Reproductive health of men has declined in recent past with reduced sperm count and increased incidence of infertility and testicular cancers mainly attributed to endocrine disruption in early life. Present study aims to evaluate whether testicular stem cells including very small embryonic-like stem cells (VSELs) and spermatogonial stem cells (SSCs) get affected by endocrine disruption and result in pathologies in adult life. Effect of treatment on mice pups with estradiol (20 μg on days 5–7) and diethylstilbestrol (DES, 2 μg on days 1–5) was studied on VSELs, SSCs and spermatogonial cells in adult life. Treatment affected spermatogenesis, tubules in Stage VIII & sperm count were reduced along with reduction of meiotic (4n) cells and markers (Prohibitin, Scp3, Protamine). Enumeration of VSELs by flow cytometry (2–6 μm, 7AAD-, LIN-CD45-SCA-1+) and qRT-PCR using specific transcripts for VSELs (Oct-4a, Sox-2, Nanog, Stella, Fragilis), SSCs (tOct-4, Gfra-1, Gpr-125) and early germ cells (Mvh, Dazl) showed several-fold increase but transition from c-Kit negative to c-Kit positive spermatogonial cells was blocked on D100 after treatment. Transcripts specific for apoptosis (Bcl2, Bax) remained unaffected but tumor suppressor (p53) and epigenetic regulator (NP95) transcripts showed marked disruption. 9 of 10 mice exposed to DES showed tumor-like changes. To conclude, endocrine disruption resulted in a tilt towards excessive self-renewal of VSELs (leading to testicular cancer after DES treatment) and blocked differentiation (reduced numbers of c-Kit positive cells, meiosis, sperm count and fertility). Understanding the underlying basis for infertility and cancer initiation from endogenous stem cells through murine modelling will hopefully improve human therapies in future.

中文翻译：

---

新生儿内分泌干扰改变了睾丸VSEL和SSC的生物学特性，导致成年小鼠精子发生异常，生育力降低和肿瘤发作。

近年来，男性的生殖健康状况有所下降，精子数量减少，不孕和睾丸癌的发病率增加，这主要归因于早年的内分泌干扰。目前的研究旨在评估睾丸干细胞，包括非常小的胚胎样干细胞（VSEL）和精原干细胞（SSC），是否会受到内分泌干扰的影响并导致成年后的病理。研究了成年后在VSEL，SSC和精原细胞上用雌二醇（第5-7天为20μg）和己烯雌酚（DES，第1-5天为2μg）对幼鼠的治疗效果。受治疗影响的精子发生，第八期精管和精子数量减少，减数分裂（4n）细胞和标志物（抑制素，Scp3，鱼精蛋白）减少）。通过流式细胞仪（2–6μm，7AAD-，LIN-CD45-SCA-1 +）和qRT-PCR使用VSEL的特定转录本（Oct-4a，Sox-2，Nanog，Stella，Fragilis），SSC计数VSEL（t Oct-4，Gfra-1，Gpr-125）和早期生殖细胞（Mvh，Dazl）表现出几倍的增加，但在治疗后D100上，从c-Kit阴性精子向c-Kit阳性精原细胞的转变被阻止。凋亡特异性转录物（Bcl2，Bax）仍然不受影响，但肿瘤抑制物（p53）和表观遗传调节物（NP95）。成绩单显示出明显的破坏。暴露于DES的10只小鼠中有9只显示出肿瘤样变化。总而言之，内分泌干扰导致VSEL过度自我更新（导致DES治疗后导致睾丸癌）和分化受阻（c-Kit阳性细胞数量减少，减数分裂，精子数量减少和受精）。通过鼠模型了解内源性干细胞引起不孕和癌症的潜在基础，有望在将来改善人类疗法。