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

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

作者信息

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

机构信息

Department of Obstetrics and Gynecology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.

Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Key Laboratory of Hereditary Rare Diseases of Health Commission of Henan Province, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.

出版信息

Ecotoxicol Environ Saf. 2025 Jan 15;290:117617. doi: 10.1016/j.ecoenv.2024.117617. Epub 2024 Dec 31.

DOI:10.1016/j.ecoenv.2024.117617

PMID:39742639

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.

摘要

背景

鬼臼毒素是一种具有临床效应的化合物，如抗癌和抗肢端肥大症效应，但其全身毒性导致其临床应用极其有限。

方法

以毒理学证据链（TEC）为研究方法，本团队首次构建了鬼臼毒素致大鼠卵巢损伤模型，并探究鬼臼毒素对卵巢毒性作用的机制。

结果

大鼠出现不同程度的腹泻、体表淤青和瘀点，血清生化结果显示氧化应激指标超氧化物歧化酶（SOD）和丙二醛（MDA）活性以及炎症指标肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平有显著变化。病理结果提示大鼠卵巢有明显损伤，组织学结果显示有Th17细胞分化、坏死性凋亡、热休克蛋白家族A成员9（Hspa9）表达以及其他与炎症、坏死性凋亡/凋亡或自噬相关的通路或靶点。