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ToxSci Advance Access published online on September 26, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg237
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received July 2, 2003; accepted September 3, 2003
© 2003 Society of Toxicology

Reproductive and Developmental Toxicology

Restoration of Spermatogenesis in Dibromochloropropane (DBCP)-Treated Rats by Hormone Suppression

Marvin L. Meistrich 1*, Gene Wilson 1, Karen L. Porter 1, Ilpo Huhtaniemi 2, Gunapala Shetty 1, and Gladis A. Shuttlesworth 1

1 Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030
2 Department of Physiology, University of Turku, 20520 Turku, Finland

* To whom correspondence should be addressed. E-mail: meistrich{at}mdanderson.org.


  Abstract

Exposure of men to the nematocide dibromochloropropane (DBCP) has caused prolonged oligo- and azoospermia, which occasional reverses spontaneously. We recently demonstrated that in testes of rats treated with a dose of DBCP sufficient to reduce the percentage of tubules producing differentiating germ cells (tubule differentiation index, TDI) to 20%, the tubules lacking differentiating cells contained type A spermatogonia. To determine whether these type A spermatogonia could be stimulated to differentiate, as had been demonstrated previously in other models of toxicant-induced sterility, we suppressed intratesticular testosterone and serum FSH levels with the GnRH agonist, Lupron (leuprolide). When the GnRH agonist was given for 10 weeks starting immediately after DBCP exposure, the TDI was maintained at 94%. Even when GnRH-agonist treatment was stopped at week 10, the TDI remained between 65%-80% 10 weeks later. Late spermatid counts averaged 10x106 per testis for the GnRH-agonist treated rats at week 20 compared with 1.7x106 per testis in rats treated with only DBCP. To determine whether spermatogonial differentiation could be stimulated after the TDI had declined to below 30%, we initiated GnRH-agonist treatment 6 weeks after DBCP exposure. The GnRH treatment increased the TDI to 53% at week 16. These results indicate that, if the same principles apply to humans, suppression of testosterone may be applied to restore spermatogenesis in men rendered azoospermic by DBCP or other reproductive toxicants.

Key Words: Spermatogonia, Gonadotropin-releasing hormone analogs, Reproductive toxicants .


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