褪黑激素介导 BMP4/MAPK 信号通路，缓解玉米赤霉烯酮诱发的小鼠胚胎发育异常

Melatonin mediates the BMP4/MAPK signaling pathway to alleviate zearalenone-induced abnormal embryonic development in mice

褪黑激素介导 BMP4/MAPK 信号通路，缓解玉米赤霉烯酮诱发的小鼠胚胎发育异常

Authors: Mengyao Wang, Zhixin Pu, Jing Zhang, Peiwen Wang, Yaxin Chen, Yating Zhu, Hongzhen Ruan, Dongmei Ji, Weiwei Zou, Huiru Cheng, Zhiming Ding, Yunxia Cao, Yajing Liu, Dan Liang

Source: Ecotoxicology And Environmental Safety

DOI: 10.1016/j.ecoenv.2025.118068

Abstract

Zearalenone (ZEA) is a common mycotoxin found in crops that poses a threat to human health, particularly the female reproductive system. Here, we show that exposing mouse zygotes to ZEA in vitro significantly impairs embryo development, leading to embryo arrest. Remarkably, treatment of ZEA-exposed mouse embryos with melatonin significantly improved the blastocyst rates from approximately 40 % to nearly 80 %. Furthermore, melatonin effectively mitigates the harmful effects of ZEA exposure by reducing reactive oxygen species (ROS) levels, preventing mitochondrial dysfunction, and decreasing cell apoptosis. Following embryo transplantation, the birth rate of offspring increased markedly from 7.2 % to 23.62 %. Further research revealed that the abnormal elevation of bone morphogenetic protein 4 (BMP4) signaling induced by ZEA exposure, coupled with the inhibition of the downstream mitogen-activated protein kinase (MAPK) signaling pathway, contributes to developmental blockade in ZEA-exposed mouse embryos. Melatonin rescued ZEA-induced defects in mouse embryo development by inhibiting BMP4 signaling and regulating the MAPK pathway. Moreover, the Bmp4 inhibitor Noggin or its receptor inhibitor DMH-1 could also effectively ameliorate the ZEA-induced impairment of embryo development. Taken together, these findings underscore the potential of melatonin as a therapeutic intervention for addressing the adverse effects of ZEA exposure on mouse embryos.

Keywords: Bone morphogenetic protein 4; Embryo development; Melatonin; Mitogen-activated protein kinase; Zearalenone.

摘要：

玉米赤霉烯酮（ZEA）是农作物中常见的霉菌毒素，对人类健康，尤其是女性生殖系统构成威胁。在这里，我们发现小鼠胚胎在体外暴露于玉米赤霉烯酮会严重影响胚胎发育，导致胚胎停育。值得注意的是，用褪黑激素处理暴露于ZA的小鼠胚胎可显著提高囊胚率，从约40%提高到近80%。此外，褪黑素还能降低活性氧（ROS）水平、防止线粒体功能障碍和减少细胞凋亡，从而有效减轻ZA暴露的有害影响。胚胎移植后，后代的出生率从 7.2% 显著提高到 23.62%。进一步的研究发现，暴露于ZEA诱导的骨形态发生蛋白4（BMP4）信号异常升高，再加上下游丝裂原活化蛋白激酶（MAPK）信号通路受到抑制，导致暴露于ZEA的小鼠胚胎发育受阻。褪黑激素通过抑制 BMP4 信号传导和调节 MAPK 通路，挽救了棣亚乙酸诱导的小鼠胚胎发育缺陷。此外，Bmp4抑制剂Noggin或其受体抑制剂DMH-1也能有效改善ZEA诱导的胚胎发育障碍。综上所述，这些研究结果强调了褪黑激素作为一种治疗干预措施的潜力，可用于解决灶乙醇胺暴露对小鼠胚胎的不良影响。

关键词：骨形态发生蛋白4；胚胎发育；褪黑素；丝裂原活化蛋白激酶；玉米赤霉烯酮