基于Illumina RNA-Seq分析的三种内分泌干扰物对斑马鱼神经毒性效应与机制

郭子一; 王伟伟; 宋杰; 王慧利

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中国环境科学 ›› 2023, Vol. 43 ›› Issue (2) : 946-956.

环境毒理与健康

基于Illumina RNA-Seq分析的三种内分泌干扰物对斑马鱼神经毒性效应与机制

郭子一¹, 王伟伟², 宋杰¹, 王慧利¹

作者信息 +

Neurotoxicity effects of the three endocrine disruptors on zebrafish and the underlying molecular mechanisms by using the Illumina RNA-seq technique

GUO Zi-yi¹, WANG Wei-wei², SONG Jie¹, WANG Hui-li¹

Author information +

文章历史 +

摘要

三氯生、三氯卡班和双酚A均具内分泌干扰作用,但从转录组学层面上揭示其靶分子及神经毒性机制鲜有报道,因此,本文借助RNA-Seq测序获得它们暴露斑马鱼幼鱼的转录组数据,基于生物信息分析证明:三种药物暴毒组差异表达基因(DEGs)的GO功能和KEGG代谢途径富集在生物过程、细胞组成和分子功能上,富集的DEGs数量和功能均不同,在神经相关途径上均有富集,但具体信号通路和途径不同.PPI网络节点关联度计算发现:富集在神经通路的Hub基因也不同,且与神经标志功能基因之间存在丰富间接的互作网络.将DEGs与TCGA数据库中胶质母细胞瘤GBM突变基因整合,证实其环境暴露均有诱发GBM风险,但发生途径和调控信号通路不同,故从分子水平上解析了三种污染物诱导神经毒性机制的根源.

Abstract

Triclosan (TCS), triclocarban (TCC), and bispenol A (BPA) are all proved to possess endocrine disrupting effects; however, little data are available on their neurotoxicity effects on zebrafish (Danio rerio) and the underlying molecular mechanisms. Herein, zebrafish transcriptomic data was obtained with the aid of RNA-Seq after exposure to the aforementioned three pollutants. By means of bioinformatics analysis, nine common positively differential expression genes (DEGs) were screened in the three exposure treatments. The GO functions and KEGG pathways of nine DEGs were mainly attributable to biological process, cellular component, and molecular function, in which the number and function were different with varying chemical exposure. Notably, most of the DEGs were found to be enriched in the nerve-related pathways, but their detailed pathways were different for three chemicals. The computation of node-correlation degree of PPI network showed that the hub genes enriched in neural pathways were different in the three treatments, which had rich and indirect interaction networks with neural marker genes. By integrating DEGs with GBM mutant gene of glioblastoma in the TCGA database, we confirmed that chemical exposure induced GBM risk, but the related occurrence pathway and regulatory signaling pathway were different. Therefore, the underlying neurotoxicity mechanisms induced by the three pollutants were disclosed at the molecular level.

导出引用

郭子一, 王伟伟, 宋杰, 王慧利. 基于Illumina RNA-Seq分析的三种内分泌干扰物对斑马鱼神经毒性效应与机制[J]. 中国环境科学. 2023, 43(2): 946-956

GUO Zi-yi, WANG Wei-wei, SONG Jie, WANG Hui-li. Neurotoxicity effects of the three endocrine disruptors on zebrafish and the underlying molecular mechanisms by using the Illumina RNA-seq technique[J]. China Environmental Science. 2023, 43(2): 946-956

