Department of Toxicology, Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei, 230000, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, 230000, China.
Department of Toxicology, Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei, 230000, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, 230000, China; Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214000, China.
Food Chem Toxicol. 2024 Oct;192:114940. doi: 10.1016/j.fct.2024.114940. Epub 2024 Aug 14.
Infertility caused by lipopolysaccharide (LPS) exposure due to infection is endangering male fertility worldwide, but the mechanism remains unclear. The blood-testis barrier (BTB) is essential for maintaining spermatogenesis and male fertility. In the present study, we showed that LPS (5.0 mg/kg) treatment markedly down-regulated the expression of BTB-related proteins, expanded the biotin penetration distance and caused histopathological injury in seminiferous tubules in mouse testes. Notably, testicular macrophage M1 polarization induced by LPS seems to be related to BTB damage, which was well confirmed by co-culture of RAW264.7 and TM4 cells in vitro. Interestingly, a low-dose LPS (0.1 mg/kg) pretreatment attenuated down-regulation of BTB-related proteins expression and histopathological injury and shorten biotin penetration distance in seminiferous tubules caused by LPS. Correspondingly, a low-dose LPS pretreatment suppresses testicular macrophage M1 polarization induced by LPS in mouse testes. Further experiments revealed that histone deacetylase 5 (HDAC5) was markedly down-regulated at 2 h and slightly down-regulated at 8 h, but up-regulated at 24 h in mouse testes after LPS treatment. Additionally, low-dose LPS pretreatment against the down-regulation of HDAC5 protein caused by LPS treatment. Notably, the suppressed testicular macrophage M1 polarization by low-dose LPS pretreatment was broken by BRD4354, a specific inhibitor of HDAC5 in vitro. These results suggest suppressed testicular macrophage M1 polarization by HDAC5 enforces insensitivity to LPS-elicited BTB damage.
脂多糖 (LPS) 暴露于感染引起的不育症正在威胁着全球男性的生育能力，但机制尚不清楚。血睾屏障 (BTB) 对于维持精子发生和男性生育能力至关重要。在本研究中，我们表明 LPS（5.0mg/kg）处理显着下调了 BTB 相关蛋白的表达，扩大了生物素渗透距离，并导致小鼠睾丸曲细精管的组织病理学损伤。值得注意的是，LPS 诱导的睾丸巨噬细胞 M1 极化似乎与 BTB 损伤有关，这在 RAW264.7 和 TM4 细胞的体外共培养中得到了很好的证实。有趣的是，低剂量 LPS（0.1mg/kg）预处理可减轻 LPS 引起的 BTB 相关蛋白表达下调和组织病理学损伤，并缩短曲细精管中生物素的渗透距离。相应地，低剂量 LPS 预处理可抑制 LPS 诱导的小鼠睾丸中睾丸巨噬细胞 M1 极化。进一步的实验表明，LPS 处理后 2 小时 HDAC5 明显下调，8 小时轻微下调，24 小时上调。此外，低剂量 LPS 预处理可防止 LPS 处理引起的 HDAC5 蛋白下调。值得注意的是，体外 HDAC5 的特异性抑制剂 BRD4354 破坏了低剂量 LPS 预处理对睾丸巨噬细胞 M1 极化的抑制作用。这些结果表明，HDAC5 抑制睾丸巨噬细胞 M1 极化可增强对 LPS 诱导的 BTB 损伤的不敏感性。
