由于胎儿期暴露于内分泌干扰物（EDCs）的发展性增加，男性的生殖健康正在逐渐下降。我们之前报道了新生儿接触内分泌干扰物导致第八期精索小管数量减少、精子数量减少、不育以及65％的苯鸟氧烯（DES）处理过的小鼠出现睾丸肿瘤。由于EDCs导致的表观遗传变化，致使VSELs从静止状态转入细胞周期并进行过度自我更新，而c-KIT-干细胞向c-KIT + 生殖细胞的转变则受到MMR轴（Np95、Pcna、Dnmts）的改变所阻碍，并伴有全局低甲基化（5-甲基胞嘧啶表达减少）以及Igf2-H19和Dlk1-Meg3区域失活。本研究旨在首次展示DES处理睾丸的FACS分选VSELs中存在类似缺陷，并进一步探讨（i）通过口服剂型的白藜芦醇纳米制剂（XAR）或（ii）间质干细胞（MSCs）的管间移植来逆转睾丸病理学。基于RNA测序数据，在DES处理小鼠的FACS分选VSELs中明显存在与前文报道的睾丸相似的缺陷。结果显示，这两种策略均是有效的，能改善精子生成，增加第八期精索小管数量，使VSELs和c-KIT + 细胞数量恢复到正常水平，改善VSELs的表观遗传状态以恢复静止状态，并将DES处理导致的癌症发生率从65％降至分别为13.33％和20％的XAR处理或MSCs移植。这些结果为开展临床研究奠定了基础，研究属于《联合国可持续发展目标3》的范畴，旨在确保所有人的健康生活和福祉。© 2023 版权所有。本文作者授予施普林格科学与商业媒体有限公司，施普林格自然发布独家许可。

Reproductive health of men is declining in today's world due to increased developmental exposure to endocrine-disrupting chemicals (EDCs). We earlier reported that neonatal exposure to endocrine disruption resulted in reduced numbers of seminiferous tubules in Stage VIII, decreased sperm count, and infertility along with testicular tumors in 65% of diethylstilbestrol (DES) treated mice. Epigenetic changes due to EDCs, pushed the VSELs out of a quiescent state to enter cell cycle and undergo excessive self-renewal while transition of c-KIT- stem cells into c-KIT + germ cells was blocked due to altered MMR axis (Np95, Pcna, Dnmts), global hypomethylation (reduced expression of 5-methylcytosine) and loss of imprinting at Igf2-H19 and Dlk1-Meg3 loci. The present study was undertaken to firstly show similar defects in FACS sorted VSELs from DES treated testis and to further explore the reversal of these testicular pathologies by (i) oral administration of XAR (a nano-formulation of resveratrol) or (ii) inter-tubular transplantation of mesenchymal stromal cells (MSCs). Similar defects as reported earlier in the testes were evident, based on RNAseq data, on FACS sorted VSELs from DES treated mice. Both strategies were found effective, improved spermatogenesis, increased number of tubules in Stage VIII, normalized numbers of VSELs and c-KIT + cells, improved epigenetic status of VSELs to restore quiescent state, and reduced cancer incidence from 65% after DES to 13.33% and 20% after XAR treatment or MSCs transplantation respectively. Results provide a basis for initiating clinical studies and the study falls under the umbrella of United Nations Sustainable Development Goal 3 to ensure healthy lives and well-being for all of all ages.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.