Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\n
Thank you all for being part of the journey. 5,000 times thank you!
\\n\\n
Now with 5,000 titles available Open Access, which one will you read next?
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n
"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\n\n
Thank you all for being part of the journey. 5,000 times thank you!
\n\n
Now with 5,000 titles available Open Access, which one will you read next?
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\r\n\tCysticercosis, caused by the metacestode stage of Taenia solium, is a serious health and veterinary problem in many developing countries and is considered one of the most important neglected tropical diseases in developed countries. In humans, T. solium cysticerci cause neurocysticercosis, which affects ~50 million people worldwide, and it has been considered as an emergent disease in the United States. T. solium also infects pigs, its intermediate host, leading to major economic losses.
\r\n
\r\n\tWhen humans ingest undercooked contaminated pork meat, the adult worm develops in the small intestine. After two months of asymptomatic infection, this tapeworm starts producing thousands of eggs, that, once released with the stools, can contaminate the environment, infecting pigs (rapidly differentiating into cysticerci mainly in the muscle) and humans (where most severe symptoms are observed due to the presence of cysticerci in the brain). Thus, maintenance of the parasite's life cycle depends on the adult tapeworm development. Even in communities which do not rear or consume pigs, human neurocysticercosis can be found, because of the presence of a tapeworm carrier. Furthermore, tapeworm development in turn depends on scolex evagination, the initial step through which a single cysticercus becomes an adult parasite with the capability of producing infective eggs. A great deal of scientific advances on the field has been producing in recent times, all on the most important fields of the disease: vaccination, epidemiology, current drug design, diagnostic and host-parasite interaction at all levels. However, to date, there is no actualized book dealing with the recent advances in such an important disease in the world.
\r\n
\r\n\tThis book will intend to provide the reader with a comprehensive overview of the current state-of-the-art in cysticercosis featuring an easy-to-follow, vignette-based format that focuses on the most important evidence-based developments in this critically important area.
",isbn:"978-1-83969-395-3",printIsbn:"978-1-83969-394-6",pdfIsbn:"978-1-83969-396-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"16dae70f4745a1873fbeb34e67007b24",bookSignature:"Prof. Jorge Morales-Montor, Dr. Abraham Landa and Dr. Luis Terrazas",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10354.jpg",keywords:"Delivering Methods, DNA Vaccines, Diagnostic of Cysticercosis, Diagnostic of Taeniosis, Epidemiology of Cysticercosis, Epidemiology of Neurocysticercosis, New Drugs Available, Drug-Design, Taenia Solium, Clinical Trials, Taenia Crassiceps, Immune Response",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 23rd 2020",dateEndSecondStepPublish:"December 21st 2020",dateEndThirdStepPublish:"February 19th 2021",dateEndFourthStepPublish:"May 10th 2021",dateEndFifthStepPublish:"July 9th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher in Neuroinmunoendocrinology of several parasite infections, including cysticercosis. He has published over 153 papers, has edited 12 books, and written around 50 book chapters. Head of the Laboratory of Neuroimmunoendocrinology, Institute of Biomedical Research in UNAM, Mèxico.",coeditorOneBiosketch:"A pioneering researcher in molecular parasitology of Taenia solium cysticerci. He was part of the team that sequenced the Taenia solium genome. He has published over 33 papers on cysticercosis. Head of the Laboratory of Molecular Parasitology in UNAM, Mèxico.",coeditorTwoBiosketch:"A pioneering researcher in studying the immunology of taeniasis/cysticercosis, appointed Head of the Unit of Experimental Biomedicine. Recently appointed as Director of the Office of Development and Cultural and Scientific Relationships in the School of Superior Studies Iztacala, UNAM.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.jpg",biography:"Dr. Jorge Morales-Montor studied biology at the Iztacala UNAM Faculty of Higher Studies, obtaining the title in 1992. He obtained a\ndoctor’s degree in October 1997. His doctoral thesis was recognized with the Lola and Igo Flisser-PUIS Award to the best graduate thesis at thenational level in theareaofparasitology,a recognition that he has also later received as a tutor, since one of his doctorate students won the same award in 2008. In November 1997, he began a postdoctoral stay at theDepartment of CellularBiology at the UniversityofGeorgia, USA, in the laboratory of Dr. Raymond T. Damia´n, one of the most recognized parasitologists in the world. Dr. Morales received a grant from the Fogarty Foundation (one of the most prestigious in Ibero-America) to carry out research on schistosomiasis in the baboon, being a Pan American Fellow for 4 years. Dr. Ray Damia´n would write years later, which assured that\nwithout a doubt, Jorge Morales-Montor had been the best postdoctoral researcher with whom he collaborated in his nearly 35-year career. He was repatriated to Mexico in 2001 by CONACYT and joined the Department of Immunology of the Institute of Biomedical\nResearch of UNAM as Associate Investigator “C”. In just 9 years, he managed to climb the entire ladder of university academic positions, to receive its tenure track positionas a Definitive C Titular Researcher at the Institute of Biomedical Research. The same is reflected in the Level of Premiums for Academic Performance, where it has reached the highest level currently: Level D, for the third\nconsecutive period. Also in the National System of Researchers, he has had the same growth, starting in 1997 as a candidate, and, to date, being promoted to Level III, the highest, for the third consecutive period. Dr.Morales-Montor has been invited to participate\nin different congresses (more than 100). In addition, he is part of the editorial committee of more than 15 indexed international\njournals, nd Editor in Chief of 3. Some of his most important contributions are partially determining the role of steroid hormones in immunological sexual dimorphism, in the polarization of the immune response, and in the antigenic presentation.He has alsomade very relevant studies in relation to how different physiological stages, how the estrous cycle, age, sex, or pregnancy affect the functioning of\nthe immune, endocrinological, and nervous system, and what molecules could be the determinants in this context of net. It has been\nshown that the central nervous system is involved in the regulation of the immune response to parasitic infections, and the effect\nof this activation on various behaviors of the infectedhost. But the centralnervous system has provided interesting data about its\nimpact in the parasitology approach. For instance, a modern concept is depicted by how the central nervous system modulates\nthe gene and proteomic regulation of the different sex steroids in parasites,which are involved in important functions of parasites\nsuch as establishment, growth, and reproduction. Finally, the practical use of the knowledge acquired by the earlier mentioned\nstudies has been applied to a theory that he calls old drugs, new uses: the use of hormones and antihormones as antiparasitic\ntherapy. He has also entered the study of environmental contamination, specifically endocrine disruptors and disease, studying\ntheir role in two very important diseases in the country: cancer and obesity, projects with which he has formed two consortiums\nof investigation. Its results are a very important contribution to the health of both Mexicans and Latin Americans in general, since\nthis is where serious health problems related to parasitic infections, cancer, and obesity are concentrated.His investigations are characterized by an exhaustive and meticulous experimental work, and his scientific production already has 153 articles in international indexed journals, and the majority as the first author or corresponding author. He hasmore than 3000 citations to his works, and an h-index of 29, one of the highest in the country’s scientific community. His articles published in high-impact international\njournals include Nature, PlosOne, Journal of Immunology, Journal of Infectious Diseases, Journal of Interferon and Cytokine Research,\nand among others. In fact, recently, his 2015 article, The Role of Cytokines in Breast Cancer Development and Progression, published in the Journal of Interferon and Cytokine Research, was the subject of a press release released by Mary Ann Liebert Publications. This is sent all over the world, to newspapers, Journals, scientists, radio, TV, popular magazines, to what is considered as a very important contribution in a certain area of science. Very few scientific articles are released as “press release.” He is also the 4th most cited author in the area of parasitology in the country. He has also edited several books and published more than 55 chapters in books, national and foreign. In this area, recently, the chapter “The Role of Sex Steroids in the Host-Parasite Interaction,” published in the international\nbook “Sex Steroids” in 2012, reached the figure of 68,000 downloads, which means the degree of attention that has after receiving\nhis work; the foregoing makes it clear that Dr. Morales-Montor’s work is highly relevant and widespread amongthenational and international academic community, and his brilliant career has earned him more than 30 awards, such as the Miguel Aleman Valdez Award in the area of Health 2006, the Distinction National University for Young Academics in the area of Research in Natural Sciences 2006, the CANIFARMA Veterinary Prize 2007 and 2009 the Heberto Castillo Martı´nez Capital City Award for Young Latin American Academics in Basic Research, and for the third consecutive congress, in 2011, one of his works was awarded the “Dr. Jose Eleuterio Gonza´lez” Award, for the best work of and research at the XXVI National Congress of Research in Medicine, to name just a few of its achievements. He has also mentored and graduated more thn 60 students at all levels (Baccularate, Masters and Doctorate) and also been awarded many distinctions, such as joining the Mexican Academy of Sciences (2005), and being one of the few Mexican scientists to be inducted to the Latin American Academy of Sciences (2008), The National Academy of Medicine, the New York Academy of Sciences, the American Association of Immunologists are deserved recognitions for his academic quality and career. His academic leadership is reflected in the trust and respect that his peers confer on him, having been President of the Mexican Society\nof Parasitology (one of the oldest and most prestigious scientific societies in the country) and currently being President, and founding member, of the Mexican Society of Neuroimmunoendocrinology, since 2011. Due to its scientific curiosity, it is in the process of founding the Mexican Society for Translational Environmental Biomedicine. He has been invited to edit special volumes\nin various magazines with international circulation and is a member of the editorial committee of magazines of\nimportance in his area of work, such as ParasiteImmunology, The OpenParasitologyJournal, among others. He has been a jury for\nthe Arturo Rosenblueth Awards for the best CINVESTAV Doctoral Thesis, a jury for the Lola and Igo Flisser-PUIS 2010 Awards, and\na jury for the Heberto Castillo Award, for the best Latin American Researcher 2012, awarded by the Federal District Government.\nIt is noteworthy that he is an outstanding scientist, who has contributed to the scientific research of Mexico with the generation of new frontier knowledge in the world and with the training of high-level human resources.",institutionString:"National Autonomous University of Mexico",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Autonomous University of Mexico",institutionURL:null,country:{name:"Mexico"}}}],coeditorOne:{id:"332210",title:"Dr.",name:"Abraham",middleName:null,surname:"Landa",slug:"abraham-landa",fullName:"Abraham Landa",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:'He is a Master and Doctor of Science from UNAM, he did his post-doctorate at the Harvard University School of Public Health and his sabbatical at the Tufts University in Boston. He began his career as a teacher at the Faculty of Medicine UNAM in 1992, as an assistant in the subject of Biochemistry and Molecular biology to later be the owner of it. Is currently Full Professor "C" of T.C Definitive. It is Level “D” of the PRIDE and Level III of the National Research System. Academic-administrative positions: Representative of Postgraduate Tutors in Biological Sciences (2003-2006), in Biological Sciences (2003-2006), Member of the Review Commission of Nonconformities of the Personnel Performance Bonus Program Academic (PRIDE, 2002-2005), Secretary of the Mexican Society of Parasitology (2010-2011), Member of the Technical Council of the Faculty of Medicine (2006-2013) and currently a Member of the Judging Commission Research and Postgraduate Program CAABQyS of the FES-Iztacala (2015-1017).