Critical components of testicular function and sensitivity to disruption.

Toxic agents can interfere with the male reproductive system at many targets. Radiation and cancer chemotherapeutic drugs represent one class of toxins the sterilizing effects of which can be analyzed qualitatively and quantitatively in terms of testicular cell kinetics. The cells most sensitive to killing by these agents are the rapidly dividing, differentiating spermatogonia. Cells past the DNA-synthetic stages, including spermatocytes, spermatids, and nongerminal cells, are generally resistant. The slow cycling stem spermatogonia show an intermediate sensitivity, but appear to be the critical targets for the resulting long-term oligo- or azoospermia and infertility. The extent of recovery of spermatogenesis and the duration of infertility can be predicted on the basis of stem cell survival alone, independent of the antineoplastic agent used. When murine stem cells are killed, regeneration of their number and repopulation of the seminiferous epithelium begin almost immediately. In man, recovery can be delayed for years after exposure to agents that kill stem cells. This is a result of the regulation of stem cell regeneration and differentiation in man, the mechanisms of which are unknown. This regulation can explain quantitative differences in interspecies sensitivities to toxic agents. For example, man is much more sensitive than the mouse to reduction in sperm count by radiation at short times after exposure, but not when sufficient recovery times are allowed.