Ginsenoside Rg3 ameliorates di-(2-ethylhexyl) phthalate-induced spermatogenic impairment.

Ginsenoside Rg3 ameliorates di-(2-ethylhexyl) phthalate-induced spermatogenic impairment via attenuating ferroptosis and restoring sertoli cell secretory dysfunction.

Xiang Gao, Nan Ma, Yuanchao Zhang, Jin-guo Zhang, Zhuo-lin Liu, Haiyan Zhu, Xu Gong, Yongtao Sun, Dovina Qu, Jianguo Hu, Zai-mo Wang, Wei Li

J Environ Sci (China)

Jun 30, 2026

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Abstract

It has been demonstrated that di-(2-ethylhexyl) phthalate (DEHP) and its metabolite mono-phthalate (2-ethylhexyl) (MEHP) adversely affect male reproductive development and function. Oxidative damage might be one of the critical mechanisms of DEHP-induced spermatogenic damage. 20(R)-ginsenoside Rg3 (Rg3), a major compound derived from ginseng with good antioxidant effects, has been shown to have potential in ameliorating testicular damage induced by heat stress. However, its effects on DEHP-induced spermatogenesis disorders remained unexplored. The aim of this work was to explore the preventive role of Rg3 and its related mechanisms by establishing DEHP-induced spermatogenesis disorder in mice and MEHP-induced damage to mouse testicular Leydig cell TM3 and mouse testicular Sertoli cell TM4 in vitro. The results showed that treatment of mice with Rg3 could significantly ameliorate DEHP-induced oxidative stress, ferroptosis and apoptosis. Rg3 pretreatment also protected the TM3 and TM4 cells from MEHP-induced damage by improving the expression of testosterone synthesis-related proteins as well as secretion function-related proteins. Importantly, molecular docking and dynamics simulations also clearly indicated strong binding affinity between Rg3 and the androgen receptor protein AR. These findings suggest that Rg3 might potentially alleviate the damage to Sertoli cells and Leydig cells by inhibiting DEHP-induced oxidative stress, thereby restoring the normal progress of testicular spermatogenesis and showing potential as a novel preventive ingredient against spermatogenic damage.