\r\nAwards and distinctions won the Scholarship awarded by the McArthur Foundation (1988-1989), Second place in the IV Parasitology Prize "Lola and Igo Flisser" 1992, the "Gabino Barreda" medal for his Doctorate in Science studies, 1997 and the medal "Nayarit for Scientific and Technological Research in 2001". Contributions and Scientific Productivity His research has been directed to the study of the molecular biology of Cestodes, especially of Taenia solium. He pioneered cloning and characterization of cestode genes and participated in the Consortium that carried out the university megaproject of the Taenia solium genome and three genomes\r\nmore than cestodes that resulted in a 2013 publication in the journal Nature. He has obtained with collaborators from the Institute of Chemistry, Faculty of Chemistry and from UAM the first crystal and inhibitor for a protein in cestodes (Cu / Zn superoxide dismutase), developed a recombinant antibody that inhibits triose phosphate isomerase. Has characterized the 3 glutathione transferases (24, 25, 26 kDa) that form the main system of detoxification and has contributed knowledge about the regulation of transcription, the foregoing has allowed reasonable knowledge of the cestodes and the diseases they cause. As a result of your work\r\nscientist has 58 publications, 12 book chapters, plus 2 books. Teaching and Training of Human Resources: Has taught since 1991, 30 courses and topics at the Postgraduate level. He has also directed 30 undergraduate theses, 9 Master\'s, 1 Specialization and 9 Doctorate. Almost all of his students PhD students are active researchers in Mexico and abroad. Doctor Landa is an active participant in conferences, as a member of committees tutorials, professional degree examinations in all programs of Postgraduate of the UNAM.',institutionString:"National Autonomous University of Mexico",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Autonomous University of Mexico",institutionURL:null,country:{name:"Mexico"}}},coeditorTwo:{id:"332215",title:"Dr.",name:"Luis",middleName:null,surname:"Terrazas",slug:"luis-terrazas",fullName:"Luis Terrazas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031RIzxQAG/Profile_Picture_1600754945533",biography:'He is a Master and Doctor of Science from UNAM, he did his post-doctorate at the Harvard University School of Public Health and his sabbatical at the Tufts University in Boston. He began his career as a teacher at the Faculty of Medicine UNAM in 1992, as an assistant in the subject of Biochemistry and Molecular biology to later be the owner of it. Is currently Full Professor "C" of T.C Definitive. It is Level “D” of the PRIDE and Level III of the National Research System. Academic-administrative positions: Representative of Postgraduate Tutors in Biological Sciences (2003-2006), in Biological Sciences (2003-2006), Member of the Review Commission of Nonconformities of the Personnel Performance Bonus Program Academic (PRIDE, 2002-2005), Secretary of the Mexican Society of Parasitology (2010-2011), Member of the Technical Council of the Faculty of Medicine (2006-2013) and currently a Member of the Judging Commission Research and Postgraduate Program CAABQyS of the FES-Iztacala (2015-1017).\r\nAwards and distinctions won the Scholarship awarded by the McArthur Foundation (1988-1989), Second place in the IV Parasitology Prize "Lola and Igo Flisser" 1992, the "Gabino Barreda" medal for his Doctorate in Science studies, 1997 and the medal "Nayarit for Scientific and Technological Research in 2001". Contributions and Scientific Productivity His research has been directed to the study of the molecular biology of Cestodes, especially of Taenia solium. He pioneered cloning and characterization of cestode genes and participated in the Consortium that carried out the university megaproject of the Taenia solium genome and three genomes\r\nmore than cestodes that resulted in a 2013 publication in the journal Nature. He has obtained with collaborators from the Institute of Chemistry, Faculty of Chemistry and from UAM the first crystal and inhibitor for a protein in cestodes (Cu / Zn superoxide dismutase), developed a recombinant antibody that inhibits triose phosphate isomerase. Has characterized the 3 glutathione transferases (24, 25, 26 kDa) that form the main system of detoxification and has contributed knowledge about the regulation of transcription, the foregoing has allowed reasonable knowledge of the cestodes and the diseases they cause. As a result of your work\r\nscientist has 58 publications, 12 book chapters, plus 2 books. Teaching and Training of Human Resources: Has taught since 1991, 30 courses and topics at the Postgraduate level. He has also directed 30 undergraduate theses, 9 Master\'s, 1 Specialization and 9 Doctorate. Almost all of his students PhD students are active researchers in Mexico and abroad. Doctor Landa is an active participant in conferences, as a member of committees tutorials, professional degree examinations in all programs of Postgraduate of the UNAM.',institutionString:"National Autonomous University of Mexico",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Autonomous University of Mexico",institutionURL:null,country:{name:"Mexico"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"280415",firstName:"Josip",lastName:"Knapic",middleName:null,title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/280415/images/8050_n.jpg",email:"josip@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copy-editing and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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1. Introduction
Reproductive efficiency in dairy and beef cows is dependent on achieving high submission rates and high conception rates per service. However, to achieve good submission and conception rates cows must resume ovarian cyclicity, have normal uterine involution, be detected in estrus, and inseminated at an optimum time. In seasonally calving herds the aim is to achieve conception by 85 days following parturition so that calving to calving intervals are maintained at 365 days. Reproductive performance of cows affects the efficiency of milk production in the herd because of its influence on the calving to first service interval, calving pattern, length of lactation and culling rate.
The pattern of resumption of ovarian function in both dairy and beef cows was recently reviewed (Crowe 2008). Resumption of ovarian cyclicity is largely dependent on LH pulse frequency. Both dairy and beef cows have early resumption of follicular growth within 7 to 10 days post partum. The fate of the dominant follicle within the first follicular wave is dependent on LH pulsatility. This chapter will focus on the factors contributing to resumption of ovulation in postpartum dairy and beef cows.
2. Ovarian follicle growth in cattle
Ovarian follicle growth takes a period of 3-4 months and can be categorized into gonadotropin independent and gonadotropin dependent stages (Webb et al. 2004). Gonadotropin dependent follicle growth in cattle occurs in waves (Rajakoski 1960; Matton et al. 1981; Ireland and Roche 1987; Savio et al. 1988; Sirois and Fortune 1988). Each wave of growth involves emergence, selection and dominance followed by either atresia or ovulation. Emergence of a follicle wave is defined as growth of a cohort of follicles ≥ 5mm in diameter and coincides with a transient increase in FSH secretion (Adams et al. 1992; Sunderland et al. 1994). Selection is the process by which the growing cohort of follicles is reduced to the ovulatory quota for the species (in cattle it is generally one), selection occurs in the face of declining FSH concentrations (Sunderland et al. 1994). The selected follicle survives in an environment of reduced FSH due to the development of LH receptors in granulosa cells (Xu et al. 1995, Bao et al. 1997) and increased intrafollicular bioavailable insulin-like growth factor-I (IGF-I; Austin et al. 2001; Canty et al. 2006). The increased bioavailable IGF-I is achieved by reduced IGF-I binding proteins (IGFBP) due to increased IGFBP protease activity. Dominance is the phase during which the single selected follicle actively suppresses FSH concentrations and ensures suppression of all other follicle growth on the ovaries (Sunderland et al. 1994). The fate of the dominant follicle is then dependent on the prevailing LH pulse frequency during the dominance phase. In the presence of elevated progesterone (luteal phase of cyclic animals) LH pulse frequency is maintained at 1 pulse every 4 hours and the dominant follicle undergoes atresia, in the follicular phase (preovulatory period in cyclic animals) the LH pulse frequency increases to one pulse per hour and this stimulates final maturation, increased estradiol concentrations and positive feedback on gonadotropin-releasing hormone (GnRH), LH (and FSH) in a surge that induces ovulation (Sunderland et al. 1994). Normal follicle waves have an inherent lifespan of 7 to 10 days in duration from the time of emergence of a wave until emergence of the next wave (indicating either ovulation or physiological atresia of the dominant follicle). In cyclic heifers during the normal 21 day estrous cycle there are normally 3 waves (sometimes 2 waves and rarely 1 or 4 waves; Savio et al. 1988; Murphy et al. 1991).
2.1. Pattern of gonadotropin secretion and follicle growth during pregnancy
During pregnancy follicular growth continues during the first two trimesters (Ginther et al. 1989; Ginther et al. 1996) at regular 7 to 10 day intervals. In late pregnancy (last 22 days) the strong negative feedback of progestagens (mostly from the CL of pregnancy and partly of placental origin) and estrogens (mostly placental in origin) suppresses the recurrent transient FSH rises that stimulate follicle growth (Ginther et al. 1996; Crowe et al. 1998; Figure 1) so that the ovaries during the last 20 – 25 days are largely quiescent.
2.2. Resumption of gonadotropin secretion and follicle growth post partum
At the time of parturition progesterone and estradiol concentrations cascade to basal concentrations. This allows for the almost immediate resumption of recurrent transient increases in FSH concentrations (within 3 to 5 days of parturition) that occur at 7 to 10 day intervals (Crowe et al. 1998). The first of these increases stimulates the first postpartum wave of follicle growth that generally produces a dominant follicle by 7-10 days post partum (Savio et al. 1990a; Murphy et al. 1990; Crowe et al. 1993). The fate of this first follicular wave dominant follicle is dependent on its ability to secrete sufficient estradiol to induce a gonadotropin surge. The capacity for estradiol secretion is in turn dependent on the prevailing LH pulse frequency during the dominance phase of the follicle wave, the size of the dominant follicle and IGF-I bioavailability (Austin et al. 2001; Canty et al. 2006). So the major driver for ovulation of a dominant follicle during the postpartum period is the LH pulse frequency. This has been tested and validated by the LH pulsatile infusion studies of Duffy et al. (2000) in early postpartum anestrous beef cows. The LH pulse frequency required to stimulate a dominant follicle towards ovulation is one LH pulse per hour. Figure 2 is a schematic indicating the likely fate of the early postpartum dominant follicles in beef and dairy cows. In beef cows the first dominant follicle generally does not ovulate (Murphy et al. 1990, Stagg et al. 1995), but rather it undergoes atresia. With beef cows in good body condition the first postpartum dominant follicle to ovulate is generally from wave 3.2 ± 0.2 (~ 30 days; Murphy et al. 1990); whereas for beef cows in poor body condition there are typically 10.6 ± 1.2 waves of follicular growth before ovulation occurs (~ 70-100 days; Stagg et al. 1995; Figure 3). In the case of dairy cows ovulation of the first postpartum dominant follicle typically occurs in 50 to 80% of cows, it undergoes atresia in 15 to 60% of cows or becomes cystic in 1-5% of cows (Savio et al. 1990b; Beam and Butler 1997; Sartori et al. 2004; Sakaguchi et al. 2004).
