Kaushik Ankita, Metkari S M, Ali Subhan, Bhartiya Deepa
Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive & Child Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India.
Epigeneres Biotech Pvt Ltd, Lower Parel, Mumbai, 400 013, India.
Stem Cell Rev Rep. 2023 Oct;19(7):2525-2540. doi: 10.1007/s12015-023-10601-6. Epub 2023 Aug 10.
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.
在当今世界，由于在发育过程中接触内分泌干扰化学物质（EDC）的情况增多，男性的生殖健康正在下降。我们之前报道过，新生小鼠暴露于内分泌干扰环境会导致VIII期生精小管数量减少、精子数量下降、不育，并且在65%的己烯雌酚（DES）处理小鼠中出现睾丸肿瘤。EDC引起的表观遗传变化，促使非常小胚胎样干细胞（VSEL）从静止状态进入细胞周期并进行过度自我更新，而c-KIT干细胞向c-KIT+生殖细胞的转变因错配修复轴（Np95、Pcna、Dnmts）改变、整体低甲基化（5-甲基胞嘧啶表达降低）以及Igf2-H19和Dlk1-Meg3位点印记丢失而受阻。本研究旨在首先展示从DES处理的睾丸中通过荧光激活细胞分选（FACS）获得的VSEL存在类似缺陷，并进一步探索通过以下方式逆转这些睾丸病变：（i）口服XAR（白藜芦醇的纳米制剂）或（ii）间质基质细胞（MSC）的管间移植。基于RNA测序数据，在从DES处理小鼠中通过FACS获得的VSEL上，之前报道的睾丸中类似缺陷很明显。两种策略均被证明有效，改善了精子发生，增加了VIII期小管数量，使VSEL和c-KIT+细胞数量正常化，改善了VSEL的表观遗传状态以恢复静止状态，并将癌症发病率从DES处理后的65%分别降低到XAR治疗或MSC移植后的13.33%和20%。研究结果为启动临床研究提供了依据，该研究属于联合国可持续发展目标3的范畴，即确保所有年龄段的人都能享有健康生活和福祉。
