Female-specific reproductive toxicites following preconception exposure to xenobiotics

  • Jack B. Bishop
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 518)


There are only a few testing strategies directed specifically at female reproductive toxicity. (Generoso et al, 1971; Generoso and Cosgove, 1973; Bishop et al., 1997). There are some elegant molecular studies of female germ cell and reproductive biology (Eichenlaub-Ritter, et al., 1988; Albertini, et al., 2001; Hunt et al, 1995) but few, if any, of these investigations involve toxicological perspectives. Future research efforts in female, as well as male, reproductive toxicology would benefit greatly by enhanced integration of knowledge and methodology from molecular developmental and cell biology. In this chapter, I will review some basic reproductive biology, emphasizing differences between females and males, describe tests for female reproductive toxicology used by the National Toxicology Program (NTP) at NIEHS, summarize NTP test data and discuss some of the dogmas of germ cell mutagenesis that have recently been dispelled by these data.


Germ Cell Male Germ Cell Reproductive Toxicity National Toxicology Program Female Germ Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albertini, D.F., Combelles, CM., Benecchi, E., Carabatsos, M.J., 2001, Cellular basis for paracrine regulation of ovarian follicle development. Reproduction.121:647–653.PubMedCrossRefGoogle Scholar
  2. Ashby, J., and Tinwell, H., 2001, Continuing ability of the rodent bone marrow micronucleus assay to act as a predictor of the possible germ cell mutagenicity of chemicals. Mutat Res. 478:211–213.PubMedCrossRefGoogle Scholar
  3. Bishop, J.B., Morris, R.W., Seely, J.C., Hughes, L.A., Cain, K.T., Generoso, W.M., 1997, Alterations in the reproductive patterns of female mice exposed to xcnobiotics. Fundamental and Applied Toxicology. 40:191–204.PubMedCrossRefGoogle Scholar
  4. Brewen, J.G., Payne, H.S., Jones, K.P., Preston, R.J., 1975, Studies on chemically induced dominant lethality: I. The cytogenetic basis of MMS-induced dominant lethality in postmeiotic male germ cells. Mutat Res. 33:239–249.PubMedCrossRefGoogle Scholar
  5. Eichenlaub-Ritter, U., Chandley, A.C., Gosden, R.G., 1988, The CBA mouse as a model for age-related aneuploidy in man: studies of oocyte maturation, spindle formation and chromosome alignment during meiosis. Chromosoma. 96:220–226.PubMedCrossRefGoogle Scholar
  6. Generoso, W.M., Stout, S.K., Huff, S.W., 1971, Effects of alkylating chemicals on reproductive capacity of adult female mice. Mutat Res. 13:171–184.CrossRefGoogle Scholar
  7. Generoso, W.M., and Cosgove, G.E., 1973, Total reproductive capacity procedure in female mice. In Chemical Mutagenesis-Principles and Methods for Their Detection (A Hollaender ed) pp. 241–258. Plenum, New York.Google Scholar
  8. Generoso, W.M., Preston, R.J., Brewen, J.G., 1975, 6-mercaptopurine, an inducer of cytogenetic and dominant-lethal effects in premeiotic and early meiotic germ cells of male mice. Mutat Res. 28:437–447.PubMedCrossRefGoogle Scholar
  9. Hunt, P., LeMaire, R., Embury, P., Sheean, L., Mroz, K., 1995, Analysis of chromosome behavior in intact mammalian oocytes: monitoring the segregation of a univalent chromosome during female meiosis. Hum Mol Genet. 4:2007–2012.PubMedCrossRefGoogle Scholar
  10. Katoh, M.A., Cain, K.T., Hughes, L.A., Foxworth, L.B., Bishop, J.B., Generoso, W.M., 1990, Femalespecific dominant lethal effects in mice. Mutat Res. 230:205–217.PubMedCrossRefGoogle Scholar
  11. Lockhart, A.C., Bishop, J.B., Piegorsch, W.W., 1991, Issues regarding data acquisition and analysis in the dominant lethal assay. Proceedings of the Biopharmaceutical Section of the American Statistical Association, pp. 234–237.Google Scholar
  12. Marchetti, F., Bishop, J.B., Lowe, X., Generoso, W.M., Hozier, J., Wyrobek, A.J., 2001, Etoposide induces heritable chromosomal aberrations and aneuploidy during male meiosis in the mouse. Proc Natl Acad Sci USA. 98:3952–3957.PubMedCrossRefGoogle Scholar
  13. Marchetti, F., Lowc, X., Bishop, J. and Wyrobek, A.J., 1997, Induction of chromosomal aberrations in mouse zygotes by acrylamide treatment of male germ cells and their correlation with dominant lethality and heritable translocations. Environ Mol Mutagen. 30:410–417.PubMedCrossRefGoogle Scholar
  14. Russell, L.B., Hunsicker, P.R., Johnson, D.K., Shelby, M.D., 1998, Unlike other chemicals, etoposide (a topoisomerase-II inhibitor) produces peak mutagenicity in primary spermatocytes of the mouse. Mutat Res. 400:279–286.PubMedCrossRefGoogle Scholar
  15. Russell, L.B., Hunsicker, P.R., Hack, A.M., Ashley, T., 2000a, Effect of the topoisomerase-II inhibitor etoposide on meiotic recombination in male mice. Mutat Res. 464:201–212.Google Scholar
  16. Russell, L.B., Hunsicker, P.R., Kerley, M.K., Johnson, D.K., Shelby, M.D., 2000b, Bleomycin, unlike other male-mouse mutagens, is most effective in spermatogonia, inducing primarily deletions. Mutat Res. 469:95–105.Google Scholar
  17. Shelby, M.D., Bishop, J.B., Hughes, L.A., Morris, R.W., Generoso, W.M., 2001, Primary spermatocytes are the main targets for induction of etoposide dominant lethals and heritable translocations in male mice. Mutat Res. (in press)Google Scholar
  18. Sudman, P.D., and Generoso, W.M., 1991, Female-specific mutagenic response of mice to hycanthone. Mutat Res. 246:31–43.PubMedCrossRefGoogle Scholar
  19. Sudman, P.D., Rutledge, J.C., Bishop, J.B., Generoso, W.M., 1992, Bleomycin: female-specific dominant lethal effects in mice. Mutat Res. 296:143–156.PubMedCrossRefGoogle Scholar
  20. Teramoto, S., Saito, R., Aoyama, H., Shirasu, Y., 1980, Dominant lethal mutation induced in male rats by l,2-dibromo-3chloropropane (DBCP). Mutat Res. 77:71–78.PubMedCrossRefGoogle Scholar
  21. Tinwcll, H., Brinkworth, M.H., Ashby, J., 2001, Further evidence for the rodent bone marrow micronucleus assay acting as a sensitive predictor of the possible germ cell mutagenicity of chemicals. Mutat Res. 473:259–261.CrossRefGoogle Scholar
  22. Witt, K.L., Hughes, L.A., Burka, L.T., Bishop, J.B., 2002, The mouse micronucleus assay is not a predictor of the N-hydroxymethyl acrylamide induced germ cell mutagenicity seen in the mouse dominant lethal assay. Mutat Res. (in press)Google Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Jack B. Bishop
    • 1
  1. 1.NIEHS

Personalised recommendations