Figure 1.
Follicle-stimulating hormone (FSH), progesterone (P4), estradiol (E2) and follicular diameter profiles in two representative beef cows from ~30 days prepartum until 50 days postpartum (Crowe et al. 1998).
Figure 2.
Diagrammatic scheme of resumption of dominant follicles and ovarian cycles during the postpartum period in dairy and beef suckler cows not nutritionally stressed. LH pulse frequency is that occurring during an 8 h window where cows are blood sampled every 15 min. Short cycles occur in most (70%), but not all cows after first ovulation (Reprinted with permission Crowe, 2008).
First ovulation in both dairy and beef cows is generally silent (i.e., no behavioural estrus; Kyle et al. 1992) and is generally (>70%) followed by a short cycle, usually containing just one follicle wave. This first luteal phase is reduced in length due to the premature release of prostaglandin F2α (PGF2α; Peter et al. 1989) presumably arising from the increased estradiol produced from the formation of the post-ovulatory dominant follicle on days 5-8 of the cycle inducing premature estradiol and oxytocin (Zollers et al., 1993) receptors. Thus the corpus luteum regresses prematurely around days 8-10 of the cycle, with the second ovulation (of this post-ovulatory dominant follicle) occurring around days 9-11 after the first ovulation. This second ovulation is generally associated with the expression of estrus and a normal length luteal phase.
Cyclic postpartum cows may have 2, 3 or occasionally 4 follicle waves during the estrous cycles that occur in the postpartum period (Savio et al. 1990a; Sartori et al. 2004). Unlike non-lactating heifers, lactating Holstein postpartum dairy cows tend to have two follicle waves per 18-23 day cycle (Sartori et al. 2004). Progesterone concentration is the major factor that affects LH pulse frequency in cyclic animals. Generally lactating Holstein dairy cows tend to have lower progesterone concentrations during the cycle than cyclic heifers (Sartori et al. 2004; Wolfenson et al. 2004). These lower progesterone concentrations tend to allow a subtle increase in LH pulse frequency and allows for prolonged growth of each dominant follicle rather than the faster atresia that occurs in cyclic heifers. Cows with prolonged luteal phases tend to have a fourth follicle wave (Savio et al. 1990a). The number of follicle waves or rate of turnover of dominant follicles are directly related to the duration of dominance of each dominant follicle, and cattle with shorter durations of dominance for the ovulatory dominant follicles tend to have higher conception rates (Austin et al. 1999). Therefore nutrition, by altering metabolic clearance of progesterone can affect the duration of dominance of a dominant follicle, the number of follicle waves per cycle and have an indirect effect on conception rates.
Figure 3.
Pattern of growth and regression of dominant follicles from calving to second ovulation in (a) a beef suckler cow with two non-ovulatory follicle waves prior to first ovulation, and (b) a beef suckler cow with 14 non-ovulatory waves prior to first ovulation. Arrows indicate ovulation. Reproduced with permission Stagg et al. (1995); Crowe 2008.
3. Post-partum anestrus
3.1. Factors contributing to LH pulse frequency in early post-partum beef cows
The major factors that control LH pulse frequency (and therefore the fate of early postpartum dominant follicles) in postpartum beef cows include maternal bond / calf presence (presumably due to effects on opioid release), suckling inhibition (Myers et al. 1989), and poor body condition (Canfield and Butler 1990). Calf presence has a very clear negative effect on resumption of ovulation in beef suckler cows nursing calves. Restricted suckling of beef cows (once per day) from day 30, where calves were in an isolated pen away from sight of the cows, significantly advanced the interval from calving to first ovulation (51 days) compared with ad libitum suckled control cows (79 days). The effect of calf presence can be further compartmentalized into suckling stimuli (mammary sensory pathways) and maternal behaviour / bonding effects (Silveira et al. 1993; Williams et al. 1993) but requires positive calf identification by either sight or olfaction (Griffith and Williams 1996). Beef cows that calve down in poor BCS (<2.5; scale 1-5 as described by Lowman et al. 1976) are more likely to have a prolonged anestrous period (Stagg et al. 1995) due presumably to lower LH pulse frequency (Stagg et al. 1998). Similarly anestrus can be induced by chronic nutrition restriction in post-partum beef cows, and occurs when cows lose 22-24% of their initial body weight (Richards et al, 1989).
As beef suckler cows (with prolonged anovulatory anestrus) approach their first postpartum ovulation LH pulse frequency increases (observed during each sequential follicle wave from 6 waves before ovulation until the ovulatory wave; Stagg et al. 1998). Concentrations of IGF-I increased linearly from 75 days before first ovulation until ovulation which was associated with a linear decrease in growth hormone concentrations during the same period (Stagg et al. 1998). Thus postpartum beef cows require increased LH pulse frequency that is mediated largely by suckling inhibition and plane of nutrition, in addition to increased IGF-I concentrations to help stimulate dominant follicle maturation and growth so that there is sufficient secretion of estradiol to induce an LH surge and ovulation. Management may be used to encourage earlier ovulation by restricting suckling / access of the cows to the calves from approximately day 30 post partum (Stagg et al. 1988) or by increased plane of nutrition and body condition.
3.2. Factors contributing to LH pulse frequency in early postpartum dairy cows
In dairy cows the major factors affecting resumption of ovulation include BCS and energy balance (yield and dry matter intake), parity, season and disease (Bulman and Lamming 1978; Beam and Butler 1997; Beam and Butler 1999; Opsomer et al. 2000; Wathes et al. 2007). Energy intake, BCS and milk yield interact to affect energy balance in dairy cows. There is evidence to link many of these factors to reduced LH pulse frequency; indeed a negative association between energy balance and prolonged post-partum anestrous interval is well established for dairy cows (Butler et al. 1981; Canfield and Butler 1990; Staples et al. 1990) and is mediated by reduced LH pulse frequency (Canfield and Butler, 1990). A number of studies have been conducted in dairy cows of various yield potential that have categorised the pattern of resumption of ovarian function with the use of milk progesterone. These range from a study by Fagan and Roche (1986) using what would now be classified as traditional moderate yielding Friesian cows (4,000 – 5,000 kg milk per lactation) to that of Opsomer et al. (1998) using modern high yielding Holstein type cows (6,900 – 9,800 kg milk per lactation). The data from these two studies are summarised in Table 1. Furthermore, this pattern of resumption of ovarian function has been validated in a series of equivalent papers and the two key problem categories (prolonged interval to first ovulation and prolonged luteal phase) are summarized in Figure 4. Risk factors for these two ovarian abnormalities have been determined in a large epidemiological study by Opsomer et al. (2000). The major risk factors for a prolonged interval to first ovulation included (odds ratio in parentheses): acute body condition score loss up to 60 days post calving (18.7 within 30 days, 10.9 within 60 days), clinical ketosis (11.3), clinical diseases (5.4), abnormal vaginal discharge (4.5), and difficult calving (3.6).
Figure 4.
Percentage of cows defined as having either i) delayed resumption of ovulation or ii) prolonged luteal phases based on evaluation of milk progesterone profiles across a number of studies in dairy cows (compiled by Benedicte Grimard, France, personal communication; Reproduced with permission, Crowe 2008).
The greatest of these risk factors is acute body condition score loss. Current evidence suggests that dairy cows should calve down in a BCS of 2.75 – 3.0 (Scale 1-5; as described by Edmonson et al. 1989) and not lose more than 0.5 of a BCS unit between calving and first service (Overton and Waldron 2004; Mulligan et al. 2006) rather than earlier recommendations of 3.0 – 3.5 (Buckley et al. 2003). Cows that lose excessive body condition (≥ 1.0 BCS unit) have a longer postpartum interval to first ovulation. Thus monitoring BCS from before calving to first service is essential to good reproductive management. Body condition score changes are good indicators of energy balance and reflect milk yield and dry matter intake. It is necessary to prevent a steep decline in energy balance and shorten the duration of postpartum negative energy balance. This is best achieved by ensuring that dry matter intake in the early postpartum period is maximized and by having cows in appropriate BCS (2.73 – 3.0) at calving. Cows that are mobilizing tissue at a high rate have increased blood non-esterified fatty acids, and β-hydroxy butyrate, but reduced concentrations of insulin, glucose and IGF-I (Grummer et al. 2004). The metabolic status associated with high rates of tissue mobilization increases the risk of hypocalcaemia, acidosis, fatty liver, ketosis and displaced abomasa (Gröhn and Rajala-Schultz 2001; Overton and Waldron 2004, Maizon et al. 2004). Cows affected by these metabolic disorders are more prone to anestrus, mastitis, lameness and reduced conception rate to AI (Fourichon et al. 1999; Gröhn and Rajala-Schultz 2001; Lucy 2001; Lopez-Gatius et al. 2002; Maizon et al. 2004). It is hypothesized that serum IGF-I concentrations could be useful as a predictor of nutritional status and hence reproductive efficiency in dairy cows (Zulu et al. 2002a). Plasma IGF-I concentrations before calving and in the first few weeks of lactation have been linked to subsequent cyclicity and conception rate (Taylor et al. 2006). This emphasizes the critical role of correct nutritional management to ensure that the deficit in energy balance post calving is mild rather than severe. Current approaches to minimize the energy balance deficit post calving includes: the optimization of body condition score at calving (2.75 - 3.0), shorter dry periods and maintenance of normal rumen function (Mulligan et al. 2006).
Item
Fagan and Roche 1986 Moderate yielding Friesian cows
Opsomer et al. 1998 High yielding Holstein cows
No. of cows / postpartum periods
463
448
Normal cyclic patterns (%)
78
53.5*
Prolonged interval to 1st ovulation (%)
7
20.5*
Prolonged luteal phase (%)
3
20*
Temporary cessation of ovulation (%)
3
3
Short cycles (%)
4
0.5
Other irregular patterns (%)
4
2.5
Table 1.
Pattern of resumption of ovarian cyclicity in postpartum dairy cows (traditional moderate yielding Friesians vs modern high yielding Holsteins), using milk progesterone profiling (samples collected twice weekly). *Categories with a major disparity between the two studies.
Disease state may also regulate follicle fate via LH and other mechanisms. Uterine conditions such as retained foetal membranes, endometritis and metritis contribute to reproductive efficiency via various mechanisms. Local infection of the uterus in postpartum cows delays uterine involution, causes inflammation of the endometrium, reduce conception rate to first insemination (Sheldon 2004), but may also affect follicle growth, decrease estradiol secretion from dominant follicles, and delay the interval to first ovulation (LeBlanc et al. 2002; Sheldon et al. 2002; Sheldon and Dobson 2004; Williams et al. 2007; Sheldon et al. 2008). These effects on follicle growth and ovulation implicate potential roles mediated by either direct effects within follicles and reduced LH secretion / failure of the gonadotropin surge. Indeed the evidence supports both possible mechanisms: uterine disease associated with E. Coli or infusion of endotoxins reduces estradiol secretion from dominant follicles (Sheldon et al. 2002; Herath et al. 2007) and delays the LH surge and ovulation (Suzuki et al. 2001). Other diseases such as mastitis (Huzenicza et al. 2005) and lameness (Petersson et al. 2006) delay resumption of luteal activity by 7 to 17 days, respectively. For these there is considerable evidence that this is mediated due to acute stressors reducing GnRH and hence LH pulse frequency, leading to decreased estradiol production by dominant follicles and preventing or reducing the gonadotropin surge, thus delaying ovulation.
