Sperm Chromatin

Sperm Chromatin Armand Zini • Ashok Agarwal Editors Sperm Chromatin Biological and Clinical Applications in Male Infertility and Assisted Reproduction Editors Armand Zini, MD Ashok Agarwal, PhD, HCLD (ABB) Department of Surgery Center for Reproductive Medicine Division of Urology Glickman Urological and Kidney Institute McGill University OB-GYN and Women’s Health Institute St. Mary’s Hospital Center Cleveland Clinic, Cleveland, OH, USA Montreal, QC, Canada [email protected] [email protected] ISBN 978-1-4419-1781-2 e-ISBN 978-1-4419-6857-9 DOI 10.1007/978-1-4419-6857-9 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011932679 © Springer Science+Business Media, LLC 2011 All rights reserved. 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The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Foreword The composition, stability, and integrity of sperm chromatin have major bearings on the fertilizing potential of male gametes and their capacity to sup- port normal embryonic development. This assertion is supported by clinical data generated over the past 10–15 years, indicating the existence of significant correlations between DNA damage in spermatozoa and a variety of adverse reproductive outcomes including reduced conception rates, a high fre- quency of miscarriage and an escalation in the incidence of birth defects. Despite this wealth of correlative data, uncertainties remain with respect to such key questions as the precise nature of the DNA damage, the relative importance of genetic, epigenetic and environmental factors in its etiology, and the most effective method for detecting its presence. Answers to these questions are critical if we are to develop rational strategies for alleviating or, ultimately, preventing DNA damage in spermatozoa. Furthermore, answers to these questions are needed if clinicians are to provide patients with informed v vi Foreword advice about the significance of their DNA damage results. In Sperm Chromatin: Biological and Clinical Application in Male Infertility and Assisted Reproduction Ashok Agarwal and Armand Zini have assembled contributions from a panel of world experts in this area and, in so doing, created an invalu- able text that brings us up-to-date with recent advances in this field. The remodeling of sperm chromatin during spermiogenesis is as remarkable as it is complex. It involves a dramatic morphological and biochemical trans- formation of chromatin structure through the coordinated movement of proteins in and out of the nucleus to generate a unique, highly compacted matrix. Furthermore, this extraordinary metamorphosis takes place in the absence of de novo gene transcription. Indeed, spermiogenesis is an object lesson in how biological processes can be controlled through the regulated translation of pre- existing mRNA species. If we could only replicate this process in vitro, research into the underlying control mechanisms would be greatly facilitated. Unfortunately, this is not possible at the present time and, as a result, progress in this area has been painfully slow. Nevertheless, as the pioneer of sperm chromatin research, Rod Balhorn, indicates in Chap. 1, we might anticipate more rapid progress in this area in the future because we now have an array of sophis- ticated tools to investigate the chromatin remodeling process. Thus, our new found ability to generate detailed inventories of proteins and mRNA species in selected cells and tissues is one of the driving forces behind the modern systems approach to biological research, and the analysis of sperm chromatin will be one of the major beneficiaries of these technical developments. In the first section of this book, we see beautifully illustrated reviews of spermatogenesis (Chap. 2) and chromatin organization (Chaps. 4 and 5) followed by a number of authoritative reviews on aspects of the genome (Chap. 6), epigenome (Chap. 7), transcriptome (Chap. 8), and proteome (Chap. 3) from a spermatozoon’s perspective. The detailed chemical analysis of sperm chromatin using the tools of the -omics revolution will certainly provide important clues as to the formation and ultimate function of this material and act as a major stimulus for increased understanding in this area. The impetus to study the composition and integrity of sperm chromatin from a clinical perspective can be traced back to the pioneering studies of Don Evenson, who not only initiated research in this area long before it became fashionable but also pioneered one of the major analytical techniques used in the assessment of sperm chromatin, the Sperm Chromatin Structure Assay (SCSA) (Chap. 9). This assay has now become the industry standard against all other techniques. In the second section of this book Agarwal and Zini have gathered together a very impressive list of authors, all of whom share an interest in the laboratory evaluation of sperm chromatin composition and integrity. The list of techniques is extensive and comprises, in addition to SCSA, meth- ods that have been borrowed from research in toxicology (Comet; Chap. 15) or somatic cell apoptosis (TUNEL; Chap. 14) as well as a range of protocols that are more specific to the male germ line including the Sperm Chromatin Dispersion assay (Chap. 10), the acridine orange test (Chap. 13), the isolation, purification and quantification of protamines (Chap. 16), the aniline blue test for histone retention (Chap. 12), gene expression profiling (Chap. 18), and analyses of epigenetic modifications to the haploid paternal genome (Chap. 17). Foreword vii Additional probes such as toluidine blue and chromomycin 3 (CMA3) are also important because they provide indirect evidence of the efficiency of chromatin packaging (Chap. 11). In this context, Denny Sakkas deserves special men- tion for his work on the development of CMA3 as an extremely valuable diagnostic probe, which has consistently been found to generate significant information about sperm chromatin status in infertile men. The clinical and environmental factors that contribute to the etiology of DNA damage are reviewed in the third section of this book. The range of possible contributory factors is again extensive and includes oxidative stress (Chap. 19), apoptosis (Chap. 20), and defective repair of physiological DNA nicks (Chap. 21). The primary drivers for the oxidative stress, abortive apoptosis, and defective DNA repair include infertility (Chap. 22), age (Chap. 23), cancer (Chap. 24), environmental pollutants (Chap. 25), infection (Chap. 26), and cryopreservation (Chap. 27). If we understood more about the chemical nature of the DNA damage seen in human spermatozoa, we might be able to reduce this long list of potential causative factors down to the major culprits. However, at present, the only clue we have to the types of DNA damage present in human spermatozoa is the high prevalence of oxidative base lesions detected in the patient population. The mechanism by which such stress is generated is still something of an unresolved mystery. If we do not understand the etiology of DNA damage, then there is little we can do to treat this condition or prevent it from arising. However, we can try to develop strategies for limiting the impact of such damage on human embryos conceived in vitro including antioxidant therapy (Chap. 30), electro- phoretic sperm isolation (Chap. 29), and the selective binding properties of hyaluronic acid polymers (Chap. 28), all of which help select non-DNA damaged spermatozoa for the insemination of oocytes. The importance of developing strategies for avoiding conception with DNA damaged spermatozoa is generally supported by the clinical data, although the results are not always as clean cut as one would like (Chaps. 31 and 32). A major problem with such clinical studies is that pregnancy is a very bad test of sperm function because it depends on so many confounding variables. By contrast, the animal data are incontrovertible in demonstrating that DNA damage in the male germ line has profound, lasting effects on the viability of pregnancy and the health of the offspring (Chap. 33). In light of such certainty, it is critical that the information available on this topic is assembled and presented for careful consideration. Agarwal and Zini have done a remarkable job of pulling together the protagonists in this field and creating a compendium of knowledge that will be of intense interest to clinicians and scientists who share an appreciation of the significant contributions made by the male gamete to a healthy start to life. Callaghan, NSW R. John Aitken, PhD, ScD, FRSE Preface The evaluation of sperm DNA and chromatin abnormalities has gained significant importance in the past several years, largely as a result of the recent advances in assisted reproductive technologies (ARTs). In vitro fertil- ization (IVF) and intracytoplasmic sperm injection (ICSI) have revolution- ized the treatment of male-factor infertility. However, we have come to realize that in the context of these ARTs, the genetic integrity of the sperm is a key aspect of the paternal contribution to the offspring.

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