中图分类号： X171

参考文献

[1] 王杨,吴国辉,钱秋慧,等.三氯生对斑马鱼发育和脂质代谢的影响 [J]. 中国环境科学, 2022,(3):1394-1400. Wang Y, Wu G G, Qian Q H, et al. Effects of triclosan environmental exposure on zebrafish development and lipid metabolism [J]. China Environmental Science, 2022,(3):1394-1400.
[2] 赵晨曦,王杨,钱秋慧,等.三氯卡班环境暴露对斑马鱼神经行为的影响 [J]. 中国环境科学, 2022,(1):456-464. Zhao C X, Wang Y, Qian Q H, et al. Effects of environmental exposure to triclocarban on the neurobehavior of zebrafish(Danio rerio) [J]. China Environmental Science, 2022,(1):456-464.
[3] Gomes M F, de Paula V C S, Martins L R R, et al. Sublethal effects of triclosan and triclocarban at environmental concentrations in silver catfish (Rhamdia quelen) embryos [J]. Chemosphere, 2021,263: 127985.
[4] Yun H, Liang B, Kong D, et al. Fate, risk and removal of triclocarban: A critical review [J]. Journal of hazardous materials, 2020,387: 121944.
[5] Gao C J, Kannan K. Phthalates, bisphenols, parabens, and triclocarban in feminine hygiene products from the United States and their implications for human exposure [J]. Environment international, 2020, 136:105465.
[6] 宋静文,靳亚茹,刘红玲.典型酚类污染物内分泌干扰效应研究—对斑马鱼发育及核受体介导基因调控的分子影响 [J]. 中国环境科学, 2020,(9):4065-4076. Song J W, Jin Y R, Liu H L. Research on the endocrine disruption effect of typical phenolic pollutants: The embryonic development effects and molecule effects of gene regulation mediated by nuclear receptor on Zebrafish [J]. China Environmental Science, 2020,(9): 4065-4076.
[7] Kim S S, Hwang K S, Yang J Y, et al. Neurochemical and behavioral analysis by acute exposure to bisphenol A in zebrafish larvae model [J]. Chemosphere, 2020,239:124751-124752.
[8] Lee J, Moon K W, Ji K. Systematic review of exposure to bisphenol A alternatives and its effects on reproduction and thyroid endocrine system in zebrafish [J]. Applied Sciences, 2021,11(4):1832-1837.
[9] Coumailleau P, Trempont S, Pellegrini E, et al. Impacts of bisphenol A analogues on zebrafish post-embryonic brain [J]. Journal of Neuroendocrinology, 2020,32(8):e12879.
[10] Qiu W, Liu S, Chen H, et al. The comparative toxicities of BPA, BPB, BPS, BPF, and BPAF on the reproductive neuroendocrine system of zebrafish embryos and its mechanisms [J]. Journal of hazardous materials, 2021,406:124300-124304.
[11] Gyimah E, Xu H, Dong X, et al. Developmental neurotoxicity of low concentrations of bisphenol A and S exposure in zebrafish [J]. Chemosphere, 2021,262:128043-128046.
[12] Buechner P, Hinderer M, Unberath P, et al. Requirements analysis and specification for a molecular tumor board platform based on cBioPortal [J]. Diagnostics, 2020,10(2):92-93.
[13] Kim J E, Lee D S, Kim T H, et al. Glutathione regulates GPx1expression during CA1neuronal death and clasmatodendrosis in the rat hippocampus following status epilepticus [J]. Antioxidants, 2022,11(4):744-756.
[14] Humphries B, Wang Z, Yang C. Rho GTPases: big players in breast cancer initiation, metastasis and therapeutic responses [J]. Cells, 2020, 9(10):2166-2167.
[15] Kalpachidou T, Spiecker L, Kress M, et al. Rho GTPases in the physiology and pathophysiology of peripheral sensory neurons [J]. Cells, 2019,8(6):591-598.
[16] Liu X, Blazejewski S M, Bennison S A, Toyo-Oka K. Glutathione S-transferase Pi (Gstp) proteins regulate neuritogenesis in the developing cerebral cortex [J]. Hum. Mol. Genet., 2021,30(1):30-45.
[17] Butturini E, Carcereri de Prati A, Mariotto S. Redox regulation of STAT1 and STAT3 signaling [J]. International Journal of Molecular Sciences, 2020,21(19):7033-7037.
[18] Tan A C, Ashley D M, López G Y, et al. Management of glioblastoma: State of the art and future directions [J]. CA: a cancer journal for clinicians, 2020,70(4):299-312.
[19] Alexander B M, Cloughesy T F. Adult glioblastoma [J]. Journal of Clinical Oncology, 2017,35(21):2402-2409.
[20] Braun J M. Early-life exposure to EDCs: Role in childhood obesity and neurodevelopment [J]. Nature Reviews Endocrinology, 2017,13(3): 161-173.