4. Abnormal ovarian function during the post-partum period
4.1. Prolonged luteal phases
Irregular estrous cycles in cows once they have resumed ovulation tend to be predominantly prolonged luteal phases. The incidence of prolonged luteal phases has increased from 3% (Fagan and Roche 1986) to 11-22% (Lamming and Darwash 1998; Opsomer et al. 1998; Shrestra et al. 2004; Figure 4). It is generally considered that prolonged luteal phases are associated with an abnormal uterine environment that disrupts prostaglandin production. Interestingly in the study of Opsomer et al. (1998), where the incidence of cows with prolonged luteal phases was 20% (89/448 cows), only 43/89 cows had abnormal uterine content, 2/89 had ovarian cysts and 44/89 had no detectable abnormalities. However in this study abnormalities were identified only by rectal palpation. The major risk factors for a prolonged luteal phase in cows having resumed ovulation included (odds ratio in parentheses; Opsomer et al. 2000): metritis (11.0), abnormal vaginal discharge (4.4), retained placenta (3.5), parity (2.5 for parity 4+ vs primiparous), earlier resumption of ovulation (2.8 for resumption < 19 days post partum, 2.4 for resumption 19-24 days post partum). These data support the concept that prolonged luteal phases are related to uterine problems rather than ovarian problems.
4.2. Follicular cysts
These occur where dominant follicles in the early postpartum period (often the first dominant follicle postpartum) fail to ovulate. Cysts typically continue to grow to diameters >20-25 mm over a 10 to 40 day period in the absence of a CL (Savio et al. 1990a; Gümen et al. 2002, Hatler et al. 2003). This continued growth appears to be due to lack of positive feedback induced by estradiol and thus failure of the LH/FSH pre-ovulatory surge, despite increased LH pulse frequency (to an intermediate level). At this time progesterone concentrations are low, while estradiol concentrations are elevated above normal pro-estrus concentrations (Savio et al. 1990b; Hatler et al. 2003), resulting in many cases in strong exhibition of estrous behaviour by cows in the early phases of a follicular cyst. This is followed by a period of time when there is an absence of estrous behaviour in the second half of the cysts lifespan. The elevated estradiol in conjunction with elevated inhibin suppresses FSH concentrations, so that no new follicle waves emerge during the early active phase of a follicular cyst. The cyst then becomes estrogen inactive (despite being morphologically still present) and a new follicle wave emerges. The dominant follicle of this new wave may either ovulate, undergo atresia or become cystic. Many cows with follicular cysts correct themselves, but some develop sequential follicular cysts. The metabolic risk factors associated with cows that develop cysts in the early postpartum period are over conditioned cows, a reduction in insulin (Vanholder et al. 2005) and IGF-I, and increased non-esterified fatty acids (Zulu et al. 2002b).
5. Induction of estrus and ovulation in anovulatory anestrous cows
From the previous sections it is clear that in many cases (especially with dairy cows) anovulatory anestrus is associated with management risk factors and other diseases (excessive loss of BCS, severe lameness, uterine disease, displaced abomasum, etc). Therefore before embarking on a specific treatment for anestrus, the underlying factors and diseases should be first addressed before commencement of specific treatments for the ovarian problems.
5.1. GnRH
The major cause of delayed ovulation in postpartum cows is an infrequent LH pulse frequency (and by inference GnRH pulse frequency). GnRH treatment was used with variable effectiveness in numerous studies of postpartum cows when the follicle status of the animals was unknown. A single injection, two injections 10 days apart, or frequent low dose injections at 1- to 4-h intervals of GnRH or GnRH analogues failed consistently to induce ovulation in over 90% of treated anestrous cows (Mawhinney et al. 1979; Riley et al. 1981; Walters et al. 1982; Edwards et al. 1983). However, when a GnRH analogue (20 µg Buserelin) was used at known stages of follicle growth (determined by daily ultrasound scanning) of the first postpartum DF, all cows ovulated when administered during the growing phase of the DF (12/12) and the majority (7/10) ovulated when the first postpartum DF was in its plateau / early declining phase of growth (Crowe et al. 1993). In a further study conducted by Ryan et al. (1998), 250 µg GnRH resulted in ovulation in 20 of 20 cows when given at dominance of a follicular wave, this was followed by emergence of a new wave of ovarian follicular growth 1.6 ± 0.3 days later and dominance of the subsequent wave was attained in 5 ± 0.3 days. However, there was no effect of GnRH on follicular dynamics when given at emergence of a follicular wave. The existing cohort of follicles continued to develop unaffected in 17 of 17 cows, and dominance occurred 3.6 ± 0.5 days later. Thus, GnRH may cause ovulation or no effect on follicle development depending on the animal’s stage of follicle development at treatment. Thus when GnRH is used as part of an ovsynch protocol (GnRH-PGF2α-GnRH treatment) in postpartum anestrous cows the effectiveness of the treatment is wholly dependent on the presence or absence of a DF at the time the first GnRH injection is administered.
5.2. Progesterone
Treatment of anestrous cows with progesterone (and estradiol) will induce estrus and shorten the postpartum interval to conception (Rhodes et al. 2003). Anestrous cows require progesterone treatment to ensure that the first ovulation is associated with expression of estrus and a normally functioning luteal phase. The use of eCG may accompany progesterone treatment in cows that are in deep anovulatory anestrus to ensure ovulation (Mulvehill and Sreenan 1977), but care must be taken not to induce too high an ovulation rate.
5.3. Restricted suckling (beef cows)
Earlier onset of ovulation in beef cows may be induced by restricting suckling by calves from 30 days post partum (Stagg et al. 1998). Restricted suckling involves once or twice daily access of calves to cows for suckling and at other times of the day the calves are isolated and out of sight of the cows (Stagg et al. 1998).
6. Conclusions
Follicular growth generally resumes within 7-10 days post partum in the majority of cows associated with a transient FSH rise that occurs within 3 to 5 days of parturition. A summary of reproductive parameters for beef and dairy cows is presented in Table 2. Delayed resumption of ovulation is invariably due to a lack of LH pulse frequency whether it is due to suckling inhibition in beef cows or metabolic related stressors in high yielding dairy cows. First ovulation in both dairy and beef cows is generally silent and followed by a short cycle. The key to optimizing resumption of ovulation in both beef and dairy cows is appropriate pre-calving nutrition and management so that cows calve down in optimal body condition (body condition score 2.75-3.0) with postpartum body condition loss restricted to <0.5 body condition score units.
Dairy cows
Beef cows
Emergence of the 1st follicle wave (days post partum)
5-10
5-10
% cows that ovulate the 1st dominant follicle
50-80
20-35
Postpartum interval to first estrus (days)
25-45
30-130
Nature of 1st ovulation
silent
silent
% short cycles after 1st ovulation
"/>70
"/>70
Regulation of LH pulse frequency
•declining energy balance •BCS at calving •dry matter intake
•suckling •maternal bond •declining energy balance •BCS at calving
Table 2.
Reproductive parameters in the early postpartum period of dairy and beef suckler cows
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/42979.pdf",chapterXML:"https://mts.intechopen.com/source/xml/42979.xml",downloadPdfUrl:"/chapter/pdf-download/42979",previewPdfUrl:"/chapter/pdf-preview/42979",totalDownloads:2386,totalViews:350,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"December 11th 2011",dateReviewed:"March 22nd 2012",datePrePublished:null,datePublished:"February 20th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/42979",risUrl:"/chapter/ris/42979",book:{slug:"gonadotropin"},signatures:"Mark A. Crowe and Michael P. Mullen",authors:[{id:"147299",title:"Dr.",name:"Mark",middleName:"Alan",surname:"Crowe",fullName:"Mark Crowe",slug:"mark-crowe",email:"mark.crowe@ucd.ie",position:null,institution:{name:"University College Dublin",institutionURL:null,country:{name:"Ireland"}}},{id:"147300",title:"Dr.",name:"Michael",middleName:null,surname:"Mullen",fullName:"Michael Mullen",slug:"michael-mullen",email:"michael.mullen@teagasc.ie",position:null,institution:{name:"University College Dublin",institutionURL:null,country:{name:"Ireland"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Ovarian follicle growth in cattle",level:"1"},{id:"sec_2_2",title:"2.1. Pattern of gonadotropin secretion and follicle growth during pregnancy",level:"2"},{id:"sec_3_2",title:"2.2. Resumption of gonadotropin secretion and follicle growth post partum",level:"2"},{id:"sec_5",title:"3. Post-partum anestrus",level:"1"},{id:"sec_5_2",title:"3.1. Factors contributing to LH pulse frequency in early post-partum beef cows",level:"2"},{id:"sec_6_2",title:"3.2. Factors contributing to LH pulse frequency in early postpartum dairy cows",level:"2"},{id:"sec_8",title:"4. Abnormal ovarian function during the post-partum period",level:"1"},{id:"sec_8_2",title:"4.1. Prolonged luteal phases",level:"2"},{id:"sec_9_2",title:"4.2. Follicular cysts",level:"2"},{id:"sec_11",title:"5. Induction of estrus and ovulation in anovulatory anestrous cows",level:"1"},{id:"sec_11_2",title:"5.1. GnRH",level:"2"},{id:"sec_12_2",title:"5.2. Progesterone",level:"2"},{id:"sec_13_2",title:"5.3. Restricted suckling (beef cows)",level:"2"},{id:"sec_15",title:"6. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'AdamsG. P.MatteriR. L.KastelicJ. P.KoJ. C. H.GintherO. 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S.\n\t\t\t\t\t1993\n\t\t\t\t\tConcentrations of progesterone and oxytocin receptors in endometrium of postpartum cows expected to have a short or normal oestrous cycle. Journal of Reproduction and Fertilty\n\t\t\t\t\t97\n\t\t\t\t\t329337 .'},{id:"B85",body:'ZuluV. C.NakaoT.SawamukaiY.\n\t\t\t\t\t2002a\n\t\t\t\t\tInsulin-like growth factor-I as a possible hormonal mediator of nutritional regulation of reproduction in cattle. Journal of Veterinary Medical Science\n\t\t\t\t\t64\n\t\t\t\t\t657665 .'},{id:"B86",body:'ZuluV. C.SawamukaiY.NakadaD.KidaK.MoriyoshiM.\n\t\t\t\t\t2002b\n\t\t\t\t\tRelationship among insulin-like growth factor-I blood metabolites and postpartum ovarian function in dairy cows.\n\t\t\t\t\tJournal of Veterinary Medical Science\n\t\t\t\t\t64\n\t\t\t\t\t879885 .'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mark A. Crowe",address:null,affiliation:'
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'}],corrections:null},book:{id:"2542",title:"Gonadotropin",subtitle:null,fullTitle:"Gonadotropin",slug:"gonadotropin",publishedDate:"February 20th 2013",bookSignature:"Jorge Vizcarra",coverURL:"https://cdn.intechopen.com/books/images_new/2542.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"142838",title:"Dr.",name:"Jorge",middleName:"Antonio",surname:"Vizcarra",slug:"jorge-vizcarra",fullName:"Jorge Vizcarra"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"42980",title:"Contribution of Chicken GnRH-II and Lamprey GnRH-III on Gonadotropin Secretion",slug:"contribution-of-chicken-gnrh-ii-and-lamprey-gnrh-iii-on-gonadotropin-secretion",totalDownloads:1615,totalCrossrefCites:0,signatures:"Jorge Vizcarra",authors:[{id:"142838",title:"Dr.",name:"Jorge",middleName:"Antonio",surname:"Vizcarra",fullName:"Jorge Vizcarra",slug:"jorge-vizcarra"}]},{id:"42970",title:"Role of Adipose Secreted Factors and Kisspeptin in the Metabolic Control of Gonadotropin Secretion and Puberty",slug:"role-of-adipose-secreted-factors-and-kisspeptin-in-the-metabolic-control-of-gonadotropin-secretion-a",totalDownloads:2089,totalCrossrefCites:0,signatures:"Clay A. 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1. Introduction
Since the conception of the term “epigenetic landscape” by Conrad Waddington in 1940, the field of epigenetics has rapidly evolved with technological advances. In the study of embryonic development, it was observed that a single gene has the ability to produce different phenotypes, so epigenetics was used to describe the mechanisms through which that happens [1]. Today, epigenetics is defined as the study of changes in organisms caused by modification of gene expression through addition and removal of chemical groups to nucleotides and proteins rather than the alteration of the genetic code itself [2]. The human genome contains approximately 3 billion bases of nucleotides and they are compacted into chromosomes in the nucleus via histone proteins. About 146 base pairs of nucleotides are wound around core histone octamers and are sealed with the linker histone (H1) to form a nucleosome. The linker histone connects multiple nucleosomes in the chromatin. The core histone octamers consist of two dimers of H2A-H2B and a tetramer of H3-H4 proteins [3]. These core histones contain two regions namely: the histone fold and the histone tails. The C-termini of H2A and N-termini of other core histones protrude out of the fold to form histone tails and are commonly subjected to epigenetic modifications [4]. DNA and RNA also undergo epigenetic modifications, and these modifications control gene expression and maintain genomic integrity. Epigenetic enzymes can be broadly categorized into three components: the writers, the erasers, and the readers. Writers are enzymes responsible for adding the modifications, erasers remove it, and readers recognize it. These modifications include but are not limited to methylation, acetylation, phosphorylation, ubiquitination, GlcNAcylation, and SUMOylation [5].
