两种酪氨酸激酶抑制剂舒尼替尼和索拉非尼对斑马鱼幼体发育和甲状腺系统的影响。
The influence of sunitinib and sorafenib, two tyrosine kinase inhibitors, on development and thyroid system in zebrafish larvae.
机构信息
The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, Hangzhou, 310015, China; Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
The Core Laboratory in Medical Center of Clinical Research, