孕期地塞米松暴露通过调控子代睾丸支持细胞Tbx2/Cx43参与精子发生异常

精子发生异常严重威胁人类生殖健康，是男性不育的关键诱因。研究提示，由支持细胞构成的血睾屏障损伤是精子发生异常的重要原因，其发生与血睾屏障功能基因连接蛋白43（Cx43）等的低表达有关。我们近期发现，孕期地塞米松暴露（PDE）可致子代精子发生异常及睾丸Cx43低表达，然而其发生机制尚未明了。T-box转录因子2（Tbx2）是Cx43的转录抑制因子，而Tbx2表达受到表观遗传调控，其转录调控区存在糖皮质激素受体（GR）结合位点。据此我们推测：地塞米松激活GR并结合于Tbx2启动子区促进其表达；同时通过上调并招募P300至Tbx2启动子区，诱导Tbx2启动子区乙酰化水平增加，导致Tbx2高表达编程并延续至出生后，进而抑制支持细胞Cx43的表达，造成血睾屏障损伤和精子发生异常。本项目拟系统阐明PDE导致血睾屏障损伤的宫内编程机制，为探寻胎源性精子发生异常的毒性靶标和早期防治策略提供理论依据。

Abnormal spermatogenesis seriously threatens human reproductive health, which is the key cause of male infertility. Researches have suggested that blood-testis barrier damage composed of sertoli cell is a key factor affecting the abnormal spermatogenesis and related to the low expression of blood-testis barrier function gene, such as connexin 43 (Cx43) and its like. Recently, we discovered that prenatal dexamethasone exposure (PDE) could induce abnormal spermatogenesis in offspring and decreased expression of Cx43 in testis. However, the mechanism involved in blood-testis barrier damage remains unclear. T-box transcription factor 2 (Tbx2) is a transcriptional repressor of Cx43, the expression of which is subject to epigenetic regulation and there is a glucocorticoid receptor (GR) binding site in its transcriptional regulatory region. Based on preliminary results, we speculate that dexamethasone could activate GR and combine with Tbx2 promoter region to increase its expression; meanwhile, upregulate and recruite P300 to Tbx2 promoter region, which induces increased acetylation level of Tbx2 promoter region, thereby leading to a high Tbx2 expression programming that continues after birth. Subsequently, to inhibit Cx43 expression of sertoli cell and result in blood-testis barrier damage and abnormal spermatogenesis. This study aims to elucidate systematically the intrauterine programming mechanism of blood-testis barrier damage induced by PDE, and provide a theoretical basis for exploring toxicity targets and early prevention strategy of fetal-originated abnormal spermatogenesis.