近日，武汉大学Hui Wang发现，产前地塞米松暴露会通过GR/KDM1B/FSTL3/TGFβ信号转导损害大鼠血液-睾丸屏障功能和成年后代的精子质量。相关论文于2024年3月12日在线发表于《中国药理学报》杂志。

研究人员探讨了产前地塞米松暴露（PDE）对成年后代精子质量和血睾屏障（BTB）功能的影响及其内在机制。怀孕的大鼠在胚胎发育至第9周至第20周期间分别注射地塞米松（0.1、0.2和0.4 mg-kg-1-d-1, s.c.）。断奶后（PW4），幼鼠以实验室饲料喂养。在PW12和PW28，雄性后代被安乐死以采集血液和睾丸样本。研究人员发现，PDE会明显降低雄性后代的精子质量（包括数量和活力），这与BTB受损和睾丸中CX43/E-cadherin表达减少有关。

研究人员证实，PDE诱导的胎儿睾丸形态异常和Sertoli细胞发育异常源于宫内。通过对胎儿睾丸Sertoli细胞的追踪，研究人员发现PDE剂量依赖性地增加了组蛋白赖氨酸去甲基化酶（KDM1B）的表达，降低了组蛋白3第9位赖氨酸的二甲基化（H3K9me2）水平，增加了Follistatin-like-3（FSTL3）启动子区域的FSTL3表达，并抑制了TGFβ信号传导和CX43/E-cadherin的表达。这些结果在地塞米松处理后的TM4 Sertoli细胞中得到了验证。同时，母体外周血单核细胞（PBMC）和胎盘中FSTL3启动子的H3K9me2水平降低，其表达增加，这与后代睾丸的变化呈正相关。

根据对人类样本的分析，研究人员发现产前地塞米松暴露后，母体血液PBMC和胎盘中FSTL3启动子的H3K9me2水平与胎儿血液中的睾酮水平呈正相关。研究人员认为：PDE可降低成年后代大鼠的精子质量，这与睾丸BTB通过表观遗传学修饰受到破坏以及Sertoli细胞中FSTL3表达的改变有关。FSTL3启动子的H3K9me2水平及其在母体血叶PBMC中的表达，可作为胎儿睾丸发育不良的产前预警标记。

研究人员表示，流行病学和动物研究均表明，妊娠期不良环境可改变子代发育计划，但产前预警较为困难。

附：英文原文

Title: Prenatal dexamethasone exposure impairs rat blood-testis barrier function and sperm quality in adult offspring via GR/KDM1B/FSTL3/TGFβ signaling

Author: Liu, Yi, Chen, Si-jia, Ai, Can, Yu, Peng-xia, Fang, Man, Wang, Hui

Issue&Volume: 2024-03-12

Abstract: Both epidemiological and animal studies suggest that adverse environment during pregnancy can change the offspring development programming, but it is difficult to achieve prenatal early warning. In this study we investigated the impact of prenatal dexamethasone exposure (PDE) on sperm quality and function of blood-testis barrier (BTB) in adult offspring and the underlying mechanisms. Pregnant rats were injected with dexamethasone (0.1, 0.2 and 0.4mg·kg-1·d-1, s.c.) from GD9 to GD20. After weaning (PW4), the pups were fed with lab chow. At PW12 and PW28, the male offspring were euthanized to collect blood and testes samples. We showed that PDE significantly decreased sperm quality (including quantity and motility) in male offspring, which was associated with impaired BTB and decreased CX43/E-cadherin expression in the testis. We demonstrated that PDE induced morphological abnormalities of fetal testicle and Sertoli cell development originated from intrauterine. By tracing to fetal testicular Sertoli cells, we found that PDE dose-dependently increased expression of histone lysine demethylases (KDM1B), decreasing histone 3 lysine 9 dimethylation (H3K9me2) levels of follistatin-like-3 (FSTL3) promoter region and increased FSTL3 expression, and inhibited TGFβ signaling and CX43/E-cadherin expression in offspring before and after birth. These results were validated in TM4 Sertoli cells following dexamethasone treatment. Meanwhile, the H3K9me2 levels of FSTL3 promoter in maternal peripheral blood mononuclear cell (PBMC) and placenta were decreased and its expression increased, which was positively correlated with the changes in offspring testis. Based on analysis of human samples, we found that the H3K9me2 levels of FSTL3 promoter in maternal blood PBMC and placenta were positively correlated with fetal blood testosterone levels after prenatal dexamethasone exposure. We conclude that PDE can reduce sperm quality in adult offspring rats, which is related to the damage of testis BTB via epigenetic modification and change of FSTL3 expression in Sertoli cells. The H3K9me2 levels of the FSTL3 promoter and its expression in the maternal blood PBMC can be used as a prenatal warning marker for fetal testicular dysplasia.

DOI: 10.1038/s41401-024-01244-5

Source: https://www.nature.com/articles/s41401-024-01244-5