[21] Aburjania Z, Jang S, Whitt J, et al. The role of Notch3 in cancer [J]. The oncologist, 2018,23(8):900-911.
[22] Hosseini-Alghaderi S, Baron M. Notch3in development, health and disease [J]. Biomolecules, 2020,10(3):484-489.
[23] Hevia C F, Engel-Pizcueta C, Udina F, et al. The neurogenic fate of the hindbrain boundaries relies on Notch3-dependent asymmetric cell divisions [J]. Cell Reports, 2022,39(10):110915.
[24] Alqudah MA, Agarwal S, Al-Keilani MS, et al. NOTCH3is a prognostic factor that promotes glioma cell proliferation, migration and invasion via activation of CCND1and EGFR. PLoS One. 2013, 8(10):e77299
[25] An S, Yang Y, Ward R, et al. A-Raf: A new star of the family of raf kinases [J]. Critical Reviews in Biochemistry and Molecular Biology, 2015,50(6):520-531.
[26] Zhou Z W, Ambrogio C, Bera A K, et al. KRASQ61H preferentially signals through MAPK in a RAF dimer-dependent manner in non–small cell lung Cancer KRASQ61H signals in a RAF dimer-dependent manner [J]. Cancer research, 2020,80(17):3719-3731.
[27] Meng L D, Shi G D, Ge W L, et al. Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1and activating the A-Raf-induced MAPK/ERK signaling pathway [J]. Cancer Letters, 2020,494:107-120.
[28] Trengove M C, Ward A C. SOCS proteins in development and disease [J]. American journal of clinical and experimental immunology, 2013, 2(1):1-6.
[29] Beldi-Ferchiou A, Skouri N, Ben Ali C, et al. Abnormal repression of SHP-1, SHP-2and SOCS-1transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma [J]. PloS one, 2017,12(4):e0174835.
[30] Nguyen C H, Glüxam T, Schlerka A, et al. SOCS2is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness [J]. Scientific Reports, 2019,9(1):1-13.
[31] Hermawan A, Putri H. Bioinformatics studies provide insight into possible target and mechanisms of action of nobiletin against cancer stem cells [J]. Asian Pacific Journal of Cancer Prevention: APJCP, 2020,21(3):611-616.
[32] Tomar V S, Patil V, Somasundaram K. Temozolomide induces activation of Wnt/β-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy [J]. Cell Biology and Toxicology, 2020,36(3):273-278.
[33] Dan L U. Anticancer mechanism of scutellarin [J]. Journal of International Oncology, 2015,42(8):682-686.
[34] Wang Q, Cai J, Fang C, et al. Mesenchymal glioblastoma constitutes a major ceRNA signature in the TGF-β pathway [J]. Theranostics, 2018,8(17):4721-4733.
[35] Ohta K, Hoshino H, Wang J, et al. Micro RNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A [J]. Oncotarget, 2015,6(5): 3211-3217.
[36] Hu K, Li J, Wu G, et al. The novel roles of virus infection-associated gene CDKN1A in chemoresistance and immune infiltration of glioblastoma [J]. Aging (Albany NY), 2021,13(5):6662.
[37] Gess B, Röhr D, Young P. Ascorbic acid and sodium-dependent vitamin C transporters in the peripheral nervous system: from basic science to clinical trials [J]. Antioxidants & redox signaling, 2013, 19(17):2105-2114.
[38] Mey J. Retinoic acid as a regulator of cytokine signaling after nerve injury [J]. Zeitschrift für Naturforschung C, 2001,56(3/4):163-176.
[39] Ho B L, Goh Q, Nikolaou S, et al. NRG/ErbB signaling regulates neonatal muscle growth but not neuromuscular contractures in neonatal brachial plexus injury [J]. FEBS letters, 2021,595(5):655-666.
[40] Hayashi Y, Nishimune H, Hozumi K, et al. A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons [J]. Sci Rep. 2016;6:23969.Published 2016Apr 4.
[41] Binari L A, Lewis G M, Kucenas S. Perineurial glia require Notch signaling during motor nerve development but not regeneration. J Neurosci. 2013,33(10):4241-4252.
[42] Travagli M B A. “Novel transmitters in brain stem vagal neurocircuitry: New players on the pitch [J].” American Journal of Physiology. Gastrointestinal and Liver Physiology, 2018,315(1): G20-G26.
[43] Ghosh A K, Brindisi M. Urea derivatives in modern drug discovery and medicinal chemistry [J]. Journal of medicinal chemistry, 2019, 63(6):2751-2788.