Exposure of male rats to cyclophosphamide, a commonly used anticancer and immunosuppressive drug, has been shown to alter fertility and progeny outcome in a male germ cell phase-specific manner. The effect of toxicant exposure on male germ cells depends in part on the stress response mechanisms present during the different stages of spermatogenesis. To assess how acute cyclophosphamide exposure affects the expression of stress response genes, we examined the expression of 216 genes, using gene expression arrays, in isolated rat spermatogenic cell types (pachytene spermatocytes, round spermatids, and elongating spermatids). Cyclophosphamide exposure affected gene expression in all cell types but most dramatically in round spermatids. Increased transcript levels were observed for 30 genes in round spermatids compared to seven genes in pachytene spermatocytes and two in elongating spermatids. The expression of genes involved in apoptosis, DNA-damage recognition and repair, transcriptional activation, and in the heat shock protein-chaperone response was most affected by cyclophosphamide in round spermatids. Our results demonstrate that cyclophosphamide alters the expression of stress response genes during spermatogenesis in a germ cell-specific manner. The greater response of round spermatids to cyclophosphamide suggests that this cell type may be more susceptible to the damaging effects induced by this drug, possibly due to the chromatin remodeling that is taking place at this stage of spermatogenesis. This observation is consistent with the reported higher level of abnormal progeny outcome seen when the germ cells were first exposed to cyclophosphamide as round spermatids.

译文

:雄性大鼠接触环磷酰胺是一种常用的抗癌和免疫抑制药物,已显示出以雄性生殖细胞阶段特异性的方式改变生育力和后代结局。有毒物质对雄性生殖细胞的影响部分取决于在精子发生不同阶段存在的应激反应机制。为了评估急性环磷酰胺暴露如何影响应激反应基因的表达,我们使用基因表达阵列检查了分离的大鼠生精细胞类型(粗大精细胞,圆形精细胞和伸长精细胞)中216个基因的表达。环磷酰胺暴露会影响所有细胞类型中的基因表达,但在圆形精子细胞中最显着。圆形精子中的30个基因的转录水平增加,而粗线精子细胞中的7个基因和伸长精子中的2个基因的转录水平增加。圆形精子中环磷酰胺对细胞凋亡,DNA损伤识别和修复,转录激活以及热休克蛋白-伴侣应答中涉及的基因表达的影响最大。我们的结果表明,环磷酰胺以生殖细胞特异性方式改变了精子发生过程中应激反应基因的表达。圆形精子对环磷酰胺的更大反应表明,这种细胞类型可能更容易受到这种药物诱导的破坏作用的影响,这可能是由于在精子发生这一阶段发生的染色质重塑。该观察结果与报告的较高水平的异常子代结局水平相一致,这是当生殖细胞首次以圆形精子细胞暴露于环磷酰胺时看到的。

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