Effects of doxorubicin on sperm DNA methylation in mouse models of testicular toxicity.
Effects of doxorubicin on sperm DNA methylation in mouse models of testicular toxicity.
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DOI：
10.1016/j.bbrc.2018.03.044
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发表时间：
2018-04
影响因子：
3.1
通讯作者：
Kazuya Sakai;Maky Ideta-Otsuka;Hirokatsu Saito;Yuki Hiradate;Kenshiro Hara;K. Igarashi;K. Tanemura
中科院分区：
文献类型：
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作者：
Kazuya Sakai;Maky Ideta-Otsuka;Hirokatsu Saito;Yuki Hiradate;Kenshiro Hara;K. Igarashi;K. Tanemura
睾丸毒性是癌症化疗中常见的不良反应，目前尚无有效的临床生物标志物。为了寻找新的生物标志物，我们重点研究了男性生殖系的表观遗传机制。我们研究了多柔比星（DXR）（一种广泛使用的抗癌药物）诱导睾丸毒性时雄性生殖系DNA甲基化状态。我们分别给药0.2 mg/kg和0.02 mg/kg的DXR，每周2次，连续5周，建立小鼠早期睾丸毒性和睾丸预毒性模型。组织学分析显示睾丸组织稀疏异常；然而，western blotting分析显示，在两个dxr处理组中，DNA甲基转移酶DNMT3a和DNMT3b的睾丸表达水平降低。有趣的是，利用甲基- cpg结合域蛋白富集基因组测序进行的精子DNA甲基化分析显示，低甲基化是DXR诱导的最常见的变化。这些发现表明，精子DNA甲基化状态可以作为传统毒性分析无法检测到的睾丸变化的早期诊断标记。
Testicular toxicity is a frequent adverse effect of cancer chemotherapy that has no effective clinical biomarker. To find new biomarkers, we focused on epigenetic mechanisms in the male germline. We investigated the DNA methylation status of the male germline during testicular toxicity induced by doxorubicin (DXR), a widely used anticancer agent. We established mouse models of early stage testicular toxicity and testicular pre-toxicity by the administration of 0.2 mg/kg and 0.02 mg/kg DXR, respectively, twice weekly for 5 weeks. Histological analysis showed sparse abnormalities in testicular tissue; however, western blotting analysis revealed reduced testicular expression levels of DNA methyltransferases DNMT3a and DNMT3b in both DXR-treated groups. Interestingly, comprehensive sperm DNA methylation analysis using Methyl-CpG binding domain protein-enriched genome sequencing revealed that hypomethylation was the most frequent change induced by DXR. These findings suggest that sperm DNA methylation status may be used as an early diagnostic marker for testicular changes not detected by conventional toxicity analysis.