract
Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects.
- Published
- 2007
- Full Text
- View/download PDF
32. Foetal and adult human CYP3A isoforms in the bioactivation of organophosphorothionate insecticides.
- Author
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Buratti FM, Leoni C, and Testai E
- Subjects
- Animals, Biotransformation, Cytochrome P-450 Enzyme System physiology, Rats, Rats, Sprague-Dawley, Cytochrome P-450 CYP3A physiology, Fetus enzymology, Insecticides pharmacokinetics, Isoenzymes physiology, Organothiophosphorus Compounds pharmacokinetics
- Abstract
In humans organophosphorothionate pesticides (OPT) prenatal exposure has been demonstrated. Since OPT-induced neurodevelopmental effects may be due to in situ bioactivation by foetal enzymes, the catalytic activity of the foetal CYP3A7 toward chlorpyrifos (CPF), parathion (PAR), malathion (MAL) and fenthion (FEN) has been assessed by using recombinant enzymes. A comparison with the adult isoforms CYP3A4 and CYP3A5 has been also carried out. CYP3A7 was able to produce significant levels of oxon or sulfoxide from the four OPTs in the range of tested concentrations (0.05-200 microM). When the efficiencies of CYP3A isoforms were compared, the ranking, expressed as CLi values, were: CPF=3A4>3A5>3A7; PAR=3A4>>3A7>>3A5; MAL=3A4>3A7>3A5; FEN (sulfoxide formation)=3A4>3A5>>3A7. The CYP3A5 efficiency appeared to be more dependent on the single insecticide than its related isozyme CYP3A4. Our results indicate that the levels of toxic metabolite formed in situ by CYP3A7 from CPF, MAL and PAR but not from FEN have the chance to inhibit acetylcholinesterase, following prenatal exposure to OPTs. However, due to the smaller weight of foetal liver, the contribution to total OPT biotransformation is relatively low. On the other hand, our results clearly indicate that at low CPF concentrations, the formation of the non-toxic metabolites is highly favoured in the foetus.
- Published
- 2006
- Full Text
- View/download PDF
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