Study design for uterotrophic and Hershberger assays.
\\n\\n
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"10321",leadTitle:null,fullTitle:"Advances in Precision Medicine Oncology",title:"Advances in Precision Medicine Oncology",subtitle:null,reviewType:"peer-reviewed",abstract:"Recent advances in precision medicine and immuno-oncology have led to highly specific and efficacious cancer therapies such as monoclonal antibodies and immune checkpoint inhibitors (ICIs). This book provides an up-to-date overview of advances in the field of immuno-oncology. Chapters cover such topics as ICIs and how they mount a robust immune response against cancer cells as well as the response of ICIs to treatment predictive biomarkers and their potential immune-related adverse events (irAEs). Additionally, the book includes a comprehensive review of the powerful FDA-approved therapeutic agent doxorubicin, highlighting the molecular mechanisms behind doxorubicin’s drug resistance and critical side effects.",isbn:"978-1-83968-868-3",printIsbn:"978-1-83968-867-6",pdfIsbn:"978-1-83968-869-0",doi:"10.5772/intechopen.91507",price:119,priceEur:129,priceUsd:155,slug:"advances-in-precision-medicine-oncology",numberOfPages:260,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"043ad1c1a6bbdcd5604917ccbff003d8",bookSignature:"Hilal Arnouk and Bassam Abdul Rasool Hassan",publishedDate:"July 21st 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10321.jpg",numberOfDownloads:4016,numberOfWosCitations:0,numberOfCrossrefCitations:2,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:3,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:5,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 24th 2020",dateEndSecondStepPublish:"October 22nd 2020",dateEndThirdStepPublish:"December 21st 2020",dateEndFourthStepPublish:"March 11th 2021",dateEndFifthStepPublish:"May 10th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"76431",title:"Dr.",name:"Hilal",middleName:null,surname:"Arnouk",slug:"hilal-arnouk",fullName:"Hilal Arnouk",profilePictureURL:"https://mts.intechopen.com/storage/users/76431/images/system/76431.jpg",biography:"Hilal Arnouk, MD, Ph.D., is an Associate Professor at the Department of Pathology, Midwestern University, Downers Grove, Illinois. Dr. Arnouk received his education and post-doctorate training at Roswell Park Cancer Institute, the State University of New York at Buffalo, the Medical College of Georgia, and the University of Alabama at Birmingham. He has directed research studies in academia and biotech industry settings. His major areas of expertise include cancer immunotherapy, biomarker discovery, and precision medicine. Additionally, Dr. Arnouk tremendously enjoys being an educator and a mentor for professional students in the medical and biomedical sciences.",institutionString:"Midwestern University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Midwestern University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"155124",title:"Dr.",name:"Bassam",middleName:"Abdul Rasool",surname:"Hassan",slug:"bassam-hassan",fullName:"Bassam Hassan",profilePictureURL:"https://mts.intechopen.com/storage/users/155124/images/system/155124.png",biography:"Bassam Abdul Rasool Hassan obtained a Ph.D. in Clinical Pharmacy from the School of Pharmacy, Universiti Sains Malaysia (USM). He worked as a senior lecturer at the Department of Pharmacy, Faculty of Medicine, Universiti Malaya (UM), in 2014–2017, and at the Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Shah Alam, Malaysia, in 2017–2019. Dr. Hassan currently works as a senior lecturer at the Department of Pharmacy, Al-Rafidain University College, Baghdad, Iraq.",institutionString:"Al-Rafidain University College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1083",title:"Medical Oncology",slug:"medical-oncology"}],chapters:[{id:"76212",title:"Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy",doi:"10.5772/intechopen.96664",slug:"immune-and-cell-cycle-checkpoint-inhibitors-for-cancer-immunotherapy",totalDownloads:287,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The rational design of immunotherapeutic agents has advanced with a fundamental understanding that both innate and adaptive immunity play important roles in cancer surveillance and tumor destruction; given that oncogenesis occurs and cancer progresses through the growth of tumor cells with low immunogenicity in an increasingly immunosuppressive tumor microenvironment. Checkpoint inhibitors in the form of monoclonal antibodies that block cancer’s ability to deactivate and evade the immune system have been widely indicated for a variety of tumor types. Through targeting the biological mechanisms and pathways that cancer cells use to interact with and suppress the immune system, immunotherapeutic agents have achieved success in inhibiting tumor growth while eliciting lesser toxicities, compared to treatments with standard chemotherapy. Development of “precise” bio-active tumor-targeted gene vectors, biotechnologies, and reagents has also advanced. This chapter presents ongoing clinical research involving immune checkpoint inhibitors, while addressing the clinical potential for tumor-targeted gene blockade in combination with tumor-targeted cytokine delivery, in patients with advanced metastatic disease, providing strategic clinical approaches to precision cancer immunotherapy.",signatures:"Erlinda M. Gordon, Nicole L. Angel, Ted T. Kim, Don A. Brigham, Sant P. Chawla and Frederick L. Hall",downloadPdfUrl:"/chapter/pdf-download/76212",previewPdfUrl:"/chapter/pdf-preview/76212",authors:[{id:"333221",title:"Dr.",name:"Erlinda M.",surname:"Gordon",slug:"erlinda-m.-gordon",fullName:"Erlinda M. Gordon"},{id:"337003",title:"Dr.",name:"Sant",surname:"Chawla",slug:"sant-chawla",fullName:"Sant Chawla"},{id:"337004",title:"Dr.",name:"Frederick",surname:"Hall",slug:"frederick-hall",fullName:"Frederick Hall"},{id:"346195",title:"Ms.",name:"Nicole",surname:"Angel",slug:"nicole-angel",fullName:"Nicole Angel"},{id:"346196",title:"Mr.",name:"Ted",surname:"Kim",slug:"ted-kim",fullName:"Ted Kim"},{id:"346197",title:"Dr.",name:"Don",surname:"Brigham",slug:"don-brigham",fullName:"Don Brigham"}],corrections:null},{id:"75496",title:"Evolving Dynamic Biomarkers for Prediction of Immune Responses to Checkpoint Inhibitors in Cancer",doi:"10.5772/intechopen.96494",slug:"evolving-dynamic-biomarkers-for-prediction-of-immune-responses-to-checkpoint-inhibitors-in-cancer",totalDownloads:273,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Immune checkpoint inhibitors (ICIs) have been approved as first or second line therapy in a large group of cancers. However, the observation of potentially long-lasting responses was restricted to limited subset of patients. Efforts have been made to identify predictive factors of response to ICIs in order to select eligible patients and to avoid exposing non-responding patients to treatment side effects. Although several biomarkers have been identified, their predictive potential remains unsatisfactory. One promising emerging approach is to focus on dynamic biomarkers to directly characterize the response and, more importantly, to identify those patients presenting an immune response failure. Several studies have shown a strong correlation between specific circulating immune cell subsets and tumor immune infiltrates. Moreover, liquid biomarkers including soluble immune checkpoint molecules have potential in predicting the modulation of the immune response under immune checkpoint blockade. In this chapter, we will discuss current advances in the study of circulatory and intra-tumoral dynamic biomarkers as predictors of responses to ICIs therapy in cancer.",signatures:"Afsheen Raza, Maysaloun Merhi, Allan Relecom, Queenie Fernandes, Varghese Inchakalody, Abdul Rahman Zar Gul, Shahab Uddin, Mohammed Ussama Al Homsi and Said Dermime",downloadPdfUrl:"/chapter/pdf-download/75496",previewPdfUrl:"/chapter/pdf-preview/75496",authors:[{id:"336904",title:"Dr.",name:"Said",surname:"Dermime",slug:"said-dermime",fullName:"Said Dermime"},{id:"339275",title:"Dr.",name:"Maysaloun",surname:"Merhi",slug:"maysaloun-merhi",fullName:"Maysaloun Merhi"},{id:"339295",title:"MSc.",name:"Queenie",surname:"Fernandes",slug:"queenie-fernandes",fullName:"Queenie Fernandes"},{id:"339296",title:"Dr.",name:"Afsheen",surname:"Raza",slug:"afsheen-raza",fullName:"Afsheen Raza"},{id:"339297",title:"Dr.",name:"Varghese",surname:"Inchakalody",slug:"varghese-inchakalody",fullName:"Varghese Inchakalody"},{id:"339298",title:"Dr.",name:"Shahab",surname:"Uddin",slug:"shahab-uddin",fullName:"Shahab Uddin"},{id:"344921",title:"Dr.",name:"Allan",surname:"Relecom",slug:"allan-relecom",fullName:"Allan Relecom"},{id:"344923",title:"Dr.",name:"Abdul Rahman",surname:"Gul",slug:"abdul-rahman-gul",fullName:"Abdul Rahman Gul"},{id:"344924",title:"Dr.",name:"Mohammed",surname:"Al Homsi",slug:"mohammed-al-homsi",fullName:"Mohammed Al Homsi"}],corrections:null},{id:"75485",title:"The Endocrinological Side Effects of Immunotherapies",doi:"10.5772/intechopen.96491",slug:"the-endocrinological-side-effects-of-immunotherapies",totalDownloads:201,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The use of immunotherapies is gaining importance in the treatment of advanced malignancies. There are many checkpoints in the immune system which prevents T-cells from attacking one’s own body cells. The cancer cells can camouflage from the T-cells and the immune system is unable to mount an effective anti-tumor response. The immunotherapies, mainly monoclonal antibodies anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) and anti-PD-1 ligand molecules (PD-L1 and L2) reactivate the immune system to act against cancerous cells but they can also cause T-cells to attack healthy cells causing various autoimmune diseases, which are known as immune related adverse events (irAEs). Current clinical data shows increased incidence of pituitary disorders with CTLA4 inhibitors and thyroid dysfunction in patients with PD-1/PD L-1 1 blockade. There have also been association of type 1 diabetes mellitus and primary adrenal insufficiency in patients with immune check point inhibitors. In this chapter we will discuss the incidence, characteristic findings, diagnosis and management of various endocrinological side effects due to targeted immunotherapies used in various malignancies.",signatures:"Anush Patel, Haisam Abid and Amrat Kumar",downloadPdfUrl:"/chapter/pdf-download/75485",previewPdfUrl:"/chapter/pdf-preview/75485",authors:[{id:"58496",title:"Dr.",name:"Anush",surname:"Patel",slug:"anush-patel",fullName:"Anush Patel"},{id:"336269",title:"Dr.",name:"Haisam",surname:"Abid",slug:"haisam-abid",fullName:"Haisam Abid"},{id:"336271",title:"Dr.",name:"Amrat",surname:"Kumar",slug:"amrat-kumar",fullName:"Amrat Kumar"}],corrections:null},{id:"75020",title:"Immunotherapy in Malignant Pleural Mesothelioma",doi:"10.5772/intechopen.95823",slug:"immunotherapy-in-malignant-pleural-mesothelioma",totalDownloads:277,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malignant pleural mesothelioma (MPM) is an extremely aggressive plural malignancy mainly caused by asbestos exposure. Basic research about the immune suppressive tumor microenvironment in MPM has suggested that MPM might be a good candidate for immune therapy. Immunocheckpoint inhibitors have shown some promising results. A phase Ib trial with pembrolizumab, an antibody specific for the programmed cell death 1 protein (anti-PD-1), showed efficacy in patients with programmed death-ligand 1 (PD-L1)-positive MPM. Among 25 patients tested, 5 patients (20%) achieved a partial response. A Japanese group evaluated the efficacy and safety of nivolumab, an