Long-Term Effects of Irradiation Before Adulthood on Reproductive Function in the Male Rhesus Monkey1

Abstract

Today, many patients, who are often young, undergo total body irradiation (TBI) followed by bone marrow transplantation. This procedure can have serious consequences for fertility, but the long-term intratesticular effects of this treatment in primates have not yet been studied. Testes and epididymides of rhesus monkeys that received doses of 4-8.5 Gy of TBI at 2-4 yr of age were studied 3-8 yr after irradiation. In all irradiated monkeys, at least some seminiferous tubule cross-sections lacked germ cells, indicating extensive stem cell killing that was not completely repaired by enhanced stem cell renewal, even after many years. Testes totally devoid of germ cells were only found in monkeys receiving doses of 8 Gy or higher and in both monkeys that received two fractions of 6 Gy each. By correlating the percentage of repopulated tubules (repopulation index) with testicular weight, it could be deduced that considerable numbers of proliferating immature Sertoli cells were killed by the irradiation. Because of their finite period of proliferation, Sertoli cell numbers did not recover, and potential adult testis size decreased from approximately 23 to 13 g. Most testes showed some dilated seminiferous tubules, indicating obstructed flow of the tubular fluid at some time after irradiation. Also, in 8 of the 29 irradiated monkeys, aberrant, densely packed Sertoli cells were found. The irradiation did not induce stable chromosomal translocations in spermatogonial stem cells. No apparent changes were seen in the epididymides of the irradiated monkeys, and the size of the epididymis adjusted itself to the size of the testis. In the irradiated monkeys, testosterone and estradiol levels were normal, whereas FSH levels were higher and inhibin levels lower when testicular weight and spermatogenic repopulation were low. It is concluded that irradiation before adulthood has considerable long-term effects on the testis. Potential testis size is reduced, repopulation of the seminiferous epithelium is generally not complete, and aberrant Sertoli cells and dilated tubules are formed. The latter two phenomena may have further consequences at still longer intervals after irradiation.

Clinical Potential and Putative Risks of Fertility Preservation in Children Utilizing Gonadal Tissue or Germline Stem Cells

“…In humans and primates where spermatozoa may be isolated in testicular biopsies, it has been shown that recovery after severe damage occurs only focally in a few seminiferous tubules. Patients will be permanently infertile if tubules become fully hyalinized or a complete Sertoli cell only pattern is established (32,33). The spermatogenic stem cells are susceptible to this type of damaging insult at all ages, but the full impact on spermatogenesis manifests itself during onset of puberty (34).…”

Unintentional exposure of neonates to conventional radiography in the Neonatal Intensive Care Units

“…4 Gonadal exposure to ionizing radiation of the neonate, particularly preterm infants, is another important issue since irradiation before adulthood may have long-term harmful effects on the size and function of the gonads. [7][8][9] Detailed studies on the field size and body tissues included in each X-ray taken on these infants are scarce. 10 Considering the health hazards of ionizing radiation, the objective of this study was to evaluate unnecessary radiation exposure to body tissues outside the anatomical region of interest in five NICUs in Israel.…”

Spermatogonia: origin, physiology and prospects for conservation and manipulation of the male germ line

“…This finding indicates a critical role for spermatogonial stem cells in the restoration process. Functional proof for this is provided from germ cell transplantation experiments in mice and monkeys revealing that continuous recolonisation of remaining or reintroduced testicular stem cells leads to reinduction of spermatogenesis (Nagano and Brinster 1998;de Rooij et al 2002;Kamischke et al 2003). Therefore, spermatogonia are considered the selective target cells for the preservation of testis tissue and function, as well as for the development of novel options for fertility preservation in oncological patients (Nordhoff and Schlatt 2003;Orwig and Schlatt 2005).…”