Abstract：
Di (2-ethylhexyl) phthalate (DEHP), identified as an endocrine-disrupting chemical, is associated with reproductive toxicity. This association is particularly noteworthy in newborns with incompletely developed metabolic functions, as exposure to DEHP can induce enduring damage to the reproductive system, potentially influencing adult reproductive health. In this study, we continuously administered 40 μg/kg and 80 μg/kg DEHP to postnatal day 5 (PD5) mice for ten days to simulate low and high doses of DEHP exposure during infancy. Utilizing single-cell RNA sequencing (scRNA-seq), our analysis revealed that varying concentrations of DEHP exposure during infancy induced distinct DNA damage response characteristics in testicular Undifferentiated spermatogonia (Undiff SPG). Specifically, DNA damage triggered mitochondrial dysfunction, leading to acetyl-CoA content alterations. Subsequently, this disruption caused aberrations in histone acetylation patterns, ultimately resulting in apoptosis of Undiff SPG in the 40 μg/kg DEHP group and autophagy in the 80 μg/kg DEHP group. Furthermore, we found that DEHP exposure impacts the development and functionality of Sertoli and Leydig cells through the focal adhesion and PPAR signaling pathways, respectively. We also revealed that Leydig cells regulate the metabolic environment of Undiff SPG via Ptn-Sdc4 and Mdk-Sdc4 after DEHP exposure. Finally, our study provided pioneering evidence that disruptions in testicular homeostasis induced by DEHP exposure during infancy endure into adulthood. In summary, this study elucidates the molecular mechanisms through which DEHP exposure during infancy influences the development of testicular cell populations.
摘要：
邻苯二甲酸二(2-乙基己基)酯(DEHP),被确定为一种内分泌干扰化学物质，与生殖毒性有关。这种关联在代谢功能不完全发育的新生儿中尤其值得注意，因为暴露于DEHP会对生殖系统造成持久的损害，可能影响成人生殖健康。在这项研究中,我们对出生后第5天(PD5)小鼠连续给药40μg/kg和80μg/kgDEHP10天,以模拟婴儿期的低剂量和高剂量DEHP暴露.利用单细胞RNA测序（scRNA-seq），我们的分析显示,婴儿期不同浓度的DEHP暴露在睾丸未分化精原细胞(UndiffSPG)中诱导了不同的DNA损伤反应特征.具体来说,DNA损伤引发线粒体功能障碍,导致乙酰辅酶A含量改变。随后，这种破坏导致组蛋白乙酰化模式异常，最终导致UndiffSPG在40μg/kgDEHP组中的凋亡和80μg/kgDEHP组中的自噬。此外，我们发现DEHP暴露通过局灶性粘附和PPAR信号通路影响Sertoli和Leydig细胞的发育和功能，分别。我们还发现，在DEHP暴露后，Leydig细胞通过Ptn-Sdc4和Mdk-Sdc4调节UndiffSPG的代谢环境。最后,我们的研究提供了开创性的证据,证明DEHP暴露在婴儿期引起的睾丸稳态破坏一直持续到成年期.总之,本研究阐明了婴儿期DEHP暴露影响睾丸细胞群发育的分子机制.
