Upregulation and nuclear translocation of testicular ghrelin protects differentiating spermatogonia from ionizing radiation injury.
Proper control of apoptotic signaling is important for maintenance of testicular homeostasis after ionizing radiation (IR). Herein, we challenged the hypothesis that ghrelin, a pleiotropic modulator, is potentially involved in IR-induced germ cell injury. Lower body exposure to 2 Gy of IR induced a notable increase of ghrelin expression in the nuclear of differentiating spermatogonia at defined stages, with an impairment in the Leydig cells (LCs)-expressing ghrelin. Unexpectedly, inhibition of the ghrelin pathway by intraperitoneal injection of a specific GHS-R1α antagonist enhanced spermatogonia elimination by apoptosis during the early recovery following IR, and thereafter resulted in impaired male fertility, suggesting that the anti-apoptotic effects of evoked ghrelin, although transient along testicular IR injury, have a profound influence on the post-injury recovery. In addition, inhibition of ghrelin signaling resulted in a significant increase in the intratesticular testosterone (T) level at the end of 21 days after IR, which should stimulate the spermatogenic recovery from surviving spermatogonia to a certain extent during the late stage. We further demonstrated that the upregulation and nuclear trafficking of ghrelin, elaborately regulated by IR-elicited antioxidant system in spermatogonia, may act through a p53-dependent mechanism. The elicitation of ghrelin expression by IR stress, the regulation of ghrelin expression by IR-induced oxidative stress and the interaction between p53 and ghrelin signaling during IR injury were confirmed in cultured spermatogonia. Hence, our results represent the first evidence in support of a radioprotective role of ghrelin in the differentiating spermatogonia. The acutely, delicate regulation of local-produced ghrelin appears to be a fine-tune mechanism modulating the balance between testicular homeostasis and early IR injury.
Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
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W
Li
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Y
Y
Zeng
Department of Human Anatomy, Histology and Embryology, Fourth Military Medical University, Xi'an 710032, China.
J
J
Zhao
Department of Emergency Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
C-J
CJ
Zhu
Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
W-G
WG
Hou
Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
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S
Zhang
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D002478:Cells, Cultured; D005260:Female; D054439:Ghrelin / Q000378:metabolism*; D007248:Infertility, Male / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000528:radiation effects; D011832:Radiation Injuries / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D013091:Spermatogenesis / Q000528:radiation effects*; D013093:Spermatogonia / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013737:Testis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D013739:Testosterone / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D054439:Ghrelin; D054440:Receptors, Ghrelin; D016159:Tumor Suppressor Protein p53; D013739:Testosterone