DNA mainly undergoes methylation, and this occurs through the action of a family of DNA methyltransferases (DNMT1, DNMT2, DNMT3a, and DNMT3b). DNMTs covalently modify DNA by catalyzing the transfer of methyl group from S-adenosylmethionine (SAM) to the C5 position on a cytosine ring. DNA methylation mostly occurs in CpG islands, a region of the DNA rich in cytosine and guanine base repeats [6]. This modification to the DNA functions to repress transcription when it occurs in gene promoters and regulates splicing when it occurs in gene bodies [7]. DNA methylation is a reversible mechanism, which can be either passive through reduced DNMT1 activity during DNA replication or active through activity of its erasers, DNA demethylases. For instance, the ten-eleven translocation proteins (TET 1/2/3) are human demethylases that catalyze the oxidation of 5-methyl-cytosine to 5-hydroxymethylcytosine [8]. Following DNA methylation, often readers such as the family of methyl binding domain proteins recognize the methylation marks to drive transcriptional repression [9].
RNA is also methylated on C5 position of cytosine (m5C) and N6 position of adenosine ring(m6A) by family of RNA methyltransferases such as Dnmt2, NOP2/Sun, Mettl3, and Mettl14. RNA methylation can be reversed by these RNA demethylases: fat mass and obesity associated protein (Fto) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (AlkBH5) [10]. Methylation modification on RNA is interpreted by readers such as the YTH domain family, and they mediate RNA splicing, export, stability, maturation, decay, secondary structure switch, and translation [11]. There have also been reports of RNA acetylation by NAT10 acetyltransferase, which functions to promote mRNA stability and efficiency in translation [12].
Moving up the central dogma, lysine and arginine residues on histone proteins are mostly subjected to various post-translational modifications by their respective epigenetic enzymes to either activate or repress transcription. Although the focus of this chapter is histone methylation, histone acetylation will be briefly discussed. Histone methyltransferases (HMTs) and histone acetylases (HATs) are the writers of histone methylation and acetylation, respectively. HMTs can be further subdivided into lysine methyltransferase (KMT) and protein arginine methyltransferase (PRMT) [13]. The families and functions of HMTs will be further explored in this chapter. On the other hand, several HATs have been discovered, with the major ones being the GNATs (Gcn5-N-acyltransferases), the MYST families, and p300/CBP [5]. These enzymes catalyze the transfer of acetyl group from acetyl Co A to the side chain amino group on histone lysine residues, inducing transcriptionally active chromatin [13]. Histone deacetylases and histone demethylases are involved in reversing the histone modifications discussed above. The families of lysine-specific histone demethylase 1 (LSD1) and Jumonji histone demethylases (JMJD) mediate the removal of methyl groups from histone through respective mechanisms [13, 14]. Readers of histone methylation include protein containing the MBT, PHD, chromo, Tudor, double/tandem Tudor, Ankyrin Repeats, zf-CW, WD40, and PWWP domains [15].
Given this array of epigenetic enzymes and their broad spectrum of function in regulating several gene expression in humans, the roles of epigenetic enzymes have been implicated in tumorigenesis. The epigenome of cancerous cells has widespread changes in DNA methylation and histone modification patterns [16]. For instance, hypermethylation of CpG islands in the promoter of chromodomain helicase DNA-binding protein 5 (CHD5), a chromatin remodeler, was observed in colon, breast, hepatocarcinoma, cervix, and glioma cell lines [17]. This results in the downregulation of CHD5, which plays a tumor suppressive role in cells. Similarly, hypomethylation of DNA at promoters of oncogenes such as insulin-like growth factor 2 (IGF2) has been observed in breast and colon cancers. The differential methylation patterns on promoters of tumor suppressors and oncogenes mediated by increased/reduced activity of DNMTs and TETs enzymes have been used as biomarkers to predict the predisposition of individuals to cancer [18]. Also, aberrant expression of histone acetyl transferases (HATs) and histone deacetylases (HDACs) has been linked to tumor development. Studies have shown that that p300/CBP acts as a coactivator with c-Myb to activate the transformation of fusion oncoproteins in myeloid leukemia [19]. Increased expression of HDACs was reported in gastric, prostate, colon, and breast carcinomas, and this results in repression of tumor suppressor genes like cyclin-dependent kinase inhibitor, see p21 [20]. Of all the histone modifications, histone methylation dysregulation is mostly attributed to poor prognosis in several cancers, which we will further elaborate in detail in Section II “Histone Methyltransferases in Cancer.”
As these epigenetic enzymes’ activity has been altered in cancer and contributes to the genomic instability in cancer cells, it is crucial to develop targeted therapeutic treatments to restore their normal function. Aside from surgery, some common treatment options for cancer patients can be broadly categorized as thus: chemotherapy, immunotherapy, radiotherapy, and precision medicine/targeted therapy [21]. These classes of treatments are not mutually exclusive and can be used in concert for treating cancer patients. Among these different therapeutic approaches, targeted therapy is the future for cancer treatment. Targeted therapy involves the use of drugs that target a specific biological molecule/pathway or drug treatment that requires genome profiling of an individual before it can be administered [22]. For optimal development of drugs for targeted therapies, it is important to identify a well-defined biological target whose activity contributes to one to several hallmarks of cancer including propagating growth signals, evading immunosurveillance, cell death resistance, activating metastatic programs, suppressing antigrowth signals, inducing angiogenesis, and enabling immortal replication of cells [23, 24]. For example, cancer patients whose tumors are driven by high activity of epidermal growth factor receptor (EGFR) signaling can be treated with specific monoclonal antibodies or small molecule kinase inhibitors antagonizing the aberrant signaling, and thereby reducing tumor proliferation [25]. Similarly, targeting an epigenetic enzyme, PRMT5, which is highly expressed in gastrointestinal cancers, with small molecule inhibitor, PR5-LL-CM01, was shown to slow down cancer cell growth and invasion in vitro [26]. The limitations of targeted therapies include cancer cell resistance to drug treatment by activating a parallel pathway or sometimes targets can undergo mutation, making drug accessibility to target difficult [27].
Given the myriad of biological targets that have been discovered to mediate cancer progression, there has been increasing interest in the development of small molecule inhibitors capable of decreasing the activity of those targets. Small molecules are intracellular targeting compounds with low molecular weight of less than 900Da. They can modulate their target activity as an agonist or antagonist [23]. The growing interest in the use of small molecules for drug development is not only due to their small size, which enables easy permeability into the cell, but also their desirable pharmacokinetics, pharmacodynamics, longer shelf life, and easy synthesis [28]. Several small molecule modulators have been developed into drugs to treat various types of cancers. The range of small molecule inhibitors developed to enable tumor regression can be broadly categorized into small molecule kinase inhibitors, proteasome inhibitors, metalloproteinases and heat shock protein inhibitors, and apoptosis targeting inhibitors [29]. The most common small molecule inhibitors, kinase inhibitors, have been used to inhibit the several protein kinases whose activity is dysregulated in cancers. The first tyrosine kinase inhibitor drug, Imatinib, is a small molecule ATP analog that competitively inhibits Bcr-Abl fusion protein kinase activity in chronic myeloid leukemia patients [30]. Similarly, a number of small molecule inhibitors targeting epigenetic enzymes implicated in tumorigenesis are in development or have been FDA approved for cancer treatment. For instance, drugs like belinostat and romidepsin are HDAC inhibitors that are FDA approved for the treatment of lymphoma [31]. After the first clinical trial in 2014, tazemetostat, an EZH2 small molecule inhibitor, moved to phase 2 clinical trial and was fast tracked by FDA in 2017 for the treatment of follicular lymphoma [32]. The use of tazemetostat for treatment of epithelioid sarcoma in adults 16 years and above was also granted accelerated approval by the FDA. These examples, among many others, show the potentials of epigenetic modifiers as a druggable target for cancer treatment. More of these small molecule inhibitors for histone methyltransferases will be explored later on in this chapter. However, challenges in the clinical application of certain small molecule inhibitors as drugs remain due to their off-target effects or development of resistance by cancer cells [29].
