Omega-3 polyunsaturated fatty acids and its metabolite 12-HEPE rescue busulfan disrupted spermatogenesis via target to GPR120
Omega-3 polyunsaturated fatty acids and its metabolite 12-HEPE rescue busulfan disrupted spermatogenesis via target to GPR120
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DOI：
10.1111/cpr.13551
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发表时间：
2023-09-24
影响因子：
8.5
通讯作者：
Yao，Bing
中科院分区：
文献类型：
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作者：
Jing，Jun;Ouyang，Lei;Yao，Bing
白消安是一种抗肿瘤药物，常伴有精原细胞自我更新和分化的异常。已证明 omega-3 多不饱和脂肪酸 (PUFA) 有益于成熟精子。然而，omega-3是否能保护内源性精原细胞及其详细机制仍不清楚。通过组织病理学分析、免疫荧光染色和蛋白质印迹检查精子发生功能（体内）的评估。通过液相色谱法测定睾丸组织中脂质代谢物的水平。我们利用共培养系统研究了脂质代谢物对支持细胞提供旁分泌因子来调节精原细胞增殖和分化的影响。在我们的研究中，我们发现，在白消安扰乱生精功能的小鼠模型中，omega-3 PUFA 显着改善了精子生成过程，并提高了未分化 Lin28+ 精原细胞和分化 c-kit+ 精原细胞的数量。质谱分析显示，喂食 omega-3 PUFA 的小鼠睾丸中几种 omega-3 代谢物的水平有所增加。二十碳五烯酸代谢物 12-羟基二十碳五烯酸 (12-HEPE) 通过激活支持细胞中的 GPR120-ERK1/2 通路上调骨形态发生蛋白 4 (BMP4) 的表达，并恢复精原细胞的增殖和分化。我们的研究提供了证据，表明 omega-3 PUFA 代谢物 12-HEPE 可以有效保护精原细胞，并揭示 GPR120 可能是接受化疗或严重生精功能障碍的男性生育力的易于处理的药理学靶点。
Busulfan is an antineoplastic, which is always accompanied with the abnormal of spermatogonia self‐renewal and differentiation. It has been demonstrated that the omega‐3 polyunsaturated fatty acids (PUFAs) benefits mature spermatozoa. However, whether omega‐3 can protect endogenous spermatogonia and the detailed mechanisms are still unclear. Evaluate of spermatogenesis function (in vivo) were examined by histopathological analysis, immunofluorescence staining, and western blotting. The levels of lipid metabolites in testicular tissue were determined via liquid chromatography. We investigated the effect of lipid metabolites on Sertoli cells provided paracrine factors to regulate spermatogonia proliferation and differentiation using co‐culture system. In our study, we showed that omega‐3 PUFAs significantly improved the process of sperm production and elevated the quantity of both undifferentiated Lin28+ spermatogonia and differentiated c‐kit+ spermatogonia in a mouse model where spermatogenic function was disrupted by busulfan. Mass spectrometry revealed an increase in the levels of several omega‐3 metabolites in the testes of mice fed with omega‐3 PUFAs. The eicosapentaenoic acid metabolite 12‐hydroxyeicosapentaenoic acid (12‐HEPE) up‐regulated bone morphogenic protein 4 (BMP4) expression through GPR120‐ERK1/2 pathway activation in Sertoli cells and restored spermatogonia proliferation and differentiation. Our study provides evidence that omega‐3 PUFAs metabolite 12‐HEPE effectively protects spermatogonia and reveals that GPR120 might be a tractable pharmacological target for fertility in men received chemotherapy or severe spermatogenesis dysfunction.