Karen L. Porter

Dibromochloropropane inhibits spermatogonial development in rats.

Exposure to the nematocide dibromochloropropane (DBCP) has caused prolonged oligo- and azoospermia in men. There are questions regarding the cellular targets resulting in this effect. In this study we characterized an animal model, in which four daily injections of DBCP produced prolonged oligospermia in LBNF(1) rats without any indication of recovery. Between 6 and 20 weeks after DBCP treatment, 70% of seminiferous tubules showed an epithelium with Sertoli cells but no differentiating germ cells. About 20% of tubules contained differentiating germ cells and 10% showed occlusion or major morphologic alterations to Sertoli cells. Since gonadotropin levels and intratesticular testosterone (ITT) concentrations were elevated in the DBCP-treated rats, the failure of spermatogonial development could not have been a result of lack of these hormones. The tubules without differentiating germ cells contained actively proliferating and dividing type A spermatogonia, which underwent apoptosis instead of differentiation. Thus, the target for the damaging effect appears not to be the killing of stem spermatogonia, but the loss of their ability to undergo differentiation. The presence of type A spermatogonia in the atrophic tubules indicates the potential for intervention to restore spermatogenesis.

Androgen Suppression-Induced Stimulation of Spermatogonial Differentiation in Juvenile Spermatogonial Depletion Mice Acts by Elevating the Testicular Temperature

Why both testosterone (T) suppression and cryptorchidism reverse the block in spermatogonial differentiation in adult mice homozygous for the juvenile spermatogonial depletion (jsd) mutation has been a conundrum. To resolve this conundrum, we analyzed interrelations between T suppression, testicular temperature, and spermatogonial differentiation and used in vitro techniques to separate the effects of the two treatments on the spermatogonial differentiation block in jsd mice. Temporal analysis revealed that surgical cryptorchidism rapidly stimulated spermatogonial differentiation whereas androgen ablation treatment produced a delayed and gradual differentiation. The androgen suppression caused scrotal shrinkage, significantly increasing the intrascrotal temperature. When serum T or intratesticular T (ITT) levels were modulated separately in GnRH antagonist-treated mice by exogenous delivery of T or LH, respectively, the inhibition of spermatogonial differentiation correlated with the serum T and not with ITT levels. Thus, the block must be caused by peripheral androgen action. When testicular explants from jsd mice were cultured in vitro at 32.5 C, spermatogonial differentiation was not observed, but at 37 C significant differentiation was evident. In contrast, addition of T to the culture medium did not block the stimulation of spermatogonial differentiation at 37 C, and androgen ablation with aminoglutethimide and hydroxyflutamide did not stimulate differentiation at 32.5 C, suggesting that T had no direct effect on spermatogonial differentiation in jsd mice. These data show that elevation of temperature directly overcomes the spermatogonial differentiation block in adult jsd mice and that T suppression acts indirectly in vivo by causing scrotal regression and thereby elevating the testicular temperature.

Hormones and Spermatogonial Development

This chapter focuses on the effects of hormones on spermatogonial development. Two hormones, primarily T but also follicle-stimulating hormone (FSH), are required for the complete process of spermatogenesis in normal animals. Deprivation of T and FSH in rats and mice also reduces the numbers of spermatocytes and round spermatids to levels dependent on the residual concentrations of these hormones. The effects of T and FSH deprivation on spermatogonial numbers in rodents are moderate. In contrast, in adult primates (both human and monkey), the deprivation of these two hormones, especially FSH, primarily affects the conversion of type A pale to B spermatogonia, resulting in 90% reductions in B spermatogonial numbers, but there are only minor losses in the development of these B spermatogonia to spermatocytes and spermatids. The recovery of spermatogenesis in rats can be stimulated with hormone treatment given after irradiation, reversing the proliferation apoptosis (PAp) block to spermatogonial development. FSH can also inhibit spermatogonial differentiation in the models with a hormone dependent PAp block.

Chapter 10:Prevention of Adverse Effects of Cancer Treatment on the Germline

For children and young adults who have cancer, the success of treatment with regimens that are toxic to gonadal function has made infertility an important problem. When the cancer is controlled, quality of life then becomes a major issue. To many of the young men who have received chemotherapy or ra...