Abstract：
Tri (2-Ethylhexyl) phosphate (TEHP), widely used as a fire retardant and plasticizer, has been commonly found in the environment. Its potential health-related risks, especially reproductive toxicity, have aroused concern. However, the potential cellular mechanisms remain unexplored. In this study, we aimed to investigate the molecular mechanisms underlying TEHP-caused cell damage in Sertoli cells, which play a crucial role in supporting spermatogenesis. Our findings indicate that TEHP induces apoptosis in 15P-1 mouse Sertoli cells. Subsequently, we conducted RNA sequencing analyses, which suggested that ER stress, autophagy, and MAPK-related pathways may participate in TEHP-induced cytotoxicity. Furthermore, we demonstrated that TEHP triggers ER stress, activates p38 MAPK, and inhibits autophagy flux. Then, we showed that the inhibition of ER stress or p38 MAPK activation attenuates TEHP-induced apoptosis, while the inhibition of autophagy flux is responsible for TEHP-induced apoptosis. These results collectively reveal that TEHP induces ER stress, activates p38, and inhibits autophagy flux, ultimately leading to apoptosis in Sertoli cells. These shed light on the molecular mechanisms underlying TEHP-associated testicular toxicity.
摘要：
磷酸三(2-乙基己基)酯(TEHP),广泛用作阻燃剂和增塑剂，在环境中普遍存在。其潜在的健康相关风险，尤其是生殖毒性,引起了关注。然而,潜在的细胞机制仍未被探索。在这项研究中,我们旨在研究TEHP引起的支持细胞损伤的分子机制，在支持精子发生中起着至关重要的作用。我们的发现表明，TEHP诱导15P-1小鼠睾丸支持细胞凋亡。随后，我们进行了RNA测序分析，这表明ER压力，自噬,MAPK相关通路可能参与TEHP诱导的细胞毒性。此外，我们证明了TEHP会引发ER压力，激活p38MAPK,并抑制自噬通量。然后，我们表明，抑制内质网应激或p38MAPK激活减弱TEHP诱导的细胞凋亡，而自噬通量的抑制是TEHP诱导的细胞凋亡的原因。这些结果共同表明，TEHP诱导ER应激，激活p38，抑制自噬通量，最终导致支持细胞凋亡。这些揭示了TEHP相关睾丸毒性的分子机制。