2. Histone methyltransferases in cancer
As we mentioned above, epigenetic enzymes, including histone methyltransferases, are novel targets for cancer therapy. In this section, we will review the role of histone methyltransferases in cancer.
2.1 Lysine methyltransferases
Lysine methylation of histones was first characterized in the 1960s [33, 34] and was initially described as an “irreversible” post-translation modification. This dogma was challenged by the discovery of histone demethylases by Shi et al. indicating a dynamic function of methylation allowing the addition and removal of methyl groups [35]. The proteins responsible for the addition of methyl groups to histones are known as lysine methyltransferases (KMTs). KMTs are broadly defined as SET [Su(var)3-9, Enhancer of Zeste, Trithorax] domain-containing proteins and non-SET domain-containing proteins [36]. The only non-SET domain-containing KMTs identified so far are DOT1 (disrupter of telomeric silencing 1) family members, which methylate K79 of histone H3 and which also do not share structural similarities with SET-containing proteins [37, 38, 39]. KMTs act by catalyzing the transfer of 1~3 methyl groups to lysine residues of histone and non-histone proteins through the addition of the cofactor S-adenosyl methionine (SAM), which acts as a methyl donor group [40]. In the case of SET domain-containing proteins, SAM interacts and orients with a lysine residue of the substrate histone tail within the catalytic pocket of the SET domain. Then, a tyrosine residue acts to deprotonate the ε-amino group of the lysine residue, which allows the lysine chain to nucleophilically attack the methyl group of the SAM molecule, transferring the methyl group to the lysine side chain [41]. In the case of non-SET domain-containing KMTs, the enzyme DOT1 acts to methylate a lysine residue in the histone core [40]. As we described above, histone methylation is a critical epigenetic modification of chromatin that can impact genomic stability, alter expression of different genes, determine cell lineage, alter DNA methylation, as well as control cell mitosis [42].
SET-containing proteins have been characterized in greater detail than non-SET-containing proteins. SET domain proteins are characterized as seven families of the superfamily of KMTs: SUV39, SET1, SET2, EZ, RIZ, SMYD, and SUV4-20 [36]. There are also several SET domain proteins that do not fall into these groups including SET7/9 and SET8 [36]. The SUV39 family has been characterized the most out of these groups of KMTs. Specifically, Schizosaccharomyces pombe Cryptic loci regulator 4 (CLR4), human SUV39H1, and murine SUV39H2 were among the first identified SET domain protein lysine methyltransferases characterized when their sequence homology between their SET domains was discovered. These proteins methylate lysine 9 of histone H3 (H3K9) [43]. SET1 and SET2 complexes are involved in the RNA polymerase II holoenzyme [44, 45]. TSET1 acts to tri-methylate H3K4 and is associated with early gene transcription as opposed to SET2-mediated methylation of H3K36, which is associated with later transcriptional elongation of downstream genes. The mammalian nuclear-receptor-binding SET domain-containing protein (NSD1, a member of the SET2 family) has an important function in methylation of H3K36 and H4K20 in development [46]. Lu et al. in our research group also reported that NSD1 could methylate non-histone protein, NF-κB, at K218/221 of its p65 subunit, leading to the activation of NF-κB and its downstream target gene expression [47, 48, 49, 50]. Another example is SETDB1, a H3K9 methyltransferase, which is amplified in primary tumors of lung cancer patients and contributes to the invasive phenotype of tumor cells [51]. Additionally, SETDB1 methylates H3K9 in euchromatin, and is also required for development [52]. Human SET7/9 acts to mono-methylate H3K4 [53]. Furthermore, SET domain enzymes’ functions are not specifically tied to histone methylation. Human SET7/9 methylates K189 on transcription factor TAF10, which increases RNA polymerase II affinity and transcriptional activity, thereby expression of TAF10-dependent genes [54]. SET7/9 is also involved in p53 methylation, which increases its stability [55]. These examples described are only a few of the many SET-containing proteins of which over 50 different proteins have been discovered [56]. While SET domain proteins are typically referred to as histone lysine methyltransferases, it may be more accurate to refer to them as protein lysine methyltransferases due to their identification of non-histone targets for these KMTs.
These examples of SET and non-SET domain-containing proteins exhibit the importance of KMTs in the regulation of histone and non-histone proteins. Therefore, it is not surprising that dysregulation of KMT function can result in dysregulation of cellular functions. Specifically several KMTs have been associated with tumorigenesis of several different cancers.
H3K9 methyltransferases SETDB1 and G9a are both known to have roles in gene silencing and embryo development [57]. G9a regulates cancer metabolism in several types of cancer [58]. Overexpression of G9a is associated with worse prognosis in patients with prostate cancer. Intriguingly, G9a knockdown in breast and lung cancer has been shown to promote E-cadherin expression and thus tumor metastasis [59, 60]. Moreover, G9a’s higher expression predicts higher mortality of ovarian cancer patients [61] and is reported to be associated with cell growth and proliferation in neuroblastoma [57]. Furthermore, G9a has been shown to have a critical role in the development of pancreatic carcinoma and acute myeloid squamous cell carcinoma. G9a-dependent repression of genes is also associated with development of leukemia as well as squamous cell carcinomas [57]. SETDB1 is another H3K9 methyltransferase reported to play a role in numerous types of human cancer. SETDB1 is involved in regulation of several cellular processes, including apoptosis, DNA damage repair, and regulation of transcription factors [62]. SETB1 is associated with oncogenic activity and is upregulated in several cancers including lung cancers, gliomas, and prostate cancer [63, 64, 65, 66]. For instance, in lung cancer, overexpression of SETDB1 promotes invasiveness and knockdown reduced lung cancer cell growth. In gliomas, cell proliferation was reduced by suppression of SETDB1. In prostate cancer, downregulation of SETDB1 led to reduced cellular proliferation, migratory ability, and invasive ability.
EZH2 (Enhancer of zeste homolog 2), a H3K27 methyltransferase, plays an important role in transcriptional repression [36]. EZH2 plays a critical regulatory role in as many as 46 types of human cancer [57, 67]. Typically, EZH2 is overexpressed in cancers, and its high expression has been linked to worse patient survival. For instance, EZH2 downregulation in breast cancer can block cell growth and survival [68]. Moreover, EZH2 knockdown inhibits invasive ability and cellular proliferation in prostate cancer [69]. Additionally, EZH2 has also been shown to have roles in gliomas and renal cell carcinoma, wherein decreased EZH2 expression reduces cellular proliferative ability and promotes apoptosis [70].
Another example is SMYD3 (SET and MYND domain-containing 3). It is a KMT that methylates H3K4 and is extremely important for initiation of transcription. High SMYD3 activity is indicative of an epigenetic signature of active enhancers [71]. SMYD3 knockdown in colorectal cancer can impair cellular proliferation [72]. In breast cancer, knockdown of SMYD3 also inhibits cell growth, and overexpression can promote carcinogenesis by regulation of the Wnt signaling pathways [73]. Additionally, reduction of SMYD3 expression in prostate cancer inhibits cellular proliferation, migration, and colony formation [74].
H3K36 methylation is critical for transcriptional elongation, and H3K36 methyltransferases have been identified to play important regulatory roles in several types of cancer. NSD1, a H3K36 KMT, is involved in prostate cancer androgen receptor transactivation, which results in prostate tumorigenesis [75]. Overexpression of NSD1 in neuroblastoma reduces cellular growth ability and colony formation [76]. NSD1 has also been reported to play a role in myelomas and lung cancers [57]. As we described above, our lab also found that NSD1 activates NF-κB to induce its target gene expression. The function of these genes is frequently involved in oncogenic phenotype, or cytokine, chemokine secretion [47]. Another example is H4K20 methylation, which is reported to be important for gene transcription. For example, overexpression of methyltransferases of H4K20 SUV420H1 and SUV420H2 is associated with decreased cell invasiveness in breast cancer, and knockdown increases epithelial to mesenchymal transition [77].
DOT1, the only known H3K79 methyltransferase and non-SET containing KMT, also plays an important role in cancer development. DOT1 is involved in cell survival and colony formation in several forms of leukemia [78]. The activity of human DOT1L (hDOT1 like) methyltransferase is compromised in mixed lineage leukemia (MLL) and is required for maintaining proliferative state of transformed cells [79]. Also, downregulation of DOT1 in lung cancer can cause cell cycle arrest and reduce cellular proliferation [80].
Together, these examples show several of the pathways regulated by KMTs and also highlight the critical importance of tight regulation of these pathways wherein dysregulation of KMTs can result in promotion of tumorigenesis.
2.2 Protein arginine methyltransferases
In contrast to KTMs, there is another important family of protein methyltransferases, namely, protein arginine methyltransferases (PRMTs). It is a family of nine members (PRMT1-9) and specifically catalyzes the methyl transfer from SAM to the guanidine nitrogen (ω-NG) of the arginine residues of protein substrates [81]. After the donation of methyl groups, SAM forms S-adenosyl-L-homocysteine (AdoHcy, SAH) and methylarginine is produced [81]. There are three forms of methylarginine recognized in mammalian cells: ω-NG-monomethylarginine (MMA), ω-NG, NG-asymmetric dimethylarginine (ADMA), and ω-NG, N’G-symmetric dimethylarginine (SDMA) [82]. The family of PRMTs is categorized into three major types: type I, II, and III. Type I and II PRMTs first catalyze the formation of MMA, and then type I PRMTs (PRMT1, 2, 3, 4, 6, and 8) further catalyze the formation of ADMA, while type II (PRMT5 and 9) would instead catalyze the production of SDMA. For type III PRMTs (PRMT7), they only catalyze the formation of MMA [83]. These three types of PRMTs methylated similar substrates, such as histone, but they also can catalyze different non-histone substrate proteins. Additionally, although the majority of PRMTs methylate glycine-arginine-rich (GAR) motifs in their substrates [84, 85], some of them display a preference of methylation on the proline-glycine-methionine rich (PGM) motifs in substrate proteins such as PRMT4 [86, 87], while PRMT5 is characterized with the methylation of both types of motifs in proteins [86, 88].
PRMTs are widely expressed in mammalian cells and regulate primary cellular processes, including cell proliferation and differentiation. The abnormal expression of some types of PRMTs such as PRMT1, 4, 5 and 6 frequently leads to tumorigenesis and malignancy.
