Humanin protects against chemotherapy-induced stage-specific male germ cell apoptosis in rats.
Humanin protects against chemotherapy-induced stage-specific male germ cell apoptosis in rats.
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作者：
Surampudi P;Chang I;Lue Y;Doumit T;Jia Y;Atienza V;Liu PY;Swerdloff RS;Wang C
人蛋白（HN）对热、激素剥夺引起的睾丸应激后的雄性生殖细胞有保护作用。为了研究HN是否对化疗诱导的雄性生殖细胞凋亡有保护作用，我们用(i)对照，（ii） HN, （iii）环磷酰胺（CP）处理四组成年大鼠；或（iv） HN+CP。为了研究HN对生殖细胞的保护作用是否需要间质细胞的存在，另外四组大鼠用乙烷二甲基磺酸（EDS）（一种间质细胞毒物）预处理，以消除间质细胞。3天后，当间质细胞被EDS耗尽时，我们给药：(i)载体，（ii） HN, (iii) CP；（iv）大鼠HN+CP。注射HN和/或CP后12 h处死大鼠，TUNEL法检测生殖细胞凋亡，计数法定量。与对照组和HN（单独）相比，CP显著增加了生殖细胞凋亡；HN +CP在精原上皮周期的早期（I-VI）和晚期（IX-XIV）显著减少CP诱导的细胞凋亡，但在中期（VII-VIII）则无显著作用。EDS预处理可显著抑制血清和睾丸内睾酮(T)水平，并显著增加中期（viii - viii）生殖细胞凋亡。CP未进一步增加eds预处理大鼠生殖细胞凋亡。HN可显著降低EDS预处理大鼠中期生殖细胞凋亡。为了研究HN是否对间质细胞功能有直接影响，我们分离了成年间质细胞并用酮康唑（KTZ）阻断睾酮合成。在体外实验中，HN不能有效地阻止KTZ减少T的产生。我们得出结论，HN以特定阶段的方式减少CP和/或eds诱导的生殖细胞凋亡。在缺乏间质细胞和睾丸内睾酮水平非常低的情况下，HN直接作用于生殖细胞以防止eds诱导的细胞凋亡。
Humanin (HN) has cytoprotective action on male germ cells after testicular stress induced by heat and hormonal deprivation. To examine whether HN has protective effects on chemotherapy-induced male germ cell apoptosis, we treated four groups of adult rats with (i) vehicle (control), (ii) HN, (iii) cyclophosphamide (CP); or (iv) HN+CP. To investigate whether the protective effects of HN on germ cells require the presence of Leydig cells, another four groups of rats were pre-treated with ethane dimethanesulfonate (EDS), a Leydig cell toxicant, to eliminate Leydig cells. After 3 days, when Leydig cells were depleted by EDS, we administered: (i) vehicle, (ii) HN, (iii) CP; or (iv) HN+CP to rats. All rats were killed 12 h after the injection of HN and/or CP. Germ cell apoptosis was detected by TUNEL assay and quantified by numerical count. Compared with control and HN (alone), CP significantly increased germ cell apoptosis; HN +CP significantly reduced CP-induced apoptosis at early (I–VI) and late stages (IX–XIV) but not at middle stages (VII–VIII) of the seminiferous epithelial cycle. Pre-treatment with EDS markedly suppressed serum and intratesticular testosterone (T) levels, and significantly increased germ cell apoptosis at the middle (VII–VIII) stages. CP did not further increase germ cell apoptosis in the EDS-pre-treated rats. HN significantly attenuated germ cell apoptosis at the middle stages in EDS pre-treated rats. To investigate whether HN has any direct effects on Leydig cell function, adult Leydig cells were isolated and treated with ketoconazole (KTZ) to block testosterone synthesis. HN was not effective in preventing the reduction of T production by KTZ in vitro. We conclude that HN decreases CP and/or EDS-induced germ cell apoptosis in a stage-specific fashion. HN acts directly on germ cells to protect against EDS-induced apoptosis in the absence of Leydig cells and intratesticular testosterone levels are very low.
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