Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering; Chongqing Key Laboratory of Pediatrics; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China.
Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering; Chongqing Key Laboratory of Pediatrics; Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China.
Environ Pollut. 2023 Sep 15;333:122091. doi: 10.1016/j.envpol.2023.122091. Epub 2023 Jun 24.
Di (2-ethylhexyl) phthalate (DEHP), one of phthalic acid esters, has been widely used in daily products. Its main metabolite, mono (2-ethylhexyl) phthalate (MEHP) was reported to possess higher testicular toxicity than DEHP. To explore the precise mechanism in MEHP-induced testis damage, multiple transcriptomic sequencing was employed in spermatogonia cell line GC-1 cells treated with MEHP (0, 100, and 200 μM) for 24 h. Integrative omics analysis and empirical validation revealed that Wnt signaling pathway was downregulated and wnt10a, one of hub genes, may be the key player in this process. Similar results were observed in DEHP-exposed rats. MEHP-induced disturbance of self-renewal and differentiation was dose-dependent. Moreover, self-renewal proteins were downregulated; the differentiation level was stimulated. Meanwhile, GC-1 proliferation was decreased. Stable transformation strain of wnt10a overexpression GC-1 cell line constructed from lentivirus was utilized in this study. The upregulation of Wnt10a significantly reversed the dysfunction of self-renewal and differentiation and promoted the cell proliferation. Finally, retinol, predicted to be useful in CONNECTIVITY MAP (cMAP), failed to rescue the damage caused by MEHP. Cumulatively, our findings revealed that the downregulation of Wnt10a induced the imbalance of self-renew and differentiation, and inhibition of cell proliferation in GC-1 cells after MEHP exposure.
邻苯二甲酸二（2-乙基己基）酯（DEHP）是邻苯二甲酸酯的一种，广泛应用于日常产品中。其主要代谢物单（2-乙基己基）邻苯二甲酸酯（MEHP）被报道具有比 DEHP 更高的睾丸毒性。为了探讨 MEHP 诱导睾丸损伤的精确机制，我们采用多种转录组测序方法，对 MEHP（0、100 和 200μM）处理 24 小时后的精原细胞系 GC-1 细胞进行了研究。综合组学分析和经验验证表明，Wnt 信号通路下调，其中一个关键基因 wnt10a 可能在这个过程中起关键作用。在 DEHP 暴露的大鼠中也观察到了类似的结果。MEHP 诱导的自我更新和分化紊乱呈剂量依赖性。此外，自我更新蛋白下调，分化水平受到刺激，同时 GC-1 细胞增殖减少。本研究构建了基于慢病毒的 wnt10a 过表达 GC-1 细胞系的稳定转化株。Wnt10a 的上调显著逆转了自我更新和分化的功能障碍，并促进了细胞增殖。最后，预测对 CONNECTIVITY MAP（cMAP）有用的视黄醇未能挽救 MEHP 造成的损伤。总之，我们的研究结果表明，Wnt10a 的下调导致 MEHP 暴露后 GC-1 细胞中自我更新和分化失衡，并抑制细胞增殖。
