Dos Santos Lais L Manção, Alves Marco G, Chies Agnaldo Bruno, Spadella Maria Angélica
Laboratory of Human Embryology, Marília Medical School - FAMEMA, Marília, Brazil.
Unit for Multidisciplinary Research in Biomedicine (UMIB) and Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.
Front Reprod Health. 2022 Jul 14;4:904804. doi: 10.3389/frph.2022.904804. eCollection 2022.
Male germ cells are particularly susceptible to radiation; infertility being a common consequence after radiotherapy as it impairs spermatogenesis. This study aimed to test whether treatment with losartan (LOS), a selective antagonist of angiotensin II receptor subtype 1 (AT1R), can prevent or attenuate the acute and long-term radiation-induced damage to testes. Wistar rats were randomly distributed into six groups, three of which were studied on day 2 after irradiation: control (CTRL 2), irradiated non-treated (IR 2), and irradiated and treated with LOS (IRLOS 2); and three other groups that were studied on day 60 after irradiation: control (CTRL 60), irradiated non-treated (IR 60), and irradiated and treated with LOS (IRLOS 60). Seven consecutive days before and on the day of irradiation with 2.5 Gy directly administered in the scrotum, the animals were treated with LOS (34 mg/kg/two times/day). This treatment was continued 2 or 60 days after irradiation. The sperm quality was assessed from epididymis cauda. In addition, the testes were submitted to histopathological and morphometric-stereological analysis as well as the proliferating cell nuclear antigen (PCNA) quantification. Serum FSH and LH and plasma testosterone levels were also determined. The data obtained 2 days after the irradiation showed germ cell apoptosis, formation of vacuoles in the seminiferous epithelium, sloughing of germ cells into the lumen, and retention and phagocytosis of step-19 spermatids in Sertoli basal cytoplasm. The treatment with LOS in this period did not prevent or attenuate a radio-induced damage to the testes, illustrating that this drug does not protect against apoptosis derived from direct effects of radiation. On the other hand, 60 days after exposure, the data evidenced the deleterious effects of ionizing radiation on the testes as decreasing of testicular, epididymal, and seminal vesicle masses; tubular atrophy; reduction of cellular proliferation; and loss of germ cells. LOS was able to prevent some of those deleterious effects, promoting improvements in seminal vesicle mass, sperm vitality, plasma testosterone levels, vacuole number, and cell proliferation. In conclusion, inhibition of the AngII/AT1R axis by LOS is effective in protecting the indirect/delayed radiation damage resulting from oxidative stress established in the tissue.
雄性生殖细胞对辐射尤为敏感；放射治疗后不育是常见的后果，因为它会损害精子发生。本研究旨在测试氯沙坦（LOS）（一种血管紧张素II 1型受体（AT1R）的选择性拮抗剂）治疗是否可以预防或减轻辐射对睾丸造成的急性和长期损伤。将Wistar大鼠随机分为六组，其中三组在照射后第2天进行研究：对照组（CTRL 2）、未治疗的照射组（IR 2）、照射并接受LOS治疗组（IRLOS 2）；另外三组在照射后第60天进行研究：对照组（CTRL 60）、未治疗的照射组（IR 60）、照射并接受LOS治疗组（IRLOS 60）。在阴囊直接给予2.5 Gy照射前连续7天及照射当天，动物接受LOS治疗（34 mg/kg/每天两次）。照射后继续该治疗2天或60天。从附睾尾部评估精子质量。此外，对睾丸进行组织病理学和形态计量学-体视学分析以及增殖细胞核抗原（PCNA）定量分析。还测定血清促卵泡激素（FSH）和促黄体生成素（LH）以及血浆睾酮水平。照射后2天获得的数据显示生殖细胞凋亡、生精上皮中出现空泡、生殖细胞脱落在管腔中以及19期精子细胞滞留在支持细胞基底细胞质中并被吞噬。在此期间用LOS治疗并不能预防或减轻辐射对睾丸的损伤，说明该药物不能保护免受辐射直接作用引起的凋亡。另一方面，照射60天后，数据证明电离辐射对睾丸有有害影响，如睾丸、附睾和精囊质量下降；小管萎缩；细胞增殖减少；生殖细胞丢失。LOS能够预防其中一些有害影响，促进精囊质量、精子活力、血浆睾酮水平、空泡数量和细胞增殖的改善。总之，LOS抑制AngII/AT1R轴可有效保护因组织中建立的氧化应激导致的间接/延迟辐射损伤。
