A Practical Approach, Second Edition=Ronald D. Ho.pdf

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CHAPTER 5Paternally Mediated Effects on DevelopmentBarbara F. Hales and Bernard RobaireCONTENTSI. Role of the Male in Mediating Developmental Toxicity ..................................................125A. Evidence from Epidemiological Studies...................................................................126B. Evidence from Animal Experimentation...................................................................127II.Potential Mechanisms Involved in Male-Mediated Developmental Toxicity...................128A. Drugs or Toxicants in Semen ....................................................................................128B. Drugs or Toxicants Affecting the Male Germ Cell ..................................................1281. Germ Cells in the Testis or the Posttesticular Excurrent Duct System .............1292. Reversibility.........................................................................................................1313. Heritability ...........................................................................................................132III. Methodological <strong>Approach</strong>es in Male-Mediated Developmental Toxicity ........................132A. Effects of Toxicants in Seminal Fluid.......................................................................132B. Effects on Sperm Quantity and Characteristics ........................................................132C. Effects on Sperm Quality ..........................................................................................1341. Sperm Chromatin Packaging and Function ........................................................1342. Sperm Genetic Integrity ......................................................................................1363. Epigenetic Changes .............................................................................................138IV. Summary and Conclusions ................................................................................................138Acknowledgments ..........................................................................................................................138References ......................................................................................................................................139I. ROLE OF THE MALE IN MEDIATING DEVELOPMENTAL TOXICITYIt is well established that there are risks to the progeny if the mother is exposed to a variety ofchemicals during pregnancy. The extent to which paternal exposures contribute to infertility andpregnancy loss is less evident. There is growing concern that paternal exposure to drugs, radiation,or environmental toxicants may result in a decrease in sperm count and an increase in male infertility,spontaneous abortions, birth defects, or childhood cancer, adversely affecting reproduction andprogeny outcome. Clear evidence that the exposure of males to xenobiotics can result in adverseeffects on progeny outcome has accumulated over the past two decades. 1 The recent publication ofthe proceedings of a multidisciplinary international conference on male-mediated developmentaltoxicity has highlighted the need for more research in this area. The goal of this research is to125© 2006 by Taylor & Francis Group, LLC
126 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONTable 5.1Paternal exposures associated with adverse progeny outcomesAgent Pregnancy Loss a Birth Defects a Childhood Cancer aRadiation 0.9–1.5 1.4–5.6 1.8–6.7Solvents 0.9–2.3 NA b 1.7–7Anesthetic gases 1.5–1.8 NA NAHeavy metals 0.9–2.3 1.5–249 3.5–7Cigarette smoke 0.6–1.4 1.3 1.2–3.9Herbicides/pesticides NA 5.7–405 2.4–7.1Anticancer drugs NA 4.1 NAaValues represent the range of OR/RR (odds ratios/relative risk) found by differentstudiesbNA = not availableSource: Adapted from Aitken, R. J. and Sawyer, D., The human spermatozoon – notwaving but drowning, in Advances in Male-Mediated Developmental Toxicity, Advancesin Experimental Medicine and Biology, Vol. 518, Robaire, B. and Hales, B.F., Eds.Kluwer Academic/Plenum Press, New York, 2003. With permission.elucidate the extent to which the father contributes to the approximately 60% of all birth defectsthat are of unknown cause. 1,2Studies of the mechanisms by which paternal exposures adversely affect progeny outcome areessential to provide the scientific basis for the development of biomarkers for risk assessment. Thetwo major mechanisms by which exposure of a male to a drug or environmental toxicant mayadversely affect his progeny are: (1) direct exposure of the conceptus during mating to a chemicalpresent in the seminal fluid and (2) toxic effects on male germ cells.Two major approaches have been taken to identify instances in which paternal exposure to axenobiotic adversely affects progeny outcome, namely, epidemiological studies and animal experiments.A. Evidence from Epidemiological StudiesEpidemiological studies have focused largely on determining the consequences of paternal occupationalexposures on progeny. The effects of paternal occupational exposures on the offspringrange from early spontaneous abortion, which may be perceived as infertility, to delayed spontaneousabortions and stillbirth, malformations, preterm delivery, delivery of a small-for-gestationalage infant, childhood cancer, altered postnatal behavior, or changes in reproductive function. 1,3–9A variety of different paternal occupations have been associated with adverse progeny outcomes(Table 5.1). 3–9 Paternal exposures to radiation, solvents, heavy metals (e.g., mercury), pesticides,and hydrocarbons were associated with an increased incidence of spontaneous abortion or miscarriage,birth defects, or childhood cancer. 3–9 Paternal occupations that have been associated with anincreased risk of having a liveborn child with a birth defect include janitor, woodworker (forestryor logging, sawmill, carpenter), firefighter, electrical worker, and printer. 6,7 Men employed inoccupations associated with solvent exposures (with painters having the highest risk) were morelikely to have offspring with anencephaly. 5 Further, an increased risk of stillbirth, preterm delivery,or delivery of a small-for-gestational age infant was associated with paternal employment in theart (painters) or textile industries. 8,9Concerns about the potential consequences to offspring of exposure to herbicides were broughtto the forefront by male Vietnam veterans. The data from some of the studies conducted to addressthese concerns suggested that there was an increased incidence of birth defects among the childrenfathered by veterans, while other inquiries did not find a positive relationship. 10–13 Arbuckle andcolleagues reported recently that adverse progeny outcomes, including an increased risk of earlyabortions, were associated with the exposure of male farmers to pesticides that included carbamates,organophosphates, and organochlorines. 14© 2006 by Taylor & Francis Group, LLC