anti-PD-L1 antibody, for patients with advanced MPM in a phase II study. Ten (29%) patients showed an objective response. Based on those results, nivolumab was approved in Japan for unresectable recurrent MPM. A phase III randomized study was conducted to compare nivolumab plus ipilimumab to platinum doublet chemotherapy as a first-line therapy in unresectable MPM. The primary endpoint, overall survival (OS), was significantly improved in the nivolumab plus ipilimumab group. Cellular therapies and cancer vaccines are limited by many challenges; therefore, improvements to overcome these difficulties are urgently warranted. Further research is needed, including large-scale clinical trials, to clarify the utility and safety of immunotherapy in MPM.",signatures:"Asako Matsuda and Nobukazu Fujimoto",downloadPdfUrl:"/chapter/pdf-download/75020",previewPdfUrl:"/chapter/pdf-preview/75020",authors:[{id:"307730",title:"Dr.",name:"Nobukazu",surname:"Fujimoto",slug:"nobukazu-fujimoto",fullName:"Nobukazu Fujimoto"},{id:"337549",title:"Dr.",name:"Asako",surname:"Matsuda",slug:"asako-matsuda",fullName:"Asako Matsuda"}],corrections:null},{id:"75475",title:"Targeted Cancer Therapy Using Nanoparticles and Antibody Fragments",doi:"10.5772/intechopen.96550",slug:"targeted-cancer-therapy-using-nanoparticles-and-antibody-fragments",totalDownloads:353,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Cancer is caused by an uncontrolled cell division, forming a tumor capable of metastasis. Cancer is the second leading cause of death worldwide. Conventional treatments kill healthy cells, causing side effects. Recently, nanomaterials are explored due to properties such as as- nano-size, high loading, and ligands’ attachment for a selective delivery. Apart from normal body cells, cancer cells express many receptors in excess, which serve as ‘targets’ for attacking the cells. Various ligands like proteins, peptides, polysaccharides can be attached to nanoparticles to allow proper and specific reach to the tumor. Such nanoparticles go to their desired site and stick onto the receptors, taken inside the cells by various methods. Antibodies are natural proteins that bind to foreign substances and remove them. IgG being the most explored antibody, suffers from many disadvantages such as non-specificity for required antigen, limited binding sites, low tumor penetration. Hence many researchers experimented by removing and adjusting the binding sites, using only the binding sites, enhancing the valency of naturally available IgG. It gave many benefits such as enhanced penetration, reduced immunogenicity, better delivery of drugs with fewer side effects. Continuing advancements in the field of protein engineering will help scientists to come up with better solutions. The properties allow easy surface interaction and entry, achieve better biodistribution, and reduce the amount of drug required. Targeting is based on Paul Ehrlich’s ‘magic bullet, ‘where the therapeutic moiety has two parts-one to identify the target and the second to eliminate it. This concept is revised to incorporate a third component, a carrier. Many nanocarriers can be used to target cancer cells containing ligands to identify malignant cells. Approaches to targeting are passive, active and physical targeting. Many such nanoparticles are in clinical trials and can be a better solution to cancer therapy.",signatures:"Sankha Bhattacharya and Kapil Gore",downloadPdfUrl:"/chapter/pdf-download/75475",previewPdfUrl:"/chapter/pdf-preview/75475",authors:[{id:"250076",title:"Dr.",name:"Sankha",surname:"Bhattacharya",slug:"sankha-bhattacharya",fullName:"Sankha Bhattacharya"},{id:"344172",title:"Mr.",name:"Kapil",surname:"Gore",slug:"kapil-gore",fullName:"Kapil Gore"}],corrections:null},{id:"75838",title:"Antibody Therapy Targeting Cancer-Specific Cell Surface Antigen AGR2",doi:"10.5772/intechopen.96492",slug:"antibody-therapy-targeting-cancer-specific-cell-surface-antigen-agr2",totalDownloads:282,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"For anterior gradient 2 (AGR2), normal cells express the intracellular form iAGR2 localized to the endoplasmic reticulum while cancer cells express the extracellular form eAGR2 localized on the cell surface and secreted. Antibodies targeting eAGR2+ cancer cells for eradication will spare normal cells. Two AGR2 monoclonal antibodies, P1G4 and P3A5, were shown to recognize specifically eAGR2+ pancreatic tumors implanted in mice. In addition, P1G4 showed enhancement in drug inhibition of tumor growth. Human:mouse chimeric antibodies of IgG1, IgG2, IgG4 were generated for both antibodies. These human IgG were shown to lyse eAGR2+ prostate cancer cells in vitro with human serum. AGR2 has an important function in distal spread of cancer cells, and is highly expressed in prostate, pancreatic, bladder metastases. Therefore, immunotherapy based on AGR2 antibody-mediated ADCC and CDC is highly promising. Cancer specificity of eAGR2 predicts possibly minimal collateral damage to healthy tissues and organs. Moreover, AGR2 therapy, once fully developed and approved, can be used to treat other solid tumors since AGR2 is an adenocarcinoma antigen found in many common malignancies.",signatures:"Alvin Y. Liu, Tatjana Crnogorac-Jurcevic, James J. Lai and Hung-Ming Lam",downloadPdfUrl:"/chapter/pdf-download/75838",previewPdfUrl:"/chapter/pdf-preview/75838",authors:[{id:"337480",title:"Associate Prof.",name:"Alvin Y.",surname:"Liu",slug:"alvin-y.-liu",fullName:"Alvin Y. Liu"},{id:"345022",title:"Dr.",name:"Tatjana",surname:"Crnogorac-Jurcevic",slug:"tatjana-crnogorac-jurcevic",fullName:"Tatjana Crnogorac-Jurcevic"},{id:"345023",title:"Dr.",name:"James J.",surname:"Lai",slug:"james-j.-lai",fullName:"James J. Lai"},{id:"345024",title:"Dr.",name:"Hung-Ming",surname:"Lam",slug:"hung-ming-lam",fullName:"Hung-Ming Lam"}],corrections:null},{id:"74972",title:"Advances in Adoptive Cellular Therapy (ACT)",doi:"10.5772/intechopen.95854",slug:"advances-in-adoptive-cellular-therapy-act-",totalDownloads:198,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Adoptive T cell therapy (ACT) is getting acknowledged as the Advanced Therapy Medicinal Products (ATMPs) in many countries and it has evolved as one of the newest regimens to treat cancer. Developed gradually by the basic understanding of cells, involved in innate and adaptive immunity, ACT has emerged as one of the successful immunotherapies in recent times. It broadly includes various cell types such as stem cells, T cells, dendritic cells and Natural Killer cells. By the applications of genetic engineering and advanced cell culture techniques, these cells from patients’ blood, can be manipulated to train them for better efficacy against specific tumor cells. However, only some cells’ subsets have shown promising regression for certain cancer cells types. To understand the reason behind this, technical knowledge about the tumor antigens presentation, tumor microenvironment (TME), hosts’ immune responses and possible issues in the manufacturing of adoptive cellular material for infusion in patients are being explored further. This chapter brings together development of immune cells from basic research to clinical use, newer approaches which have been taken to address the resistance of ACT and future promises of this therapy.",signatures:"Rajesh Kumar Yadav, Bandana Kumari, Pritanjali Singh, Asgar Ali, Sadhana Sharma and Krishnan Hajela",downloadPdfUrl:"/chapter/pdf-download/74972",previewPdfUrl:"/chapter/pdf-preview/74972",authors:[{id:"335174",title:"Prof.",name:"Sadhana",surname:"Sharma",slug:"sadhana-sharma",fullName:"Sadhana Sharma"},{id:"335348",title:"Dr.",name:"Rajesh Kumar",surname:"Yadav",slug:"rajesh-kumar-yadav",fullName:"Rajesh Kumar Yadav"},{id:"344952",title:"Dr.",name:"Bandana",surname:"Kumari",slug:"bandana-kumari",fullName:"Bandana Kumari"},{id:"344953",title:"Dr.",name:"Asgar",surname:"Ali",slug:"asgar-ali",fullName:"Asgar Ali"},{id:"344954",title:"Dr.",name:"Pritanjali",surname:"Singh",slug:"pritanjali-singh",fullName:"Pritanjali Singh"},{id:"420204",title:"Dr.",name:"Krishnan",surname:"Hajela",slug:"krishnan-hajela",fullName:"Krishnan Hajela"}],corrections:null},{id:"76116",title:"Mathematical Modeling and Dynamics of Oncolytic Virotherapy",doi:"10.5772/intechopen.96963",slug:"mathematical-modeling-and-dynamics-of-oncolytic-virotherapy",totalDownloads:197,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Oncolytic virotherapy is a cancer treatment that uses competent replicating viruses to destroy cancer cells. This field progressed from earlier observations of accidental viral infections causing remission in many malignancies to virus drugs targeting and killing cancer cells. In this chapter, we study some basic models of the oncolytic virotherapy and their dynamics. We show how the dynamical system’s theory can capture the behavior of the solutions of those models and provide different approaches to studying the models. We study the thresholds that enable us to classify asymptotic dynamics of the solutions. Fractional-derivative approach tells us about the memory of the derivative and related solutions of the models. We also study the affect of introducing control parameters on the cost of the therapy.",signatures:"Abdullah Abu-Rqayiq",downloadPdfUrl:"/chapter/pdf-download/76116",previewPdfUrl:"/chapter/pdf-preview/76116",authors:[{id:"315106",title:"Dr.",name:"Abdullah",surname:"Abu-Rqayiq",slug:"abdullah-abu-rqayiq",fullName:"Abdullah Abu-Rqayiq"}],corrections:null},{id:"73668",title:"Molecular-Level Understanding of the Anticancer Action Mechanism of Anthracyclines",doi:"10.5772/intechopen.94180",slug:"molecular-level-understanding-of-the-anticancer-action-mechanism-of-anthracyclines",totalDownloads:525,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Anthracyclines drugs are used as a treatment regime to combat cancer owing to their great chemotherapeutic potential. They are characterized by the presence of a wide range of derivatives, the most famous are doxorubicin and daunorubicin. The proposed action mechanism of anthracyclines and their derivatives to exert cytotoxic effect involves the intercalation of the drug molecule into nucleic acid and inhibition of the activity of topoisomerases. These events consequences in halting DNA replication and transcription mechanisms of the cell. Understanding of the structural and conformational changes associated with nucleic acid after binding with drugs provides significant knowledge for the development of more effective drugs. A comprehensive elucidation of the molecular mechanism(s) of action of anthracyclines drugs plays a significant role in the rational drug designing to obtain an effective, selective, and safe anti-cancer drugs.",signatures:"Manish Shandilya, Shrutika Sharma, Prabhu Prasad Das and Sonika Charak",downloadPdfUrl:"/chapter/pdf-download/73668",previewPdfUrl:"/chapter/pdf-preview/73668",authors:[{id:"325803",title:"Dr.",name:"Sonika",surname:"Charak",slug:"sonika-charak",fullName:"Sonika Charak"},{id:"326284",title:"Dr.",name:"Manish",surname:"Shandilya",slug:"manish-shandilya",fullName:"Manish Shandilya"},{id:"326287",title:"Ms.",name:"Shrutika",surname:"Sharma",slug:"shrutika-sharma",fullName:"Shrutika Sharma"},{id:"330638",title:"Dr.",name:"Prabhu Prasad",surname:"Das",slug:"prabhu-prasad-das",fullName:"Prabhu Prasad Das"}],corrections:null},{id:"74276",title:"Overview on the Side Effects of Doxorubicin",doi:"10.5772/intechopen.94896",slug:"overview-on-the-side-effects-of-doxorubicin",totalDownloads:499,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,abstract:"Doxorubicin is an anthracycline antibiotic extracted from the bacterium Streptomyces peucetius. Its