Exposure of men to certain environmental, occupational, and medical toxicants may result in prolonged oligoor azoospermia. Occasionally spermatogenesis recovers after years of azoospermia indicating that some stem (type A) spermatogonia survived but their differentiation was limited. This suggests that disruption of spermatogonial differentiation may be responsible for the failure of spermatogenesis to recover following exposure. This hypothesis will be tested in rats exposed to reproductive toxicants by modulating spermatogonial differentiation using hormones and identifying molecular changes associated with the stimulation of recovery. Radiation and dibromochloropropane (DBCP) will be used as the toxicants, because of the precision of delivery and relevance as an environmental and occupational reproductive toxicant, respectively. Radiation (and DBCP, based on preliminary data) produces in rats the loss of all differentiating spermatogenic cells despite the presence of proliferating A spermatogonia. The causes of failure of spermatogonial differentiation will be characterized as follows. The role of hormonal changes will be examined by minimizing them using unilateral irradiation. The possibility that hormone receptor levels are reduced will be examined. To determine whether the defect is in spermatogonia or stromal cells, cell transplantation techniques will be employed. The recovery of spermatogenesis can be stimulated by gonadotropin-releasing hormone (GnRH) agonist treatment given immediately after irradiation; whether the stimulation is a result of altered levels of androgens or gonadotropins will be determined. Further studies will be performed to determine if GnRH can be used to induce spormatogonial differentiation after regression has occurred. GnRH-stimulation of spermatogenic recovery, or alternative models that result in spontaneous spermatogonial differentiation and recovery of spormatogenesis from A spormatogonia, will be used to identify molecules regulating differentiation of spermatogonia. Patterns of protein or mRNA levels in testes in which A spormatogonia do not differentiate and those in which differentiation occurs (hormone-stimulated recovery, alternative models, untreated) will be compared to identify genes whose expression correlates with spermatogonial differentiation. This study should define factors that not only modulate spormatogenic recovery after toxicant exposure but also regulate normal spormatogonial differentiation. Hormones or other factors identified in this project might be used as intervention to enhance recovery of fertility in men following toxicant exposure, cancer therapy, and in some cases of idiopathic infertility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008075-04
Application #
6043487
Study Section
Reproductive Biology Study Section (REB)
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Shetty, G; Zhou, W; Weng, C C Y et al. (2016) Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat. Andrology 4:412-24
Sahin, Z; Szczepny, A; McLaughlin, E A et al. (2014) Dynamic Hedgehog signalling pathway activity in germline stem cells. Andrology 2:267-74
Meistrich, Marvin L (2013) Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 100:1180-6
Abuelhija, M; Weng, C C; Shetty, G et al. (2013) Rat models of post-irradiation recovery of spermatogenesis: interstrain differences. Andrology 1:206-15
Abuelhija, Mahmoud; Weng, Connie C; Shetty, Gunapala et al. (2012) Differences in radiation sensitivity of recovery of spermatogenesis between rat strains. Toxicol Sci 126:545-53
Drumond, Ana Luiza; Weng, Connie C; Wang, Gensheng et al. (2011) Effects of multiple doses of cyclophosphamide on mouse testes: accessing the germ cells lost, and the functional damage of stem cells. Reprod Toxicol 32:395-406
Zhou, Wei; Bolden-Tiller, Olga U; Shao, Shan H et al. (2011) Estrogen-regulated genes in rat testes and their relationship to recovery of spermatogenesis after irradiation. Biol Reprod 85:823-33
Zhou, Wei; Bolden-Tiller, Olga U; Shetty, Gunapala et al. (2010) Changes in gene expression in somatic cells of rat testes resulting from hormonal modulation and radiation-induced germ cell depletion. Biol Reprod 82:54-65
Wang, Gensheng; Shao, Shan H; Weng, Connie C Y et al. (2010) Hormonal suppression restores fertility in irradiated mice from both endogenous and donor-derived stem spermatogonia. Toxicol Sci 117:225-37
Porter, Karen L; Shetty, Gunapala; Shuttlesworth, Gladis A et al. (2009) Estrogen enhances recovery from radiation-induced spermatogonial arrest in rat testes. J Androl 30:440-51

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