PRMT1 was the first protein arginine transferase recognized in mammals and assumes the large fraction of arginine transferases activity in mammalian cells [89, 90]. It has been reported that PRMT1 is related to various kinds of cancer. Le Romancer et al. suggested that PRMT1 governed the interaction of estrogen receptor α (ERα) with steroid receptor coactivator proteins (Src), the p85 subunit of phosphatidylinositide 3-kinases (PI3K) and focal adhesion kinase (FAK) [91]. PRMT1-mediated ERα methylation is integral for the activation of the Src-PI3K-FAK signaling pathway [91]. In their subsequent report, the authors further demonstrated arginine methylation of ERα by PRMT1 might remarkably activate protein kinase B (PKB, also known as AKT) [92]. Another example is methylation of Axin by PRMT1. Cha et al. showed that arginine methylation of Axin by PRMT1 may activate the WNT pathway by destabilizing Axin and promote tumorigenesis [93, 94]. Importantly, it is reported that methylation of meiotic recombination 11 (MRE11, also known as MRE11A) and p53 binding protein 1 (53BP1) by PRMT1 can block the DNA repair pathway, contributing to cancer progression [95, 96]. MRE11 combines with DNA repair protein RAD50 and Nijmegen breakage syndrome 1 (NBS1) to form MRE11-RAD50-NBS1 complex (MRN complex). The mammalian MRN complex plays significant role in repairing DNA double-strand breaks (DSBs). Yu et al. reported that the deficiency of arginine methylation of MRE11 in its GAR motif resulted in exonuclease and DNA-binding defects and finally failing to repair DNA damage [96]. Interestingly, Boisvert et al. found that 53BP1 could not relocalize to DNA damage sites and γ-H2AX formation was decreased in fibroblasts treated with methylase inhibitors [95, 97]. Moreover, Mitchell et al. discovered that depletion of PRMT1 affected the length and stability of telomere [98]. Since dysfunction of both DNA repair pathway and telomere maintenance is known to be the cause of cancer, deregulation of PRMT1 may lead to tumorigenesis by these pathways.
In addition to PRMT1, another PRMT member, PRMT4 (also known as CARM1), is reported to be tightly associated with estrogen-mediated oncogenesis of breast cancer through the upregulation of transcription factor E2F1 expression [99]. Moreover, CARM1 is suggested to be overexpressed in human colon cancer and exert a crucial role in Wnt signaling through mediating the action of β-catenin on Wnt target genes as a transcriptional coactivator [100]. Moreover, c-fos is a proto-oncogene and overexpressed in a set of cancers. Some groups reveal that PRMT4 regulates transcriptional activation of c-fos, and that matrix metalloproteinases (MMPs), c-fos target genes, are significantly downregulated in CARM1-deficient cells [101]. Therefore, arginine methylation by PRMT4 is related to multiple oncogenic signaling pathways.
An important PRMT member that plays a critical role in cancer is PRMT5. As a primary type II PRMT, PRMT5 functions in the presence of other binding partners, such as MEP50. Hou et al. discovered that E-cadherin expression was remarkably repressed by SNAIL and PRMT5 recruited by bridge molecule AJUBA, which was favorable for tumor metastasis [102]. It was also reported that p53 can be methylated on multiple arginine sites by PRMT5 in response to DNA damage [103]. Scoumanne et al. proposed that PRMT5 inhibition may promote cancer cells to progress toward apoptosis under chemotherapy/radiotherapy [104]. Moreover, Cho et al. found methylation of E2F1 by PRMT5 weakened its ability to promote apoptosis and repress proliferation, indicating PRMT5 overexpression may enhance cancer cells’ growth and survival [105]. It is well known that continuous NF-κB activation exists in most cancers. Our group uncovered that PRMT5 dimethylated the p65 subunit of NF-κB at arginine 30 (R30) to activate NF-κB pathway [106], an important transcription factor that is involved in the progression of many cancers. Also, PRMT5 is reported to promote its own overexpression in several cancers through a feedback loop involving NF-κB signaling [107].
Besides the PRMTs we discussed above, PRMT6 is widely taken as a transcriptional repressor. Neault et al. reported that embryonic fibroblast cells from the PRMT6 knockout mouse were subjected to a premature senescence, while the cellular senescence can be rescued in PRMT6 and p53 double knockout mouse embryonic fibroblast (MEF) cells [108], affirming growth suppression effect of excess p53 due to PRMT6 deficiency. Thus, PRMT6 actively suppresses p53 cascade to promote tumorigenesis in cancer.
Taken together, many members in the PRMT family have shown essential role in cancer development and progression. Thus, it is unsurprising that these PRMTs have become the rising targets in cancer therapeutics in recent years.
3. Discovery of small molecule inhibitors for histone methyltransferases in cancer treatment
3.1 Screening assays for epigenetic drug discovery
The timeline of drug development from conception of the idea to a feasible drug available in the market for treatment of diseases takes between 12 and 15 years and can cost up to $1billion [109]. Drug discovery process begins with identifying a druggable biological target that contributes to a disease progression. These targets can be identified through text mining from online databases, microarray data mining using bioinformatic tools, proteomic data mining from proteomic databases, and chemogenomic data mining, which involves simultaneous exploration of multiple cell phenotypes by screening small molecules from chemical libraries to a number of biological targets [110]. Then, promising or known targets can be validated in vitro and in vivo to confirm that their activity influences phenotype associated with a disease. This step is followed by screening or high throughput screening (HTS), which describes the process of sifting through compound libraries for molecules with high affinity for a target of interest [111]. The two approaches of developing assays for compound library screening are the biochemical target-based approach and the cell-based approach. Biochemical target-based approach is often employed as the primary screening assay in epigenetic compound screen because it allows the direct monitoring of ability of a target activity as opposed to cell-based assays wherein changes in cell phenotypes are measured [112]. Listed below are some of screening assays used in the preclinical development of drugs for epigenetic enzymes.
AlphaLISA is a high throughput screening approach used to analyze and measure post-translational modifications, protein-protein interactions, and concentrations of analytes. The robust, highly sensitive, reproducible, miniaturized, scalable, and automated nature of AlphaLISA assays earned them their widespread application in research and drug discovery. The principle behind AlphaLISA technology is based on the mechanism of another methodology, Luminescent oxygen channeling immunoassay (LOCI). LOCI involves chemiluminescent reaction of a singlet oxygen transfer and was developed in 1994 by Ullman et al. to quantify latex particle binding [113]. Similarly, AlphaLISA assays employ biotinylated antibody bound to streptavidin donor beads and an acceptor bead bound to a second antibody. These antibodies are specific to different epitope on a protein (could also be product of a bimolecular interaction or a modified protein). The binding of these antibodies to the proteins brings the donor and the acceptor bead into proximity of at most 200nm. Upon excitation of donor beads at 680nm, a singlet oxygen is excited from the donor bead and this triggers singlet oxygen reaction with the chemical dyes (thioxene and europium) on the acceptor bead, which results in chemiluminescent emission at 615nm [114, 115]. Multiplate readers equipped with AlphaLISA screen detections can be used to record signals. A systematic method used to validate the quality of HTS assay output like AlphaLISA is called the Z-factor. The Z-factor is calculated by accounting for the positive and negative controls’ mean signal-to-mean background ratio. Hence, in the design of AlphaLISA assay, to ensure quality control, wells containing maximum signal and no signal solution mix must be included [116]. This assay is widely optimized to screen for small molecule modulators for different epigenetic enzymes. For example, in our lab, Prabhu et al. used an optimized AlphaLISA screen protocol to identify a lead compound capable of targeting PRMT5, and subsequently, the compound was shown to be more potent in reducing pancreatic and colon cancer cells’ proliferation compared to another commercially available compound EPZ015666 [26]. Not only is this assay used to screen for compounds for epigenetic targeted therapy, but also they uncover new roles of different epigenetic enzymes in cancer. Consequently, together with other assays, it was uncovered using AlphaLISA HTS assay that an inhibitor of G9a lysine methyltransferase, A-366, limits cell growth and differentiation in leukemic cells [117]. Potent small molecule inhibitors for EZH2, a methyltransferase known to silence tumor suppressor genes, are also being identified using this particular HTS assay [118]. AlphaLISA kits specific for histone methyltransferase modifications, among many other epigenetic enzymes, are commercially available for research and drug development purposes [119].
3.3 FRET (Förster/fluorescent resonance energy transfer) assay
Discovered in 1946 by Theodor Förster, FRET is cell-based assay that enables real-time observance of molecular interactions within cells [120]. This phenomenon depends on the proximal interaction (1-10nm) of a donor fluorophore and an acceptor fluorophore, whereby upon excitation, the donor fluorophore transfers energy to the acceptor, increasing its emission wavelength [121] (Figure 1). The measure of FRET is taken as the ratio of the intensities of the donor/acceptor fluorophore. Although highly sensitive in distance, FRET assay does not permit the level of sensitivity and high throughput as AlphaLISA [122]. A type of FRET, FLIM-FRET (fluorescence lifetime imaging FRET) was used to conduct epigenetic biomarker screening in ER-positive breast cancer cell line and patients. The utilization of FRET in this study was based on the presence of certain histone modifications around ERα in the nucleus. Consequently, the assay revealed H3K27ac and H4K12ac interaction with ERα, making HATs a potential therapeutic target in compound screening [123]. Another study optimized TR-FRET (time-resolved FRET) for high throughput screening, following the treatment with HDAC inhibitors, to detect the methylation levels of histone 3(H3) in U-2 OS cells using terbium-tagged antibodies specific to a particular H3 modification and green fluorescent protein (GFP)-tagged H3 [124].
Figure 1.
Schematic demonstrating the use of FRET for epigenetic screen. In the presence of histone methyltransferase and its methyl donor, SAM, a GFP-tagged Histone 3 becomes methylated on lysine-9 (K9) and undergoes FRET as terbium (Tb) conjugated antibody binds to the monomethylated K9 (K9me). This leads to increased GFP emission at 540nm wavelength (Right arm of the diagram), demonstrating the occurrence of K9 methylation. In contrast, when in the absence of K9 methylation mediated by HMTs, due to the addition of potent HMT inhibitors (Lower arm of the diagram), FRET does not occur as K9 cannot be methylated and thereby the antibody cannot bind to its epitope. As a result, the wavelength of GFP will be at lower end of the emission spectra, 520 nm.
3.4 In silico screen
In silico screening or virtual screening is a common method used in drug discovery as a pre-filtering method for identifying promising compounds that can be used for experimental studies. Drug development using this method of screening is estimated to save approximately $130 million and 0.8 years per drug [125]. The approach to virtual screening can be broadly divided into structure-based methods and ligand-based methods. Structure-based approach encompasses docking candidate molecules against available 3D structure of the target protein. When there is no crystal structure of the target protein, ligand-based approach is more useful because it relies on the screening of bioactive ligands of a similar chemical structure [126]. This approach is similar to pharmacophore-directed homology modeling: a process that involves superposing known active ligands for structurally similar targets and then extracting matching chemical properties of the ligand that are required for their bioactivity. Pharmacophore from different bioactive molecules can be generated using commercially available software such as HipHop, PHASE, DISCO, HypoGen, among others [127].