cytotoxic effect produced by intercalating with DNA causing breakdown of DNA strand which causes cancer cell apoptosis. Despite being an effective anticancer agent it causes several crucial side effects like carditoxicity, neuropathy, hepatotoxicity, nephrotoxicity, alopecia, typhlitis, myelosuppression, neutropenia, anaemia, thrombocytopenia, nausea, and diarrhoea were caused mainly due to the inability to distinguish between cancer cells and normal cells. This chapter mainly focuses on doxorubicin’s side effects, current understanding of the molecular mechanisms, and management and preventive strategies of doxorubicin’s cardiotoxicity during the treatment of various type of cancer.",signatures:"Chittipolu Ajaykumar",downloadPdfUrl:"/chapter/pdf-download/74276",previewPdfUrl:"/chapter/pdf-preview/74276",authors:[{id:"327203",title:"Assistant Prof.",name:"Chittipolu",surname:"Ajaykumar",slug:"chittipolu-ajaykumar",fullName:"Chittipolu Ajaykumar"}],corrections:null},{id:"74811",title:"Overcoming P-Glycoprotein-Mediated Doxorubicin Resistance",doi:"10.5772/intechopen.95553",slug:"overcoming-p-glycoprotein-mediated-doxorubicin-resistance",totalDownloads:468,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Intracellular concentration of doxorubicin in target cancer cells is a major determinant of therapeutic success of doxorubicin-based regimens. As known, doxorubicin is a substrate of P-glycoprotein (P-gp), the drug efflux transporter in the ABC superfamily. High expression level of P-gp in cancer cells can prevent intracellular accumulation of doxorubicin up to its effective level, leading to doxorubicin resistance and treatment failure. Moreover, these P-gp-overexpressed cells display multi-drug resistance (MDR) phenotype. Regarding this, application of P-gp modulators (suppressor of P-gp activity and expression) is likely to reverse MDR and restore cell sensitivity to doxorubicin treatment. In searching for potential chemo-sensitizer against resistant cancer, a number of phytochemicals or dietary compounds have been studied extensively for their P-gp modulating effects. Furthermore, combination between doxorubicin and P-gp modulators (e.g., plant-derived compounds, siRNA) given through specific target delivery platforms have been an effective strategic approach for MDR reversal and restore doxorubicin effectiveness for cancer treatment.",signatures:"Suree Jianmongkol",downloadPdfUrl:"/chapter/pdf-download/74811",previewPdfUrl:"/chapter/pdf-preview/74811",authors:[{id:"317928",title:"Associate Prof.",name:"Suree",surname:"Jianmongkol",slug:"suree-jianmongkol",fullName:"Suree Jianmongkol"}],corrections:null},{id:"76820",title:"Improving the Antitumor Effect of Doxorubicin in the Treatment of Eyeball and Orbital Tumors",doi:"10.5772/intechopen.95080",slug:"improving-the-antitumor-effect-of-doxorubicin-in-the-treatment-of-eyeball-and-orbital-tumors",totalDownloads:238,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malignant tumors of the orbit are the main cause for 41–45.9% of orbital tumor, and they will threaten both the organ of vision and the life of the patient. In our opinion, improving the effectiveness of treatment of malignant tumors can be implemented in the following areas: a) immobilization of doxorubicin in synthetic polymeric materials, which will fill the tissue structures that were resected and reduce the percentage of tumor recurrence. b) the use of nanomaterials for the delivery of doxorubicin to tumor cells. To develop a hydrogel implant and nanoparticles, to study the diffusion kinetics of doxorubicin in a hydrogel implant and the ability of nanoparticles to transport doxorubicin. The developed gels based on acrylic acid (AAc) were obtained by radical polymerization of an aqueous solution of monomers (AAc and N, N-methylenebisacrylamide (MBA)) at a temperature of 70°C. Matrices based on polyvinyl formal (PVF) were obtained by treatment of polyvinyl alcohol (PVA) with formaldehyde in the presence of a strong acid. Experimental studies were performed on rabbits of the Chinchilla breed, weighing 2–3 kg, aged 5–6 months, which during the study were in the same conditions. We implanted the hybrid gel in the scleral sac; orbital tissue and in the ear tissue of rabbits: Evaluation of the response of soft tissues and bone structures to implant materials was carried out on the basis of analysis of changes in clinical and pathomorphological parameters was performed after 10, 30 and 60 days. Diffusion of doxorubicin was examined by using UV spectroscopy [spectrophotometer-fluorimeter DS-11 FX + (DeNovix, USA)], analyzing samples at regular intervals during the day at a temperature of 25° C. The concentration of active substances was determined by the normalized peak absorption of doxorubicin at 480 nm. The release kinetics of the antitumor drug doxorubicin were investigated by using a UV spectrometer “Specord M 40” (maximum absorption 480 nm). The developed hydrogel implant has good biocompatibility and germination of surrounding tissues in the structure of the implant, as well as the formation of a massive fibrous capsule around it. An important advantage of the implant is also the lack of its tendency to resorption. Moreover, the results showed that the diffusion kinetics of doxorubicin from a liquid-crosslinked hydrogel reaches a minimum therapeutic level within a few minutes, while in the case of a tightly crosslinked - after a few hours. It was also found that the liquid-crosslinked hydrogel adsorbs twice as much as the cytostatic - doxorubicin. The analysis of the research results approved that the size of the nanoparticles is the main factor for improving drug delevary and penetration. Thus, nanoparticles with a diameter of less than 200 nm can penetrate into cells and are not removed from the circulatory system by macrophages, thereby prolonging their circulation in the body. About 10 nm. The developed hybrid hydrogel compositions have high mechanical strength, porosity, which provides 100% penetration of doxorubicin into experimental animal tissues. It was found that the kinetics of diffusion of drugs from liquid-crosslinked hydrogel reaches a minimum therapeutic level within a few minutes, whereas in the case of densely crosslinked hydrogel diffusion begins with a delay of several hours and the amount of drug released at equilibrium reaches much lower values (20–25%). The obtained preliminary experimental results allow us to conclude that our developed pathways for the delivery of drugs, in particular, doxorubicin to tumor cells will increase the effectiveness of antitumor therapy.",signatures:"Anatoliy Parfentievich Maletskyy, Yuriy Markovich Samchenko and Natalia Mikhailivna Bigun",downloadPdfUrl:"/chapter/pdf-download/76820",previewPdfUrl:"/chapter/pdf-preview/76820",authors:[{id:"325981",title:"Prof.",name:"Anatoliy Parfentievich",surname:"Maletskyy",slug:"anatoliy-parfentievich-maletskyy",fullName:"Anatoliy Parfentievich Maletskyy"},{id:"326712",title:"Dr.",name:"Yuriy Markovich",surname:"Samchenko",slug:"yuriy-markovich-samchenko",fullName:"Yuriy Markovich Samchenko"},{id:"333970",title:"Dr.",name:"Natalia Mikhailivna",surname:"Bigun",slug:"natalia-mikhailivna-bigun",fullName:"Natalia Mikhailivna Bigun"}],corrections:null},{id:"76515",title:"The Paradigm of Targeting an Oncogenic Tyrosine Kinase: Lesson from BCR-ABL",doi:"10.5772/intechopen.97528",slug:"the-paradigm-of-targeting-an-oncogenic-tyrosine-kinase-lesson-from-bcr-abl",totalDownloads:218,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The aberrant tyrosine phosphorylation, either due to constitutive tyrosine kinases (TKs) or to inactivation of protein tyrosine phosphatases (PTPs), is a widespread feature of many cancerous cells. The BCR-ABL fusion protein, which arises from the Philadelphia chromosome, is a molecular distinct and peculiar trait of some kind of leukemia, namely Chronic Myeloid and Acute Lymphoblastic Leukemia, and displays constitutive tyrosine kinase activity. In the chapter, we will highlight the milestones that had led to the identification of the BCR-ABL fusion gene and its role as the only molecular pathogenic event sufficient to elicit and sustain chronic myeloid leukemia. We will also discuss the effort made to unveil the molecular mechanisms of action of the chimeric tyrosine kinase that eventually lead to aberrant cell proliferation and impaired cell-death. Furthermore, we will also review the lesson learned from the selective inhibition of BCR-ABL which currently represent a breakthrough in the treatment of several tumors characterized by defective tyrosine kinase activity.",signatures:"Enrico Bracco, M. Shahzad Ali, Stefano Magnati and Giuseppe Saglio",downloadPdfUrl:"/chapter/pdf-download/76515",previewPdfUrl:"/chapter/pdf-preview/76515",authors:[{id:"58476",title:"Prof.",name:"Giuseppe",surname:"Saglio",slug:"giuseppe-saglio",fullName:"Giuseppe Saglio"},{id:"343243",title:"Assistant Prof.",name:"Enrico",surname:"Bracco",slug:"enrico-bracco",fullName:"Enrico Bracco"},{id:"352739",title:"Dr.",name:"Muhammad S.",surname:"Ali",slug:"muhammad-s.-ali",fullName:"Muhammad S. Ali"},{id:"352740",title:"BSc.",name:"Stefano",surname:"Magnati",slug:"stefano-magnati",fullName:"Stefano Magnati"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"8025",title:"Cancer Immunotherapy and Biological Cancer Treatments",subtitle:null,isOpenForSubmission:!1,hash:"e9953ff7bc3b22ae75810e286dd86b73",slug:"cancer-immunotherapy-and-biological-cancer-treatments",bookSignature:"Hilal Arnouk",coverURL:"https://cdn.intechopen.com/books/images_new/8025.jpg",editedByType:"Edited by",editors:[{id:"76431",title:"Dr.",name:"Hilal",surname:"Arnouk",slug:"hilal-arnouk",fullName:"Hilal Arnouk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"946",title:"Advancements in Tumor Immunotherapy and Cancer Vaccines",subtitle:null,isOpenForSubmission:!1,hash:"aa9eb0c98931a6c6e516ecf1962f99a4",slug:"advancements-in-tumor-immunotherapy-and-cancer-vaccines",bookSignature:"Hilal Arnouk",coverURL:"https://cdn.intechopen.com/books/images_new/946.jpg",editedByType:"Edited by",editors:[{id:"76431",title:"Dr.",name:"Hilal",surname:"Arnouk",slug:"hilal-arnouk",fullName:"Hilal Arnouk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"374",title:"Current Cancer Treatment",subtitle:"Novel Beyond Conventional Approaches",isOpenForSubmission:!1,hash:"d752cf5b05d575243ec2c2144073f579",slug:"current-cancer-treatment-novel-beyond-conventional-approaches",bookSignature:"Öner Özdemir",coverURL:"https://cdn.intechopen.com/books/images_new/374.jpg",editedByType:"Edited by",editors:[{id:"52298",title:"Prof.",name:"Oner",surname:"Ozdemir",slug:"oner-ozdemir",fullName:"Oner Ozdemir"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3273",title:"Cancer Treatment",subtitle:"Conventional and Innovative Approaches",isOpenForSubmission:!1,hash:"cdd9872a05001212b3583bff95bae979",slug:"cancer-treatment-conventional-and-innovative-approaches",bookSignature:"Letícia Rangel",coverURL:"https://cdn.intechopen.com/books/images_new/3273.jpg",editedByType:"Edited by",editors:[{id:"60359",title:"Dr.",name:"Letícia",surname:"Rangel",slug:"leticia-rangel",fullName:"Letícia Rangel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1311",title:"Advances in Cancer Therapy",subtitle:null,isOpenForSubmission:!1,hash:"24db071212f134f4a7dc3dc0cc786fec",slug:"advances-in-cancer-therapy",bookSignature:"Hala Gali-Muhtasib",coverURL:"https://cdn.intechopen.com/books/images_new/1311.jpg",editedByType:"Edited by",editors:[{id:"57145",title:"Prof.",name:"Hala",surname:"Gali-Muhtasib",slug:"hala-gali-muhtasib",fullName:"Hala Gali-Muhtasib"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3002",title:"Oncogenomics and Cancer Proteomics",subtitle:"Novel Approaches in Biomarkers Discovery and Therapeutic Targets in Cancer",isOpenForSubmission:!1,hash:"bc8990331803d9e6084b367163dcf218",slug:"oncogenomics-and-cancer-proteomics-novel-approaches-in-biomarkers-discovery-and-therapeutic-targets-in-cancer",bookSignature:"César López-Camarillo and Elena Aréchaga-Ocampo",coverURL:"https://cdn.intechopen.com/books/images_new/3002.jpg",editedByType:"Edited by",editors:[{id:"40928",title:"Dr.",name:"Cesar",surname:"Lopez-Camarillo",slug:"cesar-lopez-camarillo",fullName:"Cesar Lopez-Camarillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1001",title:"Tumor Microenvironment and Myelomonocytic Cells",subtitle:null,isOpenForSubmission:!1,hash:"a2392066cd104cd48f3b296bf72b97a6",slug:"tumor-microenvironment-and-myelomonocytic-cells",bookSignature:"Subhra K. 