Mechanistic insights into TDCPP-induced DNA damage in GT1-7 cells

IF 5.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology Pub Date : 2026-03-01 Epub Date: 2025-12-31 DOI:10.1016/j.tox.2025.154391

Bingli Lei , Jiaying Li , Yingxin Yang , Xiaoyu Lu , Tingying Liu , Na Li , Yang Li , Xinyang Li , Chenglian Feng

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引用次数: 0

Abstract

As a typical organophosphate ester compound, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) exhibits both estrogenic activity and genotoxicity. However, the involvement of estrogen signaling pathways in TDCPP-induced genotoxicity remains unclear. This study evaluated the effects of TDCPP (0.001–200 μM) on DNA damage and repair-related endpoints in GT1–7 mouse hypothalamic cells, and examined the roles of estrogen nuclear receptors (ERα/β) and G protein-coupled estrogen membrane receptor 1 (GPER1), as well as their downstream ERK1/2 and AKT signaling pathways, in TDCPP-induced DNA damage. Our results showed that TDCPP exposure elevated intracellular levels of reactive oxygen species (ROS) and malondialdehyde (MDA), induced DNA damage and G2/M cell cycle arrest, and increased mitochondrial damage and micronucleus formation. In addition, TDCPP significantly increased the protein expression of ATM and γ-H2AX, key markers of DNA double-strand breaks (DSBs), and upregulated the mRNA expression of most DSB repair-related genes, while downregulated mRNA expression of most DNA single-strand break (SSB) repair-related genes. TDCPP also upregulated both protein and gene expression of GPER1 and enhanced ERK1/2 phosphorylation. Pretreatment with the GPER1 inhibitor G15 or the ERK1/2 inhibitor U0126 significantly suppressed TDCPP-induced upregulation of ATM and γ-H2AX protein expression, reversed changes in mRNA levels of DSB/SSB repair-related genes, and reduced TDCPP-induced DNA damage in GT1–7 cells. These findings indicate that TDCPP activates the GPER1-ERK1/2 signaling pathway, which plays a critical role in mediating its DNA-damaging effects.

Capsule

TDCPP induced DNA damage in GT1–7 cells by activating GPER1-ERK1/2 signaling pathway.

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tdcpp诱导的GT1-7细胞DNA损伤机制研究

作为一种典型的有机磷酸酯化合物，三（1,3-二氯-2-丙基）磷酸（TDCPP）具有雌激素活性和遗传毒性。然而，雌激素信号通路在tdpp诱导的遗传毒性中的作用尚不清楚。本研究评估了TDCPP （0.001-200μM）对GT1-7小鼠下丘脑细胞DNA损伤和修复终点的影响，并探讨了雌激素核受体（ERα/β）和G蛋白偶联雌激素膜受体1 （GPER1）及其下游ERK1/2和AKT信号通路在TDCPP诱导的DNA损伤中的作用。我们的研究结果表明，TDCPP暴露会提高细胞内活性氧（ROS）和丙二醛（MDA）水平，诱导DNA损伤和G2/M细胞周期阻滞，并增加线粒体损伤和微核形成。此外，TDCPP显著提高了DNA双链断裂（DSB）关键标记物ATM和γ-H2AX的蛋白表达，上调了大多数DSB修复相关基因的mRNA表达，下调了大多数DNA单链断裂（SSB）修复相关基因的mRNA表达。TDCPP还上调GPER1蛋白和基因表达，增强ERK1/2磷酸化。GPER1抑制剂G15或ERK1/2抑制剂U0126预处理可显著抑制tdpp诱导的ATM和γ-H2AX蛋白表达上调，逆转DSB/SSB修复相关基因mRNA水平的变化，减轻tdpp诱导的GT1-7细胞DNA损伤。这些发现表明，TDCPP激活GPER1-ERK1/2信号通路，在介导其dna损伤作用中起关键作用。胶囊：TDCPP通过激活GPER1-ERK1/2信号通路诱导GT1-7细胞DNA损伤。

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.