In computer-aided design of epigenetic drugs, there are a plethora of databases like ZINC containing over 35 million compounds available for screening. Other databases like SPECS, Chembridge, and Enamine have been used to identify inhibitors for most subsets of histone methyltransferases [128]. Molecular dynamics simulation also aids in drug discovery as they are employed to understand the conformational changes in the different domains of a target protein [129]. For instance, a study developed analogs of eosin, a template molecule known for having anti-methyltransferase activity, using pharmacophore methods. These molecules were docked on to PRMT1, SET7, and CARM1, and the AutoDock analysis revealed that compounds that target SAM substrate-binding site were more active in PRMT1 and CARM1 while those that target lysine and co-factor binding site were more promising in SET7 [126].
4. Current small molecule inhibitors of histone methyltransferases
Development of small molecule inhibitors for histone methyltransferases has garnered remarkable attention over the past years due to their combined efficacy and potency in various cancer treatments. In this section, we will discuss small molecule inhibitors of a few HMTs that have either shown promising results in preclinical development, clinical trial stage, or that have been FDA approved.
4.1 Small molecule inhibitors of EZH2
As aforementioned, EZH2 is a lysine methyltransferase that is overexpressed and found to contribute to many cancer progressions including but not limited to breast, prostate, colon, ovarian, liver, bladder, lymphoma, skin, and lung cancer. The overabundance of EZH2 causes hypersilencing of genes that restrain proliferation and promotes differentiation [67]. As a result, several studies have been conducted to understand the mechanism of action and structure of the enzyme so that appropriate drugs can be developed to inhibit its aberrant activity. For example, FDA has approved the use of tazemetostat (EPZ6438) (Table 1), an EZH2 small molecule inhibitor, for the treatment of epithelioid sarcoma (not qualified for resection) in 16 years and above patients. Tazemetostat has an inhibition constant (Ki) of 2.5nM and works by competitively inhibiting SAM binding site on EZH2 [32]. Another small molecule inhibitor, CPI-1205 (Table 1), completed phase 1 clinical trial for B-cell lymphoma and solid advanced tumor and is in phase 1b/2 clinical trial for metastatic castration-resistant prostate cancer (mCRPC) [130, 131]. Furthermore, another potent small molecule inhibitor, GSK2816126 (Table 1), which showed remarkable preclinical potential entered phase 1 clinical trial for the treatment of lymphoma and solid cancers but proved to be unsuitable target for inhibiting EZH2 due to its unfavorable pharmacokinetic profile [132]. More than 50 small molecule inhibitors for EZH2 are in preclinical development [133]. A few are highlighted in Table 1.
List of representative small molecule inhibitors for EZH2, hDOT1L, and PRMT5.
4.2 Small molecule inhibitors of hDOT1L
There are over 20 hDOT1L small molecule inhibitors and can be categorized into four groups based on their mode of action: (i) SAH(S-adenosyl-L-homocysteine)-mimicking compounds; (ii) benzimidazole or (iii) urea group-containing compounds; and (iv) carbamate-containing compounds [143]. The activity of human homolog of yeast DOT1L or hDOT1L is mostly dysregulated in a subset of acute myeloid leukemia that has MLL gene translocation. This results in an onco-MLL protein which aberrantly recruits hDOT1L to the promoter of MLL target genes. Together with other transcription factors, hDOT1L drives the overexpression of HoxA9 and HoxA7 which leads to leukemia [141]. Hence, the need for inhibitors of hDOT1L. The first potent inhibitor of this HMT was EPZ004777 (Table 1), but it failed to progress through clinical development due to poor pharmacokinetics [139]. Another small molecule inhibitor, EPZ5676 (pinometostat) (Table 1) with Ki of less than 0.08nM, was shown to have improved pharmacokinetics and has now completed phase 1 clinical trial [138].
4.3 Small molecule inhibitors of PRMT5
PRMT5 is overexpressed in a several types of cancers. There are currently over 50 PRMT5 small molecule inhibitors, and PRMT5 is emerging as a hotspot for cancer targeted therapy [144]. Some small molecule inhibitors of PRMT5 are currently undergoing assessment in phase 1 clinical trial for non-Hodgkin lymphomas and solid cancers include GSK3326595 and JNJ-64619178 (Table 1). PRMT5 has also been implicated in the progression and metastasis of pancreatic and colon cancer. As a result, a lead compound, PR5-LL-CM01 (Table 1), has been discovered by our group to have more potent inhibitory properties compared to EPZ015666 in pancreatic and colon cancer cells [114]. However, EPZ015666 showed high potency in vitro and in mantle lymphoma cells with an IC50 of 22nM (Table 1) [145]. Another potent inhibitor of PRMT5, LLY-283 (IC50 = 20 nM) (Table 1) showed an outstanding inhibition of breast, lung, skin, ovarian, and hematological cancer cells’ proliferation [142].
5. Conclusion, perspective, and future directions
Taken together, in this chapter, we discussed the important roles that epigenetic enzymes play in a variety of cancers. We also summarized several popular methods currently used for screening small molecule inhibitors of epigenetic enzymes. As shown in Table 1, we provided a list of representative small molecule inhibitors of HMT that are either FDA approved, or at preclinical or different stages of clinical trials. Notably, compared to the well-developed HDAC small molecule inhibitors, the development of small molecule inhibitors for HMTs is a rising and cutting-edge drug development area. We can envision that in the next 5~10 years, intense attention will continuously be drawn to the discovery of HMTs small molecule inhibitors. We have no doubt that many HMTs small molecule inhibitors will be shifted into clinical trials, more will be approved by FDA, and most likely, more members of HMTs will be targeted for cancer treatment. Additionally, it is very possible that novel HTS methods will emerge, which will further accelerate the discovery of anti-HMTs drugs. Moreover, it is viable that the clinical indications of HMTs small molecule inhibitors could be further expanded to other diseases beyond cancer. In summary, the development of new classes of anti-HMTs drugs will offer brand new and exciting opportunities for diseases treatment.
Acknowledgments
This publication is made possible, in part, with support from NIH-NIGMS Grant (#1R01GM120156-01A1) (to TL), and NIH-NCI Grant (#1R03CA223906-01) (to TL).
Conflict of interest
The authors declare no potential conflicts of interest.
\n',keywords:"cancer, drug discovery, epigenetics, histone methyltransferases, small molecule inhibitors",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72479.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72479.xml",downloadPdfUrl:"/chapter/pdf-download/72479",previewPdfUrl:"/chapter/pdf-preview/72479",totalDownloads:173,totalViews:0,totalCrossrefCites:0,dateSubmitted:"August 14th 2019",dateReviewed:"May 14th 2020",datePrePublished:"July 24th 2020",datePublished:"February 3rd 2021",dateFinished:"June 13th 2020",readingETA:"0",abstract:"Cancer is the second leading cause of mortality in the United States. There are several therapeutic regimens employed to mitigate the mortality rate of cancer. This includes the use of chemotherapy, radiation, immunotherapy, and precision medicine/targeted therapy. Targeted therapy involves the use of drugs that target a specific pathway or biomolecule compromised in cancer for cancer treatment. Aberrant expression of epigenetic enzymes has been well documented for their contribution in driving tumorigenesis and other cancer hallmarks. Hence, there is an urgent need for novel drug discovery and development in epigenetics to help combat various cancer morbidities. Herein, we review the roles and consequences of dysregulated function of several epigenetic enzymes, with a focus on histone methyltransferases (HMTs). Additionally, we discussed the current efforts made in the development of small molecule inhibitors for a few representative HMTs implicated in different cancers. Furthermore, the common screening assays used in discovering potent small molecule inhibitors were also detailed in this chapter. Overall, this book chapter highlights the significance of targeting HMTs in different cancers and the clinical application potentials/limitations faced by the developed or emerging small molecule inhibitors of HMTs for the purpose of cancer therapy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72479",risUrl:"/chapter/ris/72479",signatures:"Aishat A. Motolani, Mengyao Sun, Matthew Martin, Steven Sun and Tao Lu",book:{id:"7015",title:"Translational Research in Cancer",subtitle:null,fullTitle:"Translational Research in Cancer",slug:"translational-research-in-cancer",publishedDate:"February 3rd 2021",bookSignature:"Sivapatham Sundaresan and Yeun-Hwa Gu",coverURL:"https://cdn.intechopen.com/books/images_new/7015.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"187272",title:"Dr.",name:"Sivapatham",middleName:null,surname:"Sundaresan",slug:"sivapatham-sundaresan",fullName:"Sivapatham Sundaresan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"218030",title:"Dr.",name:"Tao",middleName:null,surname:"Lu",fullName:"Tao Lu",slug:"tao-lu",email:"lut@iupui.edu",position:null,institution:null},{id:"218088",title:"BSc.",name:"Matthew",middleName:null,surname:"Martin",fullName:"Matthew Martin",slug:"matthew-martin",email:"mm217@umail.iu.edu",position:null,institution:null},{id:"323400",title:"M.Sc.",name:"Annie",middleName:null,surname:"Sun",fullName:"Annie Sun",slug:"annie-sun",email:"sun19@iu.edu",position:null,institution:null},{id:"323670",title:null,name:"Aishat A.",middleName:null,surname:"Motolani",fullName:"Aishat A. Motolani",slug:"aishat-a.-motolani",email:"amotolan@iu.edu",position:null,institution:null},{id:"323671",title:null,name:"Steven",middleName:null,surname:"Sun",fullName:"Steven Sun",slug:"steven-sun",email:"wzstevensun@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Histone methyltransferases in cancer",level:"1"},{id:"sec_2_2",title:"2.1 Lysine methyltransferases",level:"2"},{id:"sec_3_2",title:"2.2 Protein arginine methyltransferases",level:"2"},{id:"sec_5",title:"3. Discovery of small molecule inhibitors for histone methyltransferases in cancer treatment",level:"1"},{id:"sec_5_2",title:"3.1 Screening assays for epigenetic drug discovery",level:"2"},{id:"sec_6_2",title:"3.2 AlphaLISA screen (amplified luminescent proximity homogeneous assay-linked assay)",level:"2"},{id:"sec_7_2",title:"3.3 FRET (Förster/fluorescent resonance energy transfer) assay",level:"2"},{id:"sec_8_2",title:"3.4 In silico screen",level:"2"},{id:"sec_10",title:"4. Current small molecule inhibitors of histone methyltransferases",level:"1"},{id:"sec_10_2",title:"4.1 Small molecule inhibitors of EZH2",level:"2"},{id:"sec_11_2",title:"4.2 Small molecule inhibitors of hDOT1L",level:"2"},{id:"sec_12_2",title:"4.3 Small molecule inhibitors of PRMT5",level:"2"},{id:"sec_14",title:"5. 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Department of Pharmacology and Toxicology, Indiana University School of Medicine, USA
Department of Pharmacology and Toxicology, Indiana University School of Medicine, USA
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, USA
Department of Medical and Molecular Genetics, Indiana University School of Medicine, USA
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Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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CSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
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Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
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Virginia Polytechnic Institute and State University
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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CSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
The Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 15% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\n
\n\t
Virginia Polytechnic Institute and State University
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