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Toxicity, Human Health and Environment",slug:"nanomaterials-toxicity-human-health-and-environment",publishedDate:"February 19th 2020",bookSignature:"Simona Clichici, Adriana Filip and Gustavo M. do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/8137.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64160",title:"Prof.",name:"Simona",middleName:null,surname:"Clichici",slug:"simona-clichici",fullName:"Simona Clichici"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"251730",title:"Dr.",name:"Guilherme",middleName:"Fredeico Bernardo",surname:"Lenz E Silva",fullName:"Guilherme Lenz E Silva",slug:"guilherme-lenz-e-silva",email:"guilhermelenz@usp.br",position:null,institution:null},{id:"286148",title:"Dr.",name:"Camila",middleName:null,surname:"Viana",fullName:"Camila Viana",slug:"camila-viana",email:"camilaoviana@gmail.com",position:null,institution:null},{id:"286149",title:"Dr.",name:"Fernanda",middleName:null,surname:"Vieira",fullName:"Fernanda Vieira",slug:"fernanda-vieira",email:"fevieira2001@gmail.com",position:null,institution:null},{id:"286151",title:"M.Sc.",name:"Danieli",middleName:"Silva",surname:"Domingues",fullName:"Danieli Domingues",slug:"danieli-domingues",email:"danielisilva@ymail.com",position:null,institution:null}]}},chapter:{id:"66689",slug:"risk-assessment-and-health-safety-and-environmental-management-of-carbon-nanomaterials",signatures:"Guilherme Lenz e Silva, Camila Viana, Danieli Domingues and Fernanda Vieira",dateSubmitted:null,dateReviewed:"February 26th 2019",datePrePublished:"April 11th 2019",datePublished:"February 19th 2020",book:{id:"8137",title:"Nanomaterials",subtitle:"Toxicity, Human Health and Environment",fullTitle:"Nanomaterials - Toxicity, Human Health and Environment",slug:"nanomaterials-toxicity-human-health-and-environment",publishedDate:"February 19th 2020",bookSignature:"Simona Clichici, Adriana Filip and Gustavo M. do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/8137.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64160",title:"Prof.",name:"Simona",middleName:null,surname:"Clichici",slug:"simona-clichici",fullName:"Simona Clichici"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"251730",title:"Dr.",name:"Guilherme",middleName:"Fredeico Bernardo",surname:"Lenz E Silva",fullName:"Guilherme Lenz E Silva",slug:"guilherme-lenz-e-silva",email:"guilhermelenz@usp.br",position:null,institution:null},{id:"286148",title:"Dr.",name:"Camila",middleName:null,surname:"Viana",fullName:"Camila Viana",slug:"camila-viana",email:"camilaoviana@gmail.com",position:null,institution:null},{id:"286149",title:"Dr.",name:"Fernanda",middleName:null,surname:"Vieira",fullName:"Fernanda Vieira",slug:"fernanda-vieira",email:"fevieira2001@gmail.com",position:null,institution:null},{id:"286151",title:"M.Sc.",name:"Danieli",middleName:"Silva",surname:"Domingues",fullName:"Danieli Domingues",slug:"danieli-domingues",email:"danielisilva@ymail.com",position:null,institution:null}]},book:{id:"8137",title:"Nanomaterials",subtitle:"Toxicity, Human Health and Environment",fullTitle:"Nanomaterials - Toxicity, Human Health and Environment",slug:"nanomaterials-toxicity-human-health-and-environment",publishedDate:"February 19th 2020",bookSignature:"Simona Clichici, Adriana Filip and Gustavo M. do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/8137.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64160",title:"Prof.",name:"Simona",middleName:null,surname:"Clichici",slug:"simona-clichici",fullName:"Simona Clichici"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11439",leadTitle:null,title:"Crisis Management - Principles, Roles and Application",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe word "crisis" can show up anywhere, anytime - it can be an acute urgency or a long-term response; it can happen at an individual level to a global scale. It is an interdisciplinary word that takes into account geographical, demographical, religious, social, and climate differences, and, by how it is managed, consequently, can have a difference in its results. We have seen how seemingly far-away issues became "my problem" in the past.
\r\n\r\n\tThe Subprime Mortgage Crisis affected a credit crash in the international financial market. The Fukushima nuclear power plant accident threatened health problems of the Asian countries, while the radioactivity problem remains an international crisis. The Syrian Civil War, from the country's internal economic recession, job disruptions, poor harvests affected by climate change, has raised a large refugee migration crisis. The COVID-19 pandemic has forced our community, from our small family group to a global scale, to adapt to unprecedented events to the continuing instability, anxiety, and uncertainty in our lives. There is a potential crisis with personal information or identity due to the misuse or insecurity of the data management. At the core of all, these seemingly unrelated types of crises are the resultant risk and burden of consequences that can affect all individuals.
\r\n\r\n\t
\r\n\tThe purpose of this book is to provide the readers with an understanding of the characteristics of the crisis itself, recognize the wide range and multi-layer of the crisis from a real situation, give ideas on how to minimize the damage, and find ways to increase resilience in the future. To adapt to the rapidly and diversely changing world, the necessary experience and appropriate management for all kinds of crisis issues will be discussed as well. At the same time, it is intended to suggest elements such as verified scientific and empirical knowledge and applicable technologies; more effective risk management operation; modeling of the risks, manuals, management plans, and strategies.
\r\n\t
As reported carbendazim (methyl-2-benzimidazole carbamate) is used to be a systemic fungicide [1]. Both carbendazim and its parent benomyl [methyl 1-(butylcarbamoyl)-2-benzimidazole carbamate] are exhibiting low acute toxicity [2]. In contrast, carbendazim and benzimidazole chemicals induced severe reproductive and developmental toxicity in rodents [3, 4, 5, 6]. Reports showed that carbendazim and benomyl exhibited testicular toxicity such as sloughing of immature spermatids [7, 8], inhibition of microtubule assembly [9], seminiferous tubular atrophy [10], and testicular atrophy and infertility [11] in male rats. Both carbendazim and benomyl induced developmental toxicity in rodents. Prenatal treatment of carbendazim to rats during pregnancy exhibited embryonic death, growth retardation, and developmental abnormalities including exencephaly, microphthalmia and hydronephrosis in offspring [3, 12]. Treatment of benomyl to pregnant rats induced craniocerebral and systemic malformations such as cleft palate, hydrocephalus, and exencephaly in offspring of male and female rats [13]. In contrary to the more reports available on the reproductive and developmental toxicity of carbendazim and benomyl, studies for endocrine-disrupting activity or mode of action of the these two fungicides remains unclear. The earlier report on endocrine activity for carbendazim might be Rehnberg et al. (1989). They showed that administration of male rats with carbendazim raised testosterone concentration and the levels of androgen binding protein in the interstitial and seminiferous tubule fluid, meaning an association between endocrine disruption activity and carbendazim toxicity [14]. Recently Rama et al. (2014) reviewed and reported that carbendazim induced reproductive toxicity and possible hormonal effects in rats [15]. They reviewed the previous reports and generalized that carbendazim have androgenic effects acting directly in the androgen receptors and/or increasing the expression of androgen receptors. Some chemicals were reported to increase or decrease AR expression. Bisphenol A was reported to increase AR expression [16] while di-n-butyl phthalate (DBP) [17, 18] and sodium valproate [19] decrease it. We found out that it is common for estrogen receptor agonist and androgen receptor antagonist but not for androgen agonist in pesticides. Based on the chemical structure it seems to determine the AR agonist or antagonist. The degree of increase or decrease of AR expression might be depended on the chemical structure, which shared with nature ligand dihydrotestosterone. This manuscript would like to combine our unpublished data and previous studies to infer that androgen receptor plays an important role in benomyl- and carbendazim-induced reproductive and developmental toxicity and endocrine-disrupting activity in rats.
\n(1) Animals and related preparation
\nBoth male and female SD rats, 3–4week old, were obtained from the National Laboratory Animal Breeding and Research Center, Taipei, Taiwan. All rats were kept in specific-pathogen-free animal facility in Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Taichung, Taiwan. The animal rooms were kept on a 12-h light and dark cycle, 23 ± 2°C, and 50 ± 10% relative humidity. When they were transported to animal room, the rats were quarantined for at least 1 week and opened on the bases of enough body weight gain and without clinical signs of disease of injury. Both carbendazim and benomyl with 99% pure were a gift from Sinon Co., Taichung, Taiwan. These two pesticides were suspended in polyethylene glycol 200 and treated to animals orally by gavage in a volume of 2 ml/kg body weight, once daily. In reproductive toxicity studies, male rats were administered with these two pesticides and/or flutamide for 28 days. In developmental toxicity studies, both male and female rats were administered with 200 mg/kg carbendazim or 100 mg/kg benomyl for 28 days. Then the female rats were mated with male within each treatment group for 14 days. No treatment was carried out during the mating period. Pregnant dams with plug detected were kept to deliver the offspring at term and conception rates were calculated. All rat offspring were weaned at 21 days postnatal and then fed up to 6 week old [20].
\n(2) Organ and tissue weight, morphology, and histopathological examination
\nBoth testis and epididymis were weighed by right and left sides. The incidence of abnormal morphology was recorded. The half of testis or epididymis each was fixed in 10% neutral phosphate-buffered formalin solution for subsequent histopathological examinations. Tissues of testis and epididymis were processed by standard histopathological processes and stained using haematoxylin and eosin for light-microscopic examinations. Both testis and epididymis sections were stained with the Giemsa staining periodic acid-Schiff methods and then counterstained using haematoxylin as reported in Simoes and Schoning [21]. Both testis and epididymis histology were evaluated and histopathological findings were scored according to Oakberg [22] and Hess [23].
