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8 results on '"D'Angelo, Fulvio"'

1. Circulating microRNAs expression profile in newly diagnosed and imatinib treated chronic phase - chronic myeloid leukemia.

Author

Ferreira LAM, Capannacci J, Hokama NK, Nogueira CR, Ceccarelli M, Cerulo L, D'Angelo F, and de Oliveira Montandon Hokama P

Subjects
Computational Biology methods, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Humans, Imatinib Mesylate administration & dosage, Imatinib Mesylate adverse effects, Leukemia, Myeloid, Chronic-Phase blood, Leukemia, Myeloid, Chronic-Phase diagnosis, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors adverse effects, Biomarkers, Tumor, Circulating MicroRNA, Imatinib Mesylate therapeutic use, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics, Protein Kinase Inhibitors therapeutic use, Transcriptome
Abstract

Chronic myeloid leukemia (CML) is a stem cell derived malignant disorder result of translocation t(9;22)(q34;q11) called Philadelphia chromosome (Ph + ). microRNAS (miRNAs) are involved in several biological processes, altering the progression of various pathologies, including CML. This study evaluated whether circulating miRNAs display differential expression profiles in peripheral blood of CML-Chronic Phase (CML-CP) patients newly diagnosed in comparison with CML-CP treated with imatinib. We obtained peripheral blood samples from CML-CP Ph + patients divided among group 1 (untreated newly diagnosed) and group 2 (treated with imatinib). A pool of total leukocytes from healthy donors was considered as control group. Expression analyses were performed for 768 miRNAs by RT-qPCR array. Bioinformatic tools were used to identify significant pathways and interaction networks. We found 80 deregulated miRNAs between the groups and, according to bioinformatic analysis, they are involved in different pathways, including molecular mechanisms of cancer. The study allows better understanding of disease molecular behavior, and it is useful for possible monitoring CML treatment and prognostic biomarkers identification.

Published
2019
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2. Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo.

Author

Porreca I, D'Angelo F, De Franceschi L, Mattè A, Ceccarelli M, Iolascon A, Zamò A, Russo F, Ravo M, Tarallo R, Scarfò M, Weisz A, De Felice M, Mallardo M, and Ambrosino C

Subjects
Animals, Cells, Cultured, Chlorpyrifos toxicity, Ethylenethiourea toxicity, Female, Gene Expression Profiling, Hematopoiesis drug effects, Humans, Male, Mice, Rats, Thyroid Gland cytology, Thyroid Gland drug effects, Thyroid Gland metabolism, Toxicity Tests methods, Pesticides toxicity, Transcriptome drug effects
Abstract

In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

Published
2016
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3. "Stockpile" of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells.

Author

Porreca I, Ulloa Severino L, D'Angelo F, Cuomo D, Ceccarelli M, Altucci L, Amendola E, Nebbioso A, Mallardo M, De Felice M, and Ambrosino C

Subjects
Benzhydryl Compounds administration & dosage, Cell Line, DNA Damage, DNA Replication genetics, Dose-Response Relationship, Drug, Gene Expression drug effects, Humans, Phenols administration & dosage, Thyroid Gland metabolism, Time Factors, Benzhydryl Compounds toxicity, Phenols toxicity, Thyroid Gland drug effects, Transcriptome
Abstract

Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity.

Published
2016
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4. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Author

