Histopathology of the Male Reproductive System II: Interpretation

Dianne M. Creasy1

1 Huntingdon Life Sciences, East Millstone, New Jersey
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 16.4
DOI:  10.1002/0471140856.tx1604s13
Online Posting Date:  November, 2002
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Histopathology of the Male Reproductive System II: Interpretation (Diane Creasy, Huntingdon Life Sciences, East Millstone, New Jersey) Histopathology is acknowledged as the most sensitive endpoint for detecting testicular toxicity. However, identification and interpretation of chemically induced changes in the testis require fundamental knowledge of spermatogenesis, its dynamics and regulation. Changes in the rest of the reproductive tract are also frequently interÔÇÉrelated, being the result of or cause of disturbance in testicular spermatogenesis. This unit provides practical guidelines on how to evaluate testicular histopathology and how to utilize staging in a qualitative evaluation. It also provides an overview of the most common chemically induced lesions and their potential significance with respect to etiology and functional consequences.

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Table of Contents

  • Essential Knowledge for Evaluation and Interpretation of Testicular Pathology
  • Common Toxicolgically Induced Findings and Their Possible Significance
  • Practical Approach for Examination of the Testis and Epididymis for Toxicological Effects
  • Nomenclature and Severity Grading of Spermatogenic Disturbance (Germ Cell Depletion/Germ Cell Degeneration)
  • Artifacts, Spontaneous Pathology, and Immaturity
  • Figures
  • Tables
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Literature Cited

Literature Cited
   Blanchard, K.T., Lee, J., and Boekelheide, K. 1998. Leuprolide, a gonadotropin‐releasing hormone agonist reestablishes spermatogenesis after 2,5‐hexanedione‐induced irreversible testicular injury in the rat resulting in normalized stem cell factor expression. Endocrinology 139:236‐244.
   Chapin, R.E. and Conner, M.W. 1999. Testicular histology and sperm parameters. In An Evaluation and Interpretation of Reproductive Endpoints for Human Health Risk Assessment. (G. Daston and C. Kimmel, eds). pp. 28‐41. ILSI Press, Washington, D.C.
   Chapin, R.E. and Ku, W.W. 1994. The reproductive toxicity of boric acid. Environ. Health Persp. 7:87‐91.
   Chellman, G.J., Bus, J.S., and Working, P.K. 1986. Role of epididymal inflammation in the induction of dominant lethal mutations in Fisher 344 rat sperm by methyl chloride. Proc. Natl. Acad. Sci. U.S.A. 83:8087‐8091.
   Clegg, E.D., Cook, J.C., Chapin, R.E., Foster, P.M.D., and Daston, G.P. 1997. Leydig cell hyperplasia and adenoma formation: Mechanisms and relevance to humans. Reprod. Toxicol. 11:107‐121.
   Creasy, D.M. 1997. Evaluation of testicular toxicity in safety evaluation studies: The appropriate use of spermatogenic staging. Toxicol. Pathol. 25:119‐131.
   Creasy, D.M. 2001. Pathogenesis of male reproductive toxicity. Toxicol. Pathol. 29:64‐76.
   Creasy, D.M. and Foster, P.M.D. 2001. Male reproductive system, Chapter 10. In Handbook of Toxicologic Pathology, 2nd Edition (W. Haschek, C. Rousseaux, and M. Wallig, eds.) Academic Press, San Diego.
   Foley, G.M. 2001. Overview of male reproductive pathology Toxicol. Pathol. 29:49‐63.
   Hess, R.A. 1990. Quantitative and qualitative characteristics of the stages and transitions in the cycle of the rat seminiferous epithelium: Light microscopic observation of perfusion‐fixed and plastic embedded testes. Biol. Reprod. 3643:525‐542.
   Hess, R.A. 1998. Effects of environmental toxicants on the efferent ducts epididymis and fertility. J. Reprod. Fertil. Suppl. 53:247‐259.
   Hess, R.A. and Chen, P. 1992. Computer tracking of germ cells in the cycle of the seminiferous epithelium and prediction of changes in cycle duration in animals commonly used in reproductive biology and toxicology. J. Androl. 13:185‐190.
   Lee, J., Richburg, J.H., Younkin, S.C., and Boekelheide, K. 1997. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology 138:2081‐2088.
   Lee, J., Richburg, J.H., Shipp, E., Meistrich, M.L., and Boekelheide, K. 1999. The Fas system, a regulator of testicular germ cell apoptosis, is differentially up‐regulated in Sertoli cell versus germ cell injury of the testis. Endocrinology 140:852‐858.
   Linder, R.E., Strader, L.F., Slott, V.L., and Suarez, J.D. 1992. Endpoints of spermatotoxicity in the rat after short duration exposures to 14 reproductive toxicants Reprod. Toxicol. 6:491‐505.
   Meistrich, M.L. 1986. Critical components of testicular function and sensitivity to disruption. Biol. Reprod. 34:17‐28.
   Nolte, T., Harleman, J.H., and Jahn, W. 1995. Histopathology of chemically induced testicular atrophy in rats. Exp. Toxicol. Pathol. 47:267‐286.
   Rehm, S. 2001. Spontaneous testicular lesions in purpose bred beagle dogs. Toxicol. Pathol. 28:782‐787.
   Russell, L.D., Ettlin, R.A., Sinha‐Hikim, A.P., and Clegg, E.D. 1990. Histological and histopathological evaluation of the testis. pp. 62‐193. Cache River Press, Clearwater, Florida.
   Ulbrich, B. and Palmer, A.K. 1995. Detection of effects on male reproduction—A literature survey. J. Am. Coll. Toxicol. 14:2293‐3327.
Key References
   Chapin and Conner 1999. See above.
  This chapter provides an overview on how to approach and carry out histopathological evaluation of the testis including the use of staging. It also reviews the inter‐relationship of morphologic changes in the testis with functional outcome and discusses the utility of sperm parameters.
   Creasy, 1997. See above.
  This key reference provides more in‐depth consideration of the proper use of an understanding of spermatogenesis in the histopathologic interpretation of testis lesions, and will help the pathologist understand the proper application of staging in the regulatory framework.
   Creasy and Foster 2001. See above.
  This chapter provides a general overview of the structure, function and physiology of the male reproductive system as well as responses of the system to toxicologic disturbance.
   Knobil, E., Neill, J., Greenwald, G., Markert, C., and Pfaff, D. 1994. The Physiology of Reproduction, 2 nd Ed. Raven Press, New York.
  This is an invaluable and comprehensive reference text dealing with all aspects of reproductive physiology.
   Russell et. al., 1990. See above.
  This is an essential reference text for beginners as well as those experienced in testicular histopathology. It provides detailed instruction on how to identify stages of the spermatogenic cycle in the rat, mouse, and dog. It also provides a wealth of information on testicular biology, histopathological and toxicological evaluation, fixation, ultrastructure and much more.
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