\n(3) In vitro androgen receptor binding assay
\nThe ligand binding assay was processed to determine the concentration of androgen receptor in rat tissue according to Nonneman et al. [24]. The ligand [1, 2, 3, 5, 6, 7-3H(N)]-5α-androstan-17β-ol-3-one (dihydrotestosterone, 5α-DHT) (110–150 Ci/mmol) was obtained from NEN Life Science Products, Inc., Boston. Nonlabelled 5α-DHT was obtained from Sigma Chemical Company, St. Louis, MO, and recrystallized from ethanol prior to use. Both rat testis and epididymis were homogenized in ice-cold low-salt TEDG buffer, pH 7.4, consisting of 10 mM Tris, 1.5 mM ethylenediaminetetraacetic acid (EDTA), 10% glycerol, and 1 mM each of dithiothreitol, phenylmethylsulfonyl fluoride, and sodium molybdate as described by Hardy et al. [25]. Tissue homogenates were centrifuged at 30,000 × g for 1 h and the supernatant were processed to use as the low-salt extract. Before analysis, the endogenous steroids were removed from the low-salt extract by incubation with dextran-coated charcoal. The binding of [3H]-5α-DHT to androgen receptor of testis and epididymis extract each was determined by competitive inhibition binding using nonlabelled 5α-DHT. Charcoal-treated testicular and epididymal extract each was incubated with 1 nM [3H]-5α-DHT at 4°C for 24 h. The nonspecific binding was carried out with incubating the extract with 100-fold excess nonlabelled 5α-DHT. Unbinding [3H]-5α-DHT was isolated from the binding steroid by adding the extract to packed hydroxyapatite in the low-salt TEDG buffer. Mixture were incubated for 30 min with several mixings and then centrifuged at 600 × g for 3 min at 4°C. After that the supernatant was aspirated. An aliquot of the packed HAP was washed 4 times with ice-cold 50 mM Tris buffer, pH 7.3. In determination of total binding, the binding [3H]-5α-DHT was extracted from HAP with ethanol and counted for radioactivity using a Beckman model LS6000 TA liquid scintillator. For specific binding of testis and epididymis extracts they were determined by subtracting nonspecific binding from total binding and corrected for protein concentration. The protein concentration was determined according to Lowry et al. [26]. Analysis of effect of carbendazim on androgen receptor binding, specific binding of [3H]-5α-DHT to testis extract was carried out with incubation of the charcoal-treated testis extract with [3H]-5α-DHT in the presence of carbendazim at 4°C for 24 h. Incubation mixtures were carried out to the same procedures as before in the androgen receptor binding assay.
\n(4) Statistical analysis
\nAll these data were expressed as mean ± SE. All data were processed to analysis of variance followed by Student’s t-test. The level of significance was set at
This study aimed to investigate the endocrine-disrupting activity of carbendazim-induced reproductive and developmental toxicity in rats. The male rats were co-treatment with 675 mg/kg carbendazim and 50 or 100 mg/kg flutamide, an androgen receptor antagonist, once daily for 28 days decreased testis weight induced by treatment with carbendazim alone. Co-treatment of carbendazim and flutamide blocked losses of spermatozoa and cell morphology and decrease of sperm concentration induced by carbendazim. An important evidence for endocrine disrupting activity induced by carbendazim and benomyl was that premating treatment of male and female rats with 200 mg/kg carbendazim for 28 days resulted in androgenic effects including incomplete development of uterine horn, enlargement of urethra, absence of vagina, and induction of seminal vesicles in female offspring, without significant effects in male offspring. Also, premating treatment with 100 mg/kg benomyl, the parent compound of carbendazim, produced incomplete development of uterine horn and absence of vagina in female offspring and induced testis and epididymis atrophy in male offspring. When male rats were treated with 25, 50, 100, 200, 400, and 800 mg/kg carbendazim for 56 days androgen receptor concentrations were increased in testis and epididymis with dose dependent. Furthermore, additions of 5, 50, and 500 M carbendazim to testis extract from untreated rats substituted binding of [3H]5 -dihydrotestosterone to androgen receptor with concentration dependent. This study illustrated that reproductive toxicity exhibited by carbendazim is relieved by an androgen receptor antagonist flutamide in male rats and developmental toxicity of the fungicide shows androgenic properties in female offspring. The authors concluded that androgen- and androgen receptor-dependent mechanisms are quite possibly involved in carbendazim-induced toxicity.
\n(1) Animals and related preparation
\nBoth male and female rats were obtained from the National Laboratory Animal Center, Taipei, Taiwan. All rats were kept in specific pathogen-free animal facility in Taiwan Agricultural Chemicals and Toxic Substances Research Institute, Taichung, Taiwan. All animal rooms were kept under a 12-hour light and dark cycle, 23 ± 2°C, and 50 ± 10% relatively humidity. All animal had access
(2) Treatment and dose design
\nBoth carbendazim and benomyl with 99% pure were a gift from Sinon Co., Taichung, Taiwan. All other chemicals were purchased from Sigma (St. Louis, MO, USA) unless otherwise noted. Carbendazim, benomyl, or flutamide each was suspended in corn oil and treated to animals orally by gavage in a volume of 2.5 mL/kg body weight, once daily. Groups of five rats from GD 0 to 20, were treated with carbendazim at 6.25, 12.5, and 25 mg/kg; benomyl at 25, 50, and 100 mg/kg; or flutamide at 0.6, 2.5, and 10 mg/kg. Also, rats were co-treated with 25 mg/kg carbendazim and 0.6, 2.5, and 10 mg/kg flutamide or co-treated with 100 mg/kg benomyl and 0.6, 2.5 or 10 mg/kg flutamide. Female rats were checked daily for clinical signs of toxicity. Female body weight and food consumption were measured daily throughout dosing and lactation period. All rat offspring were weaned at PND 21 and fed up to 8-week-old. All rat organ weights were determined on PND 21. Conception rate on GD 21 and 22, proportion of pups born alive on PND 1, proportion of pups surviving to weaning on PND 21, and sex ratio on PND 56 were measured and recorded.
\n(3) Determination of androgen-dependent reproductive development effects
\nWhat they determined for androgen-dependent reproductive end points were signs of clinical toxicity, anogenital distance (AGD), male and female pup weight, retention of areolae and/or nipples, malformations of external genitalia, testicular descent, preputial separation, vaginal opening, and organ weight and malformation on PND 56 [28, 29]. All pups were counted and examined for signs of clinical toxicity on PND 0 and were individually identifievd by tail-labeling on PND 21. All pups with AGD, and live male and female offspring weights were measured on PND 2, 22, and 42. Day of completion of preputial separation (PPS) and body weight in PPS of male offspring during PND 40 and 50 were also measured. Day of onset of vaginal opening (VO) and body weight in VO of female offspring during PND 30 and 45 were measured. End points of gross morphology of reproductive organs, nipple retention, abnormal testis and epididymis, hypospadias, underdevelopment of prostate or/and seminal vesicle, absent prostate or/and seminal vesicle, bladder stone, and underdevelopment of levator ani bulbocavernosus muscle in male offspring were determined on PND 56.
\n(4) Necropsy of rats
\nAll pups were weaned on PND 21. Rats were euthanized by CO2 asphyxiation. All body and organ/tissue weights including liver, kidneys, adrenals, uterus, ovaries, thyroids and number of implantation sites were measured on PND 21.
\n(5) Necropsy of F1 offspring
\nBoth male and female offspring on PND 56 were euthanized by CO2 asphyxiation and blood was collected via trunk. After blood collection, the ventral surface of offspring was shaved for counting the number of nipples. External genitalia, including the scrotum, prepuce, and penis of male offspring and vaginal of female offspring were visually inspected. End points of gross internal examination of the reproductive tract such as inspection of the testes, epididymides, prostate, seminal vesicles, levator ani bulbocavernosus muscle, and penis were measured. Also, the liver, kidneys, adrenal glands and thyroids were grossly examined and weighed. Body and organ weights such as testes, epididymides, prostate, seminal vesicles with fluid, levator ani bulbocavernosus muscle, and penis, liver, kidneys, adrenals and thyroids were collected. All examined tissues were fixed in 10% neutral buffered formalin, processed, sectioned, and stained with haematoxylin and eosin.
\nBoth carbendazim (methyl 2-benzimidazolecarbamate) and benomyl are reported to exhibit reproductive and developmental toxicity in male rats. This study was mainly to detect the ability of carbendazim exposure
(1) Animals and related treatments
\nMale SD rats with three-week-old were obtained from the National Laboratory Animal Center, Taipei, Taiwan. All rats were kept in a specific-pathogen-free animal facility in the Taiwan Agricultural Chemicals and Toxic Substances Research Institute (TACTRI) in Taichung. The animal rooms were sustained at a 12-hour light and dark cycle, 23 ± 2°C and 50 ± 10% relative humidity. When the animals were transported to the room, the rats were quarantined for at least 1 week and were available for test only when they exhibited enough body weight gain and no clinical signs of disease or injury. Carbendazim with 99% pure was obtained from Sinon Co. (Taichung, Taiwan). Flutamide (FLU) and the other chemicals were obtained from Sigma (St. Louis, MO, USA), unless otherwise stated. The pesticide was suspended in corn oil and orally administered to five rats in each group once a day by gavage at a volume of 2.5 mL/kg body weight. Male rats (322 ± 15 g) were randomly assigned to each treatment group. In order to carry out the time- and dose-dependent tests, the protocol included two treatment-duration and dosages. The first one was as follows: The doses of carbendazim were 0, 25, 50, 100, 200, 400 and 800 mg/kg/day for 56 days. The doses of flutamide were 0, 6.25, 12.5, 25, 50 and 100 mg/kg/day for 28 days. In mixed doses, the rats were co-treated with 675 mg/kg/day of carbendazim and 0, 6.25, 12.5, 25, 50 and 100 mg/kg/day of flutamide for 28 days. The second one was as follows: The doses of carbendazim were 0, 6.25, 25, 100 and 400 mg/kg/day for 7 days, while the doses of flutamide were 0, 0.78, 3.13, 12.5 and 50 mg/kg/day for 7 days. The rats in the co-treatment group were given either 400 mg/kg of carbendazim and 0, 0.78, 3.13, 12.5 and 50 mg/kg/day of flutamide, or 50 mg/kg/day of flutamide and 0, 6.25, 25, 100 and 400 mg/kg/day of carbendazim for 7 days. All animal care and experimental procedures were approved by the Institution Animal Care and Use of Committee (IACUC) of TCATRI [30].
\n(2) Immunohistochemical (IHC) evaluation
\nThe testes tissues of three groups of rats were tested: (1) 0, 25, 50, 100, 200, 400 and 800 mg/kg/day of carbendazim for 56 days; (2) 0, 6.25, 12.5, 25, 50 and 100 mg/kg/day of flutamide for 28 days; and (3) co-treatment with 675 mg/kg/day of carbendazim and 0, 6.25, 12.5, 25, 50 and 100 mg/kg/day of flutamide for 28 days. Testes from the following test groups were fixed in 10% neutral buffered formalin for 1 week. The tissues were then dehydrated with increasing concentrations of ethanol, cleared in toluene and embedded in paraffin. Sections were cut into 5-mm slices and deparaffinized, hydrated and treated with 0.3% H2O2 in PBS (pH 7.6) for 30 min to block endogenous peroxidase activity, and finally treated with a protein-blocking solution (5% goat serum diluted in phosphate-buffered saline). These steps were followed by heating the sections in a microwave oven for antigen retrieval using a 0.01 M citrate buffer solution (pH 5.5). Tissue sections were immunostained with rabbit anti-AR (N-20, Santa Cruz Biotechnology, Inc., CA, USA), which was diluted 1: 250 in phosphate-buffered saline and 0.25% bovine serum albumin and maintained at room temperature overnight. The tissue sections were then developed with a streptavidin-HRP kit (Chemicon IHC Select® CA, USA), using diaminobenzidine as the chromogen, and were counterstained with haematoxylin. All images were optimized by using an inverted microscope (Leica, Wetzlar GmbH, Germany). To quantify the relative amount of AR protein in the IHC, 200 nucleus stained per field in a slide, 5 fields per slide, 5 slides per dose were counted. The intensity of AR protein stained in nucleus was graded as (0, negative), + (1, mild), ++ (2, moderate), +++ (3, intense), ++++ (4, more intense) or +++++ (5, very intense). The measurements were control group adjusted and the values were statistically analyzed.