Ceccarelli, Michele, Barthel, Floris P, Malta, Tathiane M, Sabedot, Thais S, Salama, Sofie R, Murray, Bradley A, Morozova, Olena, Newton, Yulia, Radenbaugh, Amie, Pagnotta, Stefano M, Anjum, Samreen, Wang, Jiguang, Manyam, Ganiraju, Zoppoli, Pietro, Ling, Shiyun, Rao, Arjun A, Grifford, Mia, Cherniack, Andrew D, Zhang, Hailei, Poisson, Laila, Carlotti, Carlos Gilberto, da Cunha Tirapelli, Daniela Pretti, Rao, Arvind, Mikkelsen, Tom, Lau, Ching C, Yung, WK Alfred, Rabadan, Raul, Huse, Jason, Brat, Daniel J, Lehman, Norman L, Barnholtz-Sloan, Jill S, Zheng, Siyuan, Hess, Kenneth, Rao, Ganesh, Meyerson, Matthew, Beroukhim, Rameen, Cooper, Lee, Akbani, Rehan, Wrensch, Margaret, Haussler, David, Aldape, Kenneth D, Laird, Peter W, Gutmann, David H, Network, TCGA Research, Arachchi, Harindra, Auman, J Todd, Balasundaram, Miruna, Balu, Saianand, Barnett, Gene, Baylin, Stephen, Bell, Sue, Benz, Christopher, Bir, Natalie, Black, Keith L, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S, Bowen, Jay, Bristow, Christopher A, Butterfield, Yaron SN, Chen, Qing-Rong, Chin, Lynda, Cho, Juok, Chuah, Eric, Chudamani, Sudha, Coetzee, Simon G, Cohen, Mark L, Colman, Howard, Couce, Marta, D’Angelo, Fulvio, Davidsen, Tanja, Davis, Amy, Demchok, John A, Devine, Karen, Ding, Li, Duell, Rebecca, Elder, J Bradley, Eschbacher, Jennifer M, Fehrenbach, Ashley, Ferguson, Martin, Frazer, Scott, Fuller, Gregory, Fulop, Jordonna, Gabriel, Stacey B, Garofano, Luciano, Gastier-Foster, Julie M, Gehlenborg, Nils, Gerken, Mark, Getz, Gad, Giannini, Caterina, Gibson, William J, Hadjipanayis, Angela, Hayes, D Neil, Heiman, David I, Hermes, Beth, Hilty, Joe, Hoadley, Katherine A, Hoyle, Alan P, and Huang, Mei

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Orphan Drug, Brain Cancer, Brain Disorders, Biotechnology, Human Genome, Rare Diseases, Neurosciences, Cancer, Adult, Brain Neoplasms, Cell Proliferation, Cluster Analysis, DNA Helicases, DNA Methylation, Epigenesis, Genetic, Glioma, Humans, Isocitrate Dehydrogenase, Middle Aged, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Signal Transduction, Telomerase, Telomere, Transcriptome, X-linked Nuclear Protein, TCGA Research Network, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Published
2016

5. Transcriptional landscape of mouse-aged ovaries reveals a unique set of non-coding RNAs associated with physiological and environmental ovarian dysfunctions

Author

Annacristina Petriella, Fulvio D'Angelo, Maria N. D’Agostino, Danila Cuomo, David W. Threadgill, Massimo Mallardo, William T. Barrington, Immacolata Porreca, Michele Ceccarelli, Gilda Cobellis, Francesca De Stefano, Mario De Felice, Concetta Ambrosino, Cuomo, Danila, Porreca, Immacolata, Ceccarelli, Michele, Threadgill, David W, Barrington, William T, Petriella, Annacristina, D'Angelo, Fulvio, Cobellis, Gilda, De Stefano, Francesca, D'Agostino, Maria N, De Felice, Mario, Mallardo, Massimo, and Ambrosino, Concetta

Subjects
0301 basic medicine, Senescence, Cancer Research, Transcriptional landscape, RNAs, ovarian dysfunctions, Immunology, Ovary, Biology, Bioinformatics, lcsh:RC254-282, Article, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Follicular phase, microRNA, medicine, lcsh:QH573-671, Ovarian reserve, 030219 obstetrics & reproductive medicine, lcsh:Cytology, Cell Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Follicular fluid, 030104 developmental biology, medicine.anatomical_structure, GAS5
Abstract

