Transgenerational Effects of Di-(2-ethylhexyl) Phthalate on Testicular Germ Cell Associations and Spermatogonial Stem Cells in Mice
Transgenerational Effects of Di-(2-ethylhexyl) Phthalate on Testicular Germ Cell Associations and Spermatogonial Stem Cells in Mice
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DOI：
10.1095/biolreprod.112.106104
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发表时间：
2013-05-01
影响因子：
3.6
通讯作者：
Kim, Kwan Hee
中科院分区：
文献类型：
--
作者：
Doyle, Timothy J.;Bowman, Jennifer L.;Kim, Kwan Hee
最近的证据表明，人类邻苯二甲酸酯暴露与异常生殖和激素影响有关。邻苯二甲酸酯是增塑剂，赋予塑料的灵活性和透明度，但它们很容易污染人体和环境。在本研究中，从胚胎第7天（E7）至E14，用邻苯二甲酸二（2-乙基己基）酯（DEHP）处理定时妊娠CD 1远系小鼠。然后对下一代（F1）后代进行繁殖，以产生F2、F3和F4后代，不进行任何进一步的DEHP处理。这种暴露方案破坏了睾丸生殖细胞的结合，并降低了F1至F4后代的精子数量和活力。通过精原细胞移植技术，暴露方案也破坏了F3后代的精原干细胞（SSC）功能。与移植CD 1对照生殖细胞的受体睾丸相比，移植DEHP处理组F3后代生殖细胞的W/W-V受体睾丸在曲细精管中的供体生殖细胞来源的生精恢复百分比显著降低。进一步的特征表明，供体生殖细胞来源的精子发生的主要障碍是在未分化的精原细胞出现之前。有趣的是，当再生时，移植有DEHP处理组的F3后代生殖细胞的睾丸复制了与DEHP处理组的F1至F3后代睾丸中观察到的睾丸形态相似的睾丸形态，这表明生殖细胞解体表型起源于F3后代的干细胞。总之，发现胚胎暴露于DEHP会以跨代方式破坏睾丸生殖细胞组织和SSC功能。
Recent evidence has linked human phthalate exposure to abnormal reproductive and hormonal effects. Phthalates are plasticizers that confer flexibility and transparency to plastics, but they readily contaminate the body and the environment. In this study, timed pregnant CD1 outbred mice were treated with di-(2-ethylhexyl) phthalate (DEHP) from Embryonic Day 7 (E7) to E14. The subsequent generation (F1) offspring were then bred to produce the F2, F3, and F4 offspring, without any further DEHP treatment. This exposure scheme disrupted testicular germ cell association and decreased sperm count and motility in F1 to F4 offspring. By spermatogonial transplantation techniques, the exposure scheme also disrupted spermatogonial stem cell (SSC) function of F3 offspring. The W/W-V recipient testes transplanted with F3 offspring germ cells from the DEHP-treated group had a dramatically lower percentage of donor germ cell-derived spermatogenic recovery in seminiferous tubules when compared to the recipient testes transplanted with CD1 control germ cells. Further characterization showed that the major block of donor germ cell-derived spermatogenesis was before the appearance of undifferentiated spermatogonia. Interestingly, the testes transplanted with the F3 offspring germ cells from the DEHP-treated group, when regenerated, replicated testis morphology similar to that observed in the testes from the F1 to F3 offspring of the DEHP-treated group, suggesting that the germ cell disorganization phenotype originates from the stem cells of F3 offspring. In conclusion, embryonic exposure to DEHP was found to disrupt testicular germ cell organization and SSC function in a transgenerational manner.