\n(3) Reverse transcription-polymerase chain reaction (PCR)
\nTestes (n = 5) from the following treatment groups were stored at −80°C for 7 days. Total RNA was extracted with an RNeasy® Mini Kit (QIAGEN, TAIGEN Bioscience Corporation, Dusseldorf, Germany) according to the protocol provided by the manufacturer. For the reverse transcription (RT) reaction, 3 mL of total RNA was used from the individual rats of each group. The RT-PCR reactions in this study were carried out with SuperScriptTM III One-Step RT-PCR System with Platinum® Taq DNA polymerase kits from Invitrogen (Cat. No. 12574–026) in DNA Engine® & DNA Engine Tetrad® Peltier Thermal Cyclers (PTC-200, MJ Research, Incorporated, Massachusetts 02451 USA). For AR mRNA amplification, the primers were designed to amplify a 570-bp fragment (forward, 5’-TGCTGCCTTGTTATCTAGTCTCA-3′; reverse, 5’-ACCATATGGGACTTGATTAGCAG-3′) (annealing temperature, 60°C; the number of cycles, 24, 26 and 28; product size, 570 bp). PCR was subsequently performed using an optimized protocol of between 24 and 28 cycles. Each cycle consisted of the following: 94°C, 30 s; 60°C, 30 s and 72°C, 45 s. For b-actin mRNA amplification, the primers were designed to a 359-bp fragment (forward, 5’-CTGTGCCCATCTATGAGGGTTAC-3′; reverse, 5’-AATCCACACAGAGTACTTGCGCT-3′) (annealing temperature, 60°C; the number of cycles, 24, 26 and 28; product size, 359 bp). PCR was subsequently performed using an optimized protocol of between 24 and 28 cycles. Each cycle consisted of the following: 94°C, 30 s; 60°C, 30 s and 72°C, 45 s. PCR products were resolved in a 1.2% agarose gel and stained with ethidium bromide, and DNA bands from triplicate reactions were quantified using a FOTO/Analyst® Investigator System (Fotodyne Incorporated, Hartland, WI, USA). The PCR products for β-actin served as an internal standard.
\n(4) Western blot
\nA Polytron PT3100 homogenizer (Kinematica AG, Littau, Switzerland) was used to examine frozen testicular tissues from the following treatment groups. Tissues of testes from the first protocol were homogenized for a few seconds in an M-PER® Mammalian Protein Extraction Reagent (Cat. No. 78505, Pierce). The homogenates were then centrifuged at 105,000 × g for 1 h at 4°C. The supernatants were aliquoted and stored at −86°C before use. Before western blotting, protein contents were measured by BCA protein assay (Cat. No. 23225, Pierce). Equal amounts of protein were loaded onto each polyacrylamide gel. The antibody dilutions were 1: 200 for the anti-AR antibody (N-20, Santa Cruz Co., CA) and 1: 5000 for the horseradish peroxidase conjugated goat anti-rabbit IgG (AP132P, Chemicon International). For each treatment group, five samples were analyzed in two separate blots. Total protein extracts from the testicular tissue were denatured and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with 7.5% polyacrylamide. The proteins were transferred to nitrocellulose membranes. The membranes were then blocked for non-specific binding and incubated with polyclonal primary antibodies for AR (N-20, Santa Cruz Co., CA) and β-actin (AP132P, Chemicon International). After incubation with primary antibody, the membranes were incubated with horseradish peroxidase-linked anti-goat IgG secondary antibody and visualized on film exposed to enhanced chemiluminescence (VisualizerTM Western Blot Detection Kit, Millipore, MA, USA). The relative amount of protein in the resulting immunoblot bands was estimated by measuring the optical densities of the bands on exposed films using a FOTO/Analyst® Investigator System (Fotodyne Incorporated, WI, USA). The measurements were background adjusted and the values were statistically analyzed. Protein for ß-actin served as an internal standard.
\n(5) Hormone analysis
\nSerum luteinizing hormone (LH) (RPN 2562, Amersham, UK), follicular stimulating hormone (FSH) (RPN 2560, Amersham, UK; AE R004, Biocode, Belgium), 17b-estradiol (E2) (Cayman Chemical., Ann Arbor, MI, USA) and testosterone (T) (Cayman Chemical., Ann Arbor, MI, USA) levels were determined using the relevant EIA systems. The serum samples collected from rats treated with 0, 6.25, 25, 100 and 400 mg/kg/day of carbendazim for 7 days and 0, 0.78, 3.13, 12.5 and 50 mg/kg/day of flutamide for 7 days were directly applied to the well in the kit and measurements were taken according to the procedure described by the manufacturer.
\n(6) Statistical analysis
\nThe values of AR in Western blot and RT-PCR were normalized against b-actin. All results were statistically analyzed with the t-test and
Carbendazim was widely used as a fungicide, and it was reported to exhibit reproductive and developmental toxicity. This study aimed to detect the expression of androgen receptor caused by carbendazim and the antagonistic effect of flutamide. Groups of five rats were treated with carbendazim, flutamide or a combination of both to determine androgen receptor mRNA, immune activity and protein expression. Carbendazim increased androgen receptor mRNA with dose dependent, while flutamide, an androgen receptor antagonist, blocked it. When co-treatment with carbendazim and various flutamide doses it decreased the androgen receptor mRNA dose dependent. In contrast, co-treatment with flutamide and various carbendazim doses increased the androgen receptor mRNA with dose dependent. In the immunohistochemistry (IHC) and Western blot (WB) analyses it showed that carbendazim increased androgen receptor activity particular in rat testes with dose dependent, while flutamide decreased it. Moreover, treatment with carbendazim or flutamide for 7 days raised testosterone and follicular stimulating hormone concentrations in the serum of male rats with dose dependent, which might involve the disruption of the androgen receptor. Despite the fact that we need to examine the underlying mechanism of androgen receptor involved in the reproductive toxicity and endocrine-disrupting activity exhibited by carbendazim and its parent, benomyl, we should first discuss how to take advantage of flutamide antagonism on carbendazim-produced reproductive and endocrine disrupting activity possibly in human. This study concluded that carbendazim exhibited androgen receptor expression in mRNA and protein levels, while flutamide antagonized it. As we know this is the first report on the antagonistic effect of flutamide on the carbendazim-androgenic effect on mRNA and protein levels. This study would give a light way to illuminate the mechanism of carbendazim- and chemical-produced developmental toxicity and endocrine disrupting activity.
\n(1) Chemicals
\nThe following materials were obtained: testosterone propionate (TP, purity ≥97%), Sigma-Aldrich Co. (Buchs, Switzerland); 17β-estradiol (E2, purity ≥98%), flutamide (Flu, purity ≥97%), and corn oil (0.9 g/mL), Sigma Chemical Co. (St. Louis, MO, USA); carbendazim (Mbc, purity ≥99%), and benomyl (Ben, purity ≥99%), Sino Co. (Taichung, Taiwan, ROC) [31].
\n(2) Animals, experimental conditions, castration (Cast) and ovariectomy (OVX) procedures
\nThe animal use protocol was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the Taiwan Agricultural Chemicals and Toxic Substances Research Institute. Four-week-old male and female SD rats were purchased from the National Laboratory Animal Center, Taipei, Taiwan. All rats were accustomed at least to the laboratory environment for 3 weeks before test. During the experiment period, all rats were kept, two to three per cage, in suspended aluminum cages with stainless-steel wire-mesh front and floor under the controlled conditions, containing a temperature of 21 ± 2°C, a relative humidity of 40–70%, a frequency of ventilation of more than 10 air exchanges per hour, and a 12-h light/dark cycle. Drinking water and pellet rodent diet were available
(3) Study design and clinical examination
\nThis study was designed according to standardized test guidelines, including OECD test 440 [32], USEPA OPPTS 890.1600 [33], OECD test 441 [34] and USEPA OPPTS 890.1400 [35], with modification of endpoints. Table 1 shows the treatment conditions for uterotrophic assay (estrogenic and antiestrogenic/estrogenic) and Hershberger assay (androgenic and anti-androgenic/androgenic) in young adult rats (275 ± 15 g). Each experimental group consisted of six animals. Test and reference substances were suspended or dissolved daily in vehicle (corn oil). Daily dosages of E2 and TP were 2.5 ml/kg body weight (BW) administered via oral gavage and 0.5 ml/kg BW administered via subcutaneous injection. Oral gavage was selected because it is one of the potential exposure routes of test chemicals in humans. For all experiments, clinical signs, BW and weights of liver and kidneys were assessed as indices of systemic toxicity. Clinical signs including any abnormal behavior were recorded twice a day for each animal.
\nDose (mg/kg/day) | \nUterotrophic assay6 | \nHershberger assay6 | \n||||||
---|---|---|---|---|---|---|---|---|
\n | Estrogenic | \nAnti-estrogenic/ estrogenic | \nAndrogenic | \nAnti-androgenic/ androgenic | \n||||
Treatment group1 | \n1 | \n2 | \n3 | \n4 | \n1 | \n2 | \n3 | \n4 | \n
Control (intact) | \n+7 | \n+ | \n||||||
Control (OVX) 2 | \n+ | \n-8 | \n||||||
E2 (sc) 3 | \n— | \n— | \n+ | \n+ | \n— | \n— | \n— | \n— | \n
Control (Cast) 4 | \n— | \n+ | \n||||||
TP (sc)5 | \n— | \n— | \n— | \n— | \n— | \n— | \n+ | \n+ | \n
Corn oil (oral) | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n
Benomyl (Ben) | \n\n | \n | \n | \n | \n | \n | \n | \n |
50 | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n
100 | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n
200 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
400 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
800 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
Carbendazim (Mbc) | \n\n | \n | \n | \n | \n | \n | \n | \n |
50 | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n
100 | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n
200 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
400 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
800 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
Flutamide (Flu) | \n\n | \n | \n | \n | \n | \n | \n | \n |
6.25 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
12.5 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
25 | \n— | \n+ | \n— | \n+ | \n— | \n— | \n— | \n— | \n
50 | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n
100 | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n— | \n+ | \n
Study design for uterotrophic and Hershberger assays.
All treatment groups were treated with 6 male or 6 female rats.
OVX: ovariectomy.
E2 (sc): 17β-Estradiol, 5 mg/kg/day (subcutaneous).
Cast: castrated.
TP (sc): testosterone propionate, 5 mg/kg/day (subcutaneous).
Comparison pairs for uterotrophic and Hershberger assays are as follows, respectively: treatment group 1 vs. treatment group 2; treatment group 3 vs. treatment group 4.
+: with.
−: without.
(4) Assessment of antiestrogenicity/estrogenicity in young adult rats
\nA 10-day uterotrophic assay using OVX rats was performed to determine if benomyl, carbendazim and flutamide interfere with estrogen receptor-mediated mechanisms. For assessment of antiestrogenicity/estrogenicity, 5 mg/kg/day E2 was administered daily, as a reference estrogen, by subcutaneous injection on the dorsal surface, as previously described [32, 33] with modified dosage. Benomyl, carbendazim or flutamide was administered to OVX or E2-treated OVX rats by oral gavage for 10 days. A previous study has shown that AR antagonist flutamide blocks the androgenic effect induced by carbendazim [27]. To investigate the effects of AR agonists benomyl and carbendazim (50, 100, 200, 400, and 800 mg/kg/day) and antagonist flutamide (6.25, 12.5, 25, 50, and 100 mg/kg/day) on estrogenic activity in rats, these chemicals were administered to OVX rats by oral gavage for 10 days. The dose levels of benomyl, carbendazim or flutamide have been previously described [20]. One day after the final administration, rats were euthanized by blood withdrawal from the abdominal femoral artery under light ether anesthesia and exhaust ventilation to maintain the airborne concentrations of vapors below their respective threshold values. Uterus with fluid, vagina, thymus, thyroid, liver, lung, adrenal glands, kidneys and bladder were examined for gross lesions and then dissected and weighed after careful trimming to remove fat and other contiguous tissues in a uniform manner.