The progressive and physiological decline in ovarian function depends on the rate of follicular loss by atresia, contributing to the reduction in ovarian reserve. Genetics and environmental factors play important roles in ovarian senescence and in the onset of ovarian dysfunctions such as diminished ovarian reserve. A better understanding of the mechanisms underlying ovarian aging and their regulation by genetic and environmental factors is needed to evaluate ovarian reserve and to predict fertility potential by identification of more accurate and less invasive markers. We report transcriptomic data (i) implicating novel (e.g. EIF2 signalling) and well-known pathways (e.g. TGFβ signalling), and (ii) defining a unique set of non-coding RNA (ncRNA), both associated with ovarian function. The latter includes miRNAs (e.g. Mir143 and Mir145), snoRNAs (e.g. Snord16a and Snora34), and one lncRNA (Gas5), which are differentially expressed in middle-aged ovaries (12 months) vs young-aged (3 months) from CD1 mice. Experimental analysis confirms that ovary lifespan varies across genetic backgrounds in mice and, genetics influences the response to environmental perturbations such as diet. Moreover, the identified ncRNAs were verified in a model of reproductive dysfunction promoted by the environmental toxicant ethylenthiourea. We also report the increase of miRNA143 and miRNA145 in follicular fluid of women with diminished ovarian reserve. Their levels inversely correlate with the hormonal profile and with the number of the oocytes recruited upon hormonal stimulation. Overall, we report a transcriptomic signature for ovarian dysfunction in vivo that provides a valuable resource for translational research in human reproductive aging.

Published
2018

6. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

Dominique Vidaud, Mariona Suñol, Tala, Francesco DiMeco, John de Groot, Gaetano Finocchiaro, Fulvio D'Angelo, Luc Bauchet, Marica Eoli, Véronique Lorgis, David Meyronet, Kristin Alfaro, Luciano Garofano, John M. Slopis, Laurent Capelle, Pascale Varlet, Giulia Berzero, Mario Cangiano, Veronica Saletti, Romuald Seizeur, Jing Zhang, Carlo Efisio Marras, Veronique Frattini, Walid Farah, Cinzia Lavarino, David Cachia, Genevieve Lewis, Michele Ceccarelli, Seung-Ki Kim, David E. Reuss, Hugues Loiseau, Carlos Kamiya-Matsuoka, Do-Hyun Nam, Krishna P. Bhat, Stéphane Goutagny, Karima Mokhtari, François Ducray, Anna Lasorella, Colin Watts, Francesca Pia Caruso, Hector Salvador, Antonio Iavarone, F. Vandenbos, Ian E. McCutcheon, Susanna Ronchi, Viviane Tabar, Marc Sanson, D'Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Veronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, Dimeco, Francesco, Ducray, Francoi, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stephane, Kamiya-Matsuoka, Carlo, Lavarino, Cinzia, Loiseau, Hugue, Lorgis, Veronique, Marras, Carlo E., Mccutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Sunol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, Iavarone, Antonio, D'Angelo, F., Ceccarelli, M., Garofano, L., Zhang, J., Frattini, V., Caruso, F. P., Lewis, G., Alfaro, K. D., Bauchet, L., Berzero, G., Cachia, D., Cangiano, M., Capelle, L., de Groot, J., Dimeco, F., Ducray, F., Farah, W., Finocchiaro, G., Goutagny, S., Kamiya-Matsuoka, C., Lavarino, C., Loiseau, H., Lorgis, V., Marras, C. E., Mccutcheon, I., Nam, D. -H., Ronchi, S., Saletti, V., Seizeur, R., Slopis, J., Sunol, M., Vandenbos, F., Varlet, P., Vidaud, D., Watts, C., Tabar, V., Reuss, D. E., Kim, S. -K., Meyronet, D., Mokhtari, K., Salvador, H., Bhat, K. P., Eoli, M., Sanson, M., Lasorella, A., Iavarone, A., Columbia University Medical Center (CUMC), Columbia University [New York], University of Sannio [Benevento], The University of Texas M.D. Anderson Cancer Center [Houston], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Medical University of South Carolina [Charleston] (MUSC), Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Milan, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Sungkyunkwan University [Suwon] (SKKU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Pasteur [Nice] (CHU), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], University of Birmingham [Birmingham], Memorial Sloane Kettering Cancer Center [New York], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and CHU Cochin [AP-HP]

Subjects
0301 basic medicine, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, X-linked Nuclear Protein, Neurofibromatosis 1, Adolescent, [SDV]Life Sciences [q-bio], T-Lymphocytes, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Germline mutation, CDKN2A, Antigens, Neoplasm, Glioma, medicine, Humans, Epigenetics, Neurofibromatosis, 10. No inequality, Child, Gene, neoplasms, ATRX, Germ-Line Mutation, Cancer, Neurofibromin 1, Brain Neoplasms, Reproducibility of Results, General Medicine, DNA Methylation, Middle Aged, medicine.disease, 3. Good health, nervous system diseases, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, DNA methylation, Cancer research, Genomics, Bioinformatic, Female, Transcriptome
Abstract

