Mechanism of podophyllotoxin-induced ovarian toxicity via the AMPK/TSC1/mTOR/ULK1 axis in rats on the basis of toxicological evidence chain (TEC) concept

IF 6.1 2区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Ecotoxicology and Environmental Safety Pub Date : 2025-01-15 DOI:10.1016/j.ecoenv.2024.117617

Jingjing Li , Yanzhao Zhang , Mingyue Wei , Junjie He , Huifeng Ma , Zilong Chen , Jiajia Duan , Chuanxin Liu

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引用次数: 0

Abstract

Background

Podophyllotoxin is a compound with clinical effects, such as anticancer and antiacromegaly effects, but its systemic toxicity has led to extremely limited clinical application.

Methods

Using the toxicological evidence chain (TEC) as a research method, our team constructed, for the first time, a rat model in which podophyllotoxin caused ovarian damage and investigated the mechanism of the toxic effects of podophyllotoxin on the ovaries.

Results

The rats presented different degrees of diarrhoea, body surface bruising, and petechiae, and the serum biochemical results revealed significant changes in the activities of the oxidative stress indicators SOD and MDA and the levels of the inflammatory indicators TNF-α and IL-1β. The pathological results suggested that the rat ovaries were significantly damaged, and the histological results revealed Th17 cell differentiation, necroptosis, Hspa9 expression, and other pathways or targets related to inflammation, necroptosis/apoptosis or autophagy.

Conclusion

Podophyllotoxin exerts toxic effects by altering autophagy through the AMPK/TSC1/mTOR/ULK1 signalling pathway. This study provides new insights into the mechanism of the toxic effects of podophyllotoxin and new ideas for the clinical application of podophyllotoxin.

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基于毒理学证据链（TEC）概念的鬼臼毒素通过AMPK/TSC1/mTOR/ULK1轴诱导大鼠卵巢毒性的机制

背景：足臼毒素是一种具有抗癌、抗肢端肥大等临床疗效的化合物，但其全身性毒性导致其临床应用极为有限。方法：以毒理学证据链（TEC）为研究方法，首次建立足臼毒素致卵巢损伤大鼠模型，探讨足臼毒素对卵巢的毒性作用机制。结果：大鼠出现不同程度腹泻、体表淤青、瘀点，血清生化结果显示氧化应激指标SOD、MDA活性及炎症指标TNF-α、IL-1β水平发生显著变化。病理结果显示大鼠卵巢明显受损，组织学结果显示Th17细胞分化、坏死坏死、Hspa9表达等与炎症、坏死坏死/凋亡或自噬相关的通路或靶点。结论：鬼臼毒素通过AMPK/TSC1/mTOR/ULK1信号通路改变自噬发挥毒性作用。本研究为鬼臼毒素毒性作用的机制提供了新的认识，为鬼臼毒素的临床应用提供了新的思路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ecotoxicology and Environmental Safety 环境科学-毒理学

CiteScore

12.10

自引率

5.90%

发文量

1234

审稿时长

88 days

期刊介绍： Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.