\n(5) Assessment of antiandrogenicity/androgenicity in young adult rats
\nA 10-day Hershberger assay using male rats was performed to determine if benomyl, carbendazim and flutamide interfere with AR-mediated mechanisms. For assessment of antiandrogenicity/androgenicity, 5 mg/kg/day testosterone propionate (TP) was administered daily, as a reference androgen, by subcutaneous injection on the dorsal surface as previously described [34, 35, 36] with modified dosage. Benomyl, carbendazim or flutamide was administered to Cast or TP-treated Cast rats by oral gavage for 10 days. Dosages of 50 and 100 mg/kg/day benomyl, carbendazim or flutamide [20] were administered as antagonist control for anti-androgenicity in young adult rats, as previously described. One day after the final administration, rats were euthanized by blood withdrawal from the abdominal femoral artery under light ether anesthesia and exhaust ventilation to maintain the airborne concentrations of vapors below their respective threshold values. The reproductive accessory glands/tissues (prostate, seminal vesicles with coagulating glands, levator ani plus bulbocavernosus muscles, and penis), as well as thymus, thyroid, lung, liver, adrenal glands, kidneys, bladder, and scrotum, were examined for gross lesions and dissected. All tissues were carefully trimmed to remove fat and weighed.
\n(6) Statistical analysis
\nData are expressed as mean ± SD. BW and organ weights were subjected to ANOVA followed by student’s t-test. The level of significance was set at
The both benomyl and carbendazim are widely used systemic fungicides. It has been shown that benomyl and carbendazim induce endocrine-disrupting activity, resulting in reproductive and developmental toxicity, as well as androgen receptor (AR) gene expression in rats. The aim of this study was to link AR induction by benomyl and carbendazim, observed in our previous reports, with the results of Hershberger and uterotrophic assays. In an uterotrophic assay, neither benomyl nor carbendazim, except at 800 mg/kg/day, affected weight of uterus and vagina when compared to the ovariectomized control rats. Co-treatment with 17β-estradiol (E2) and 200 mg/kg/day benomyl or co-treatment with E2 and 200, 800 mg/kg/day carbendazim significantly increased uterine weight when compared to treatment with E2 alone in an uterotrophic assay. This uterotrophic activity might be mediated through AR. Treatment with flutamide alone or in combination with E2 had no effect on uterine weight. In the Hershberger assay, treatment with 50 and 100 mg/kg/day benomyl increased weight of ventral prostate plus seminal vesicles. Carbendazim or flutamide alone exhibited no effect on reproductive accessory gland weight. Co-treatment with testosterone propionate (TP) and 50 or 100 mg/kg/day carbendazim, but not benomyl, significantly increased the weight of ventral prostate plus seminal vesicles. Co-treatment with TP and 50 or 100 mg/kg/day flutamide significantly decreased these reproductive accessory gland weights when compared with TP alone. Based on our previous report, carbendazim increases mRNA and protein expression of AR in testis, epididymis and prostate and antagonizes the reduced tissue weights of seminal vesicle and prostate of male offsprings induced by in utero exposure to flutamide in rats. This infers that benomyl and carbendazim increase the weight of ventral prostate plus seminal vesicles through induction of AR expression. Moreover, according to a previous report, TP, an AR agonist, induces fluid retention in uterus by exhibiting androgenic activity, similar to that of benomyl and carbendazim, in an uterotrophic assay. Based on these results, benomyl and carbendazim exhibit an androgenic effect, leading to increased weight of ventral prostate and seminal vesicles and uterine fluid retention in young adult rats. The exact mechanisms require further investigation.
\nOECD takes much effort to promote adverse outcome pathways (AOP) methodology. Androgen receptor-mediated reproductive and developmental toxicity and endocrine disrupting activity would be a novel AOP. It is an approach to support the use of a mode (and/or mechanism) of action basis for understanding the adverse effects of chemicals and other stressors. AR mediated reproductive and developmental toxicity and endocrine disrupting activity would be a novel future application. Specific molecular signals of AR mediated effects would be the future work.
\nIn the respect of chemical structure, benomyl and carbendazim shared the same C and D ring structure with the natural ligand, dihydrotestosterone (Figure 1). We made a schematic labeling of the benomyl, carbendazim mimicking the main ligand interaction features of the natural ligand, dihydrotestosterone, with the androgen receptor referred to the previous report by Tamura et al. (2003) [37].
\nSchematic labeling of the benomyl, carbendazim mimic the main ligand interaction features of the natural ligand, dihydrotestosterone, with the androgen receptor.
Based on the previous study firstly it proved that reproductive toxicity produced by carbendazim is relieved by an androgen receptor antagonist in male rats and developmental toxicity of the pesticide showed androgenic properties in female offspring. We concluded that androgen- and androgen receptor-dependent mechanisms are quite possibly complicated in carbendazim-produced toxicity. Secondly findings show that carbendazim exposure
The author would like to acknowledge the financial assistance of the Bureau of Animal and Plant Health Inspection and Quarantine, Council of Agriculture, Executive Yuan, Taipei, Taiwan, R.O.C. through the project 104AS-10.8.1-BQ-B1. The authors are grateful to Sinon Co., Taichung, Taiwan, for providing the benomyl and carbendazim standard material used in this study.
\nNo
LD50 | lethal dose with 50% mortality statistically |
GD 0 | gestation day, day of vaginal plug detected |
PND | postnatal day |
AGD | anogenital distance |
PPS | preputial separation |
VO | vaginal opening |
AR | androgen receptor |
OVX | ovariectomy |
TP | testosterone propionate |
OECD | Economic Co-operation and Development |
India is a fast-growing economy and agrarian country. Almost 70 percent of the Indian population depends on agriculture and its allied sectors to obtain employment and sustain livelihood. The seed is considered as a basic and key input in agriculture. High-quality seed production was the major concern in the Indian subcontinent till the 1960s. Before that India was mostly dependent on the USA for food grain (PL480) to mitigate its hunger [1] and feed large human population. In order to reduce the dependence of food on foreign countries and to meet the food and nutritional demand of burgeoning population and to become self-reliant in food grain production, Indian Government established All India Coordinated Crop Research Projects (AICCRPs) and other institutes in a systemic manner to produce a large number of varieties with assured seed quality in all major crops. The production of high-quality seeds was one of the pillars to change the position of Indian agriculture into the new world order. The ultimate intention was to introduce the newly evolved high yielding cultivars to the resource-poor farmers for broad-spectrum cultivation in the area of their adoption.
By seeing this scenario, the Government of India acknowledged seed an essential commodity under the Essential Commodities Act, 1955. On October 1964 Varietal Release System (VRS) came into existence with the formation of the Central Variety Release Committee (CVRC) at the national level, and State Variety Release Committees (SVRCs) at each state level. A Central Seed Committee (CSC) was established under the Ministry of Agriculture, Cooperation and Farmers Welfare provided in the Seeds Act, 1966. The functions of the CVRC were taken over by the CSC in 1969 to ensure the quality of seeds on sale and notification of the kinds/varieties. To perform the function at central level to release/notification, provisional notification and de-notification of cultivars, CSC constituted a Central Sub-Committee on Crop Standards, Notification & Release of Varieties for Agricultural Crops and Horticultural Crops, while to perform similar functions at state level, State Seed Sub-Committee (SSSC) was constituted [2].
Entries (pure lines/open pollinated varieties/composites/synthetics/hybrids etc.) are developed by the concerned plant breeders/agencies through scientific temperament and extensive breeding programs for the benefit (food and nutritional security) of humankind. Different conventional (Introduction, selection, hybridization followed by selection etc.) and advanced (tissue culture-based techniques like somaclonal variation, anther and pollen culture; mutation, marker assisted breeding, transgenic or genome editing techniques) breeding methods are being used by the different agencies (ICAR or non-ICAR national institutes, SAUs, private national or multinational companies etc.) to generate elite material for high yield potential, nutritional quality and other associated traits. Developed elite materials are being tested by the concerned plant breeder/s at their research station for three to four years in replications for stability and selected superior cultivars enter into the All India coordinated crop improvement projects (AICCIPs) trials for further testing in multi-environments across the country.
First AICCIP was started in way back of 1957 by ICAR on maize crop for systemic testing of entries and for release of high yielding new maize varieties. In general, the three-tier system of multi-location evaluation is used for three years except perennial fodder crops (requires four years-one for crop establishment and three for evaluation) in India. Multilocational trials are conducted by the Project Coordinator (PC)/Project Director (PD) of AICCIPs [3] with the help of concerned principle investigators. The AICCIPs have been developed for all the major crops including forage crops. The AICCIPs come under the umbrella of ICAR, has great role in the development of improved crop varieties and generation of production and protection technologies that directly benefit farmers for their economic amelioration. All AICCIP trials are well organized, systemic and conducted through a uniform testing procedure across the centers as per crop standard. It is a powerful system to screen large number of entries and recommend well-tested, superior, and adapted new cultivars to the end users. The flow chart of varietal release and notification in India is illustrated in Figure 1.
Flow chart of plant varietal release and notification system in India.
Newly entered material/entries into the three-tier system must have the following requirements.
Station trial or preliminary yield trial-Concerned plant breeder must perform station or regional trial and proposed entry must have undergone censorious evaluation process or screening (insect pests and diseases). Crop based quality parameters and tolerance to key abiotic stresses are also to be screened as per the requirement. Pre-coordinated trial data on yield, trait stability and other related agronomic traits must be available to the PC/PD in support of the relevance of his/her entry [4].
The entry must have a high degree of genotypic stability, phenotypic uniformity, germination percentage and physical purity (as per the minimum seed certification standards).
The entry must have few distinct diagnostic traits which make it different to all remaining varieties. These distinct traits help to identification of variety during legal infringement (DUS testing) [5].
All the information related to the development of entry
Private companies can enter their material into the coordinated trial system as similar to other agencies but have to pay the prescribed fee for their entries as per guideline of the Government of India.
All the material (product of selection, hybridization followed by selection, synthetics, composites, and hybrids, etc.) shall be subjected to the same system.
The AICCIP centers for various crops are located at ICAR institutes or State Agricultural Universities (SAUs) or other volunteer centers recommended by AICCIP workshop based on covered crop area, adaptability, and agro-climatic condition etc. It involves various steps [6].
The time duration of the initial varietal trial (IVT) is one year. All the entries, which were superior to their respective station trials, would be introduced into the IVT. These entries would be used for multi-location trials along with checks. In general, three checks (national, zonal and local checks) are being used for efficient evaluation of entries across the centers. The national check (a crop variety which had been released previously for whole country) would be used for a long period but zonal (a crop variety which had been released previously for specific zone) and local checks (high yielding local variety) can be replaced based on the requirement. These checks cannot be replaced after the IVT. Maintenance of genetic purity, germination and physical purity of new material are the prime objectives of the concern plant breeder/agency. The IVT trials are conducted in such a manner that minimum difference of yield (5–10%) and other ancillary traits can be measured. Experimental layout (experimental design, number of replications and treatments) is the prime responsibility of the PC/PD through concerned principle investigator. The cultural practices
Based on superiority (5–10%) over the best performing check, superior entries will enter into the AVT-I from IVT. The number of tested entries in the AVT-I will be less than IVT. The plot size is large in AVT-I as compared to IVT, therefore data generated on yield and other ancillary traits will be more realistic, accurate and minimal chances of error. The number of testing locations should be more as compare to IVT in a given zone for more realistic data on yield and other economically important traits, varietal adaptation, biotic and abiotic tolerance, quality parameters, etc. National, zonal and local checks (which were used in IVT) shall be used for critical analysis along with the entries. During AVT-I, additional data on disease and or insect pest tolerance under artificial epiphytotic condition must be generated by the experts. Same as IVT, monitoring team would be deputed by the PC/PD at different growth stages of crop and observed data shall be submitted to the concerned PC/PD. Based on the performance of entry over the best performing check-in the respective zone, the superior entries would enter into the AVT-II.