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Published
2018

7. Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Author

Lucia De Franceschi, Fulvio D'Angelo, Alessandro Weisz, Concetta Ambrosino, Achille Iolascon, Immacolata Porreca, Roberta Tarallo, Michele Ceccarelli, Maria Ravo, Massimo Mallardo, Marzia Scarfò, Mario De Felice, Alessandro Matte, Filomena Russo, Alberto Zamò, Porreca, Immacolata, D'Angelo, Fulvio, De Franceschi, Lucia, Mattè, Alessandro, Ceccarelli, Michele, Iolascon, Achille, Zamò, Alberto, Russo, Filomena, Ravo, Maria, Tarallo, Roberta, Scarfò, Marzia, Weisz, Alessandro, DE FELICE, Mario, Mallardo, Massimo, and Ambrosino, Concetta

Subjects
0301 basic medicine, Male, Thyroid Gland, Ethylenethiourea, Biology, Bioinformatics, Article, Transcriptome, 03 medical and health sciences, Mice, In vivo, Toxicity Tests, Animals, Humans, Pesticides, toxicogenomics, Gene, Cells, Cultured, Multidisciplinary, Gene Expression Profiling, In vitro, Cell biology, Hematopoiesis, Rats, Pesticide, Gene expression profiling, Haematopoiesis, 030104 developmental biology, Toxicity, Female, In vitro Omics analysis (i.e. transcriptome), Chlorpyrifos, Toxicogenomics
Abstract

In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

Published
2016

8. 'Stockpile' of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells

Author

Concetta Ambrosino, Danila Cuomo, Immacolata Porreca, Massimo Mallardo, Mario De Felice, Luisa Ulloa Severino, Michele Ceccarelli, Angela Nebbioso, Elena Amendola, Lucia Altucci, Fulvio D'Angelo, Porreca, I, Ulloa Severino, L, D'Angelo, F, Cuomo, D, Ceccarelli, M, Altucci, L, Amendola, E, Nebbioso, A, Mallardo, M, De Felice, M, Ambrosino, C., Porreca, Immacolata, ULLOA SEVERINO, Luisa, D'Angelo, Fulvio, Cuomo, Danila, Ceccarelli, Michele, Altucci, Lucia, Amendola, Elena, Nebbioso, Angela, Mallardo, Massimo, De Felice, Mario, Ambrosino, Concetta, and Ulloa Severino, Luisa

Subjects
0301 basic medicine, Genetics and Molecular Biology (all), Time Factors, Light, Benzhydryl Compounds, Cell Line, DNA Damage, DNA Replication, Dose-Response Relationship, Drug, Gene Expression, Humans, Phenols, Thyroid Gland, Transcriptome, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Microarrays, DNA rapair, lcsh:Medicine, 010501 environmental sciences, medicine.disease_cause, 01 natural sciences, Biochemistry, Medicine and Health Sciences, lcsh:Science, Benzhydryl Compound, Thyroid, Multidisciplinary, Physics, Genomics, Cell biology, Nucleic acids, Chemistry, Bioassays and Physiological Analysis, Toxicity, Physical Sciences, DNA microarray, Drug, Anatomy, Transcriptome Analysis, hormones, hormone substitutes, and hormone antagonists, Human, Research Article, Ultraviolet radiation, Programmed cell death, endocrine system, Pollutants, Time Factor, DNA repair, DNA damage, DNA recombination, Endocrine System, Biology, Research and Analysis Methods, Dose-Response Relationship, 03 medical and health sciences, Electromagnetic radiation, medicine, Genetics, Environmental Chemistry, 0105 earth and related environmental sciences, Phenol, Biology and life sciences, urogenital system, lcsh:R, Ecology and Environmental Sciences, Computational Biology, DNA Repair Pathway, DNA, Genome Analysis, Molecular biology, 030104 developmental biology, lcsh:Q, Ultraviolet C, Genotoxicity
Abstract

Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity.

Published
2016

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