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Second EditionDEVELOPMENTALandREPRO
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Published in 2006 byCRC PressTaylor
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Chapter 12Chapter 13Chapter 14Chapt
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The EditorRonald D. Hood, Ph.D., is
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Alan M. HobermanArgus ResearchHorsh
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APPENDIX ATerminology of Anatomical
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TERMINOLOGY OF ANATOMICAL DEFECTS 9
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Organ/StructureCodeNumberObservatio
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Organ/Structure10145 Ocular colobom
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Organ/StructurePulmonaryarteryPulmo
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Terminology of developmental abnorm
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Organ/StructureCervicalcentrumCodeN
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Organ/Structure10689 Misshapen thor
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Organ/StructureSacralcentrumSacralv
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968 DEVELOPMENTAL REPRODUCTIVE TOXI
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1000 DEVELOPMENTAL REPRODUCTIVE TOX
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Table 1Human Non-human Primate Rat
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Table 1 (continued)Sertoli CellsHum
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Table 2 (continued) Landmarks in th
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Table 2 (continued) Landmarks in th
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POSTNATAL DEVELOPMENTAL MILESTONES
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PART IPrinciples and Mechanisms© 2
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4 DEVELOPMENTAL REPRODUCTIVE TOXICO
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10 DEVELOPMENTAL REPRODUCTIVE TOXIC
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Table 2.6Receptor(Official Name a )
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Clearly, more research needs to be
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Formation ofchoroid plexusof latera
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Optic nervefibers presentDifferenti
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Table 6.10DescriptionMuscular Syste
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Distalphalanges offingersseparatedF
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Table 6.11DescriptionIntermediateme
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Table 6.12DescriptionComparative ge
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COMPARATIVE FEATURES OF VERTEBRATE
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CHAPTER 7Developmental Toxicity Tes
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DEVELOPMENTAL TOXICITY TESTING —
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Female 0.00-0.69 0.004-0.39 0.00-0.
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Figure 8.11775Pott DescribesScrotal
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The underlying physiology of juveni
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Table 8.5Total body composition by
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Table 8.6Serum chemistry values for
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CHAPTER 9Significance, Reliability,
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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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Prior to the early 1980s, numerous
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Figure 9.51906Food andDrugs Act2000
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Table 9.18Selected comparison point
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Table 9.33Selected comparison point
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Table 9.48What do regulatorswant to
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CHAPTER 10Testing for Reproductive
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TESTING FOR REPRODUCTIVE TOXICITY 4
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We would like to acknowledge the ef
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CHAPTER 12Role of Xenobiotic Metabo
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ROLE OF XENOBIOTIC METABOLISM IN DE
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y ESR spectrometry. 122 Further ESR
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CHAPTER 13Use of Toxicokinetics in
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USE OF TOXICOKINETICS IN DEVELOPMEN
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CHAPTER 17Statistical Analysis for
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STATISTICAL ANALYSIS FOR DEVELOPMEN
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CHAPTER 19Perspectives on the Devel
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PERSPECTIVES ON THE DEVELOPMENTAL A
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Guideline OECD 415 (One Generation)
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The Office of Prevention, Pesticide
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CHAPTER 20Human Studies — Epidemi
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HUMAN STUDIES 801I. INTRODUCTIONEpi
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HUMAN STUDIES 803is actively trying
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HUMAN STUDIES 80940003500Mean birth
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CHAPTER 21Developmental and Reprodu
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