All the requirements shall be fulfilled as similar to AVT-I. However, few additional data will be generated at AVT-II stage
Based on three year performance, best performing test entries shall be identified in the annual crop workshop or national group meet at the pre-defined institute/university. The Zonal Coordinators and Principal Investigators attend the national group meet to provide wider aspects of information on the varieties. After the approval from Deputy Director General (Crop Science) of Indian Council of Agricultural Research (ICAR), a “Varietal Identification committee (VIC)” constituted in advance of annual workshop or national group meet. All the committee members (Table 1) shall be informed well in advance by the PC or PD [3]. Principal investigators (PIs) of different disciplines can assist in the process of discussion but they do not have the right to vote. Only committee members have the right to cast vote. The VIC provides detailed information on recommended entries to the Central Sub-Committee on Crop Standards, Notification, and Release. This committee has sole right to release and notify the best-performing entry into national wise or zonal wise based on the recommendations of the VIC.
S.N. | Representative | Organizational position |
---|---|---|
1 | DDG (Crop Science)/ his or her nominee | Chairman |
2 | Project Coordinator/Project Director of AICCIP | Member Secretary |
3 | Director of Research of institute/SAUs of that region where the meeting is held | Member |
4 | Agricultural Commissioner (Department of Agriculture) | Member |
5 | One nominee of Seed organization (NSC, SSC) | Member |
6 | One representative of private seed agencies | Member |
7 | One representative of crop-based industries | Member |
8 | Project coordinator (seed technology) | Member |
9 | Two eminent scientists of that institute | Member |
Organizational setup of varietal identification committee (VIC). The committee comprises one chairman and nine members.
Source: [3] Tandon et al., 2015.
The candidate variety must have a minimum of three years of yield and other ancillary trait data from multi-location coordinated trials.
At least two-year data on disease and pest reaction at a hot spot or artificial epiphytotic condition.
The candidate variety must have at least one-year data on agronomic performance like seed rate, dates of sowing, planting density, irrigation, and fertilization. In forage crops, three year rigorous evaluation must be done for annual crops (seed yield data for third year only) and four year for perennial crops (one year for crop establishment and other three years for evaluation).
The concerned breeder must have at least a minimum requirement of nucleus seed so that breeder seed can be generated easily.
The concerned plant breeder should have pure seed for planting of 5 ha area. If he or she did not match the requirement, then identification can only be postponed for one year.
All these issues shall be discussed by the project coordinator in the annual workshop itself. The candidate variety must be phenotypically uniform (plant height, maturity, etc.) and stable in performance throughout the years.
Central Sub-Committee on Crop Standards, Notification, and Release of Varieties appointed by Central Seed Committee under Section 3 of the seed act, 1966 during 1994. The committee comprised one chairman and 17 members (Table 2).
S.N. | Representative | Organizational position |
---|---|---|
1 | Deputy Director General (Crop Sciences), ICAR | Chairman |
2 | Deputy Commissioner (QC) DAC & FW, GOI | Member Secretary |
3 | Directors of State Seed Certification Agencies, or their representatives | Member |
4 | Project Directors of Departments of Agriculture of all states, or their representatives | Member |
5 | Project Coordinators/Directors of AICCIPs | Member |
6 | Agricultural Commissioner, GOI | Member |
7 | Representatives of the seed industry, NSC, State Seed Corporations, private seed companies | Member |
8 | Representatives of ICAR, ICAR institutes, NGOs | Member |
9 | Progressive farmers | Member |
Organizational setup of central sub-committee on seed standards, release, and notification of variety (agricultural crops). The committee comprised one chairman and 17 members.
Source: [7] SeedNet India Portal; QC-Quality Control, DAC & FW-Department of Agriculture, Cooperation and Farmers Welfare, GOI-Government of India.
Central Sub-Committee releases varieties as per the benefit of the stakeholders and need of regional, zonal or national importance, and the State Seed Sub-Committee releases varieties beneficial for particular state. Notification of variety is compulsory on regulating the seed quality under the provision of Seed Act, 1966. Notification usually authorizes certified seed production throughout the country, by private or public seed multiplication organizations. Once the Central Sub-Committee accepts the proposal, the varieties/hybrids will be released for the concerned agro-climatic zone/s (may cover one or more number of states or nationally). Simultaneously, it must be notified for seed certification purpose in the country. During the release, the concerned breeder must have a minimum amount of seed which can be sown at least ten-hectare area [3]. Later on, seed multiplication is the responsibility of various seed agencies (NSC, SSC, private seed companies and progressive farmers, etc.). The significant differences between released and notified varieties are illustrated in Table 3.
S.N. | Released variety | Notified variety |
---|---|---|
1 | It is not a statutory function under the Seed Act, 1966 | Statutory function and variety will be registered under Section 5 of seed act 1966. |
2 | It cannot be used for seed certification | Only notified varieties to come under seed certification |
3 | No guarantee on seed quality for farmers | Assured seed quality |
4 | Seed law enforcement agencies (seed inspector etc.) cannot draw and test seed samples | They have the right to draw and test seed samples |
5 | These are not assets of Govt. of India | Notified varieties are assets of Govt. of India |
6 | Its main purpose is to make available the information of cultivar to the public and its area of adoption | The main purpose is seed quality regulation |
7 | Difficult to trace out the genesis | The notification of the varieties will help to trace out its genesis. |
Critical differences between released and notified varieties.
It is a legal body constituted by the Department of Agriculture, Cooperation and Farmers’ Welfare (DAC&FW), Ministry of Agriculture and Farmers’ Welfare (MoA&FW), Government of India to advise central and state government on matters related to the implementation of seed act, 1966 and other related functions. The core committee includes one chairman and eight members to be nominated by the central government and one person to be nominated by the Governments of each State (Table 4). State Seed Committee (SSC) has a similar role at the state level. The CSC and SSC are empowered to release varieties but only CSC can notify those [8].
S.N. | Representative | Organizational position |
---|---|---|
1 | Secretary, DAC&FW, MoA& FW, GOI | Chairman |
2 | Additional Secretary (In charge Seeds), MoA& FW, GOI | Member |
3 | Agricultural Commissioner, MoA& FW, GOI | Member |
4 | Deputy Director General (Crop Sciences), ICAR | Member |
5 | Joint Secretary (In charge Seeds), MoA& FW, GOI | Member |
6 | Progressive farmers/ seed growers (4) nominated by the Central Government | Member |
7 | One representative from each State Govt. | Member |
8 | Director of National Seeds Project, MoA& FW, GOI | Member Secretary |
Organizational setup of central seed committee (CSC). The committee comprises one chairman and nine other members by the central government.
Source: [9] SeedNet India Portal; MoA & FW- Ministry of Agriculture and Farmers Welfare.
The CSC has authority to release varieties (pure lines/hybrids/composites/synthetics) developed by central research institutes (ICAR/non-ICAR), AICCIPs, private or corporate sector, and other organization as per the scientific data authenticity for zonal basis (which may include more than one state) or at national level.
The CSC has authority to approve proposals received from the State Variety Release Committees/State Seed Sub-Committees for varieties developed by the State Research Institutes but is considered suitable for areas outside the state (based on their performance).
The CSC can delimit the regions or tracts for the cultivation of varieties approved for release.
The CSC can advise the ICAR regarding the manner in which the National Register of Approved Varieties may be maintained, and to suggest the standard description of crop varieties.
The CSC can notify kinds/varieties for the purpose of the Seeds Act and the areas of their notification.
The CSC specifies minimum limits of germination percentage and purity for the notified kinds/varieties of seeds as per minimum seed certification standards.
The CSC specifies the “mark” or “label” in respect of notified kinds/varieties.
The State Seed Sub-Committees are constituted by Central Seed Committee and are authorized to set up a State Seed Laboratory, State Seed Certification Agency (SSCA) and an Appeals Authority, and to appoint seed inspectors and seed analysts. The differences between Central Sub-Committee and State Sub-Committee are given in Table 5.
S.N. | Central sub-committee | State sub-committee |
---|---|---|
1 | Authorized by Central Seed Committee | Authorized by State Seed Committee |
2 | Releases varieties for regional/zonal/national level | Only for concerned state/regions within the state |
3 | Statutory body for varietal notification | It cannot notify varieties |
4 | Notification followed by seed certification | Certified seed cannot be produced without notification |
5 | Members in the committee are appointed by the Central Govt. | Members in the committee are appointed by the State Govt. |
Critical differences between central sub-committee and state sub-committee.
There are some rights which have been provided by the Central Seed Committee for proper functioning of seed chain in respective state in India. These empowerments are-
The State Seed Sub Committee will advise the state government on all matters related to the execution of the Seeds Act, 1966.
Reviewing the implementation of the Seeds Act in the state and send periodic reports to the state government and the Central Seed Committee.
Inspect, analyze and report on the State Seed Testing Laboratory.
Advise on educational and promotional measures for proper enforcement and understanding of the Seed Act.
Planning for different crop varieties to be grown in different regions of the state, and to review the assessment of seed requirements.
Considering the release of new varieties for the state and recommend their notification to the Central Seed Committee.
Monitoring the performance of newly released varieties in the state.
Being agriculture as a state subject in India, centrally released varieties are not directly accepted by all the states for which they have been released. Each state has its own regulatory system which they have to follow for varietal release in the state. They have to pass through all the steps of the concerned state release procedure before they approve for cultivation in the state
Since only notified varieties will be under the purview of Seed Law Enforcement, hence it is necessary to bring the seed of a particular crop variety under notification system. The seed inspector can only draw a sample from notified variety for analysis and ensure the seed quality [10, 11]. A released variety cannot come under seed chain without notification by the Gazette of India. Therefore, these issues will make the notification as necessary requirement for other things to act on it. The notification is made by the Central Government on the recommendation of the Central Seed Committee. Thus, notification is prerequisite for production of certified seed which ensures high quality of seeds to the farmers. After notification, variety becomes asset of government of India. The breeder seed can only be produced after the notification of variety and notified varieties enter into seed chain. Notification also helps in the genesis of original variety based on its pedigree and also regulates any kind of infringement in the later stages of varietal promotion.
Released varieties can be denotified if they are not performing well in the area of their adoption or have been in cultivation for more than 15 years or are not much in demand. Denotification can be done based on the recommendation of central seed committee by the government of India.
There are several ways and means to increase the crop production and productivity, however using genetically pure and high-quality seed is first and prime objective in agriculture. Therefore the variety which will be used by farmers must have undergone several evaluations in order to ensure its stable yield potential, tolerance to biotic and abiotic stresses and these criteria are being fulfilled by a legal varietal release system. The main objective of the varietal release system in India is to introduce newly developed, high yielding varieties to the farmers for broad-spectrum cultivation in the area of their adoption and only those varieties will be notified which are superior to existing one. It provides choice to the farmers to cultivate a specific variety, based on their need for crop diversification. In India, the systemic framework has helped farmers to get high quality of seed from market and production has increased many folds since the inception of AICCPs. Notification is mandatory to release a variety, though the release process itself does not have legal cover.
Authors acknowledge Director, ICAR-Indian Grassland and Fodder Research Institute and Project Coordinator, ICAR-All India Coordinated Research Project on Forage Crops and Utilization for their assistance, guidance and funding.
The authors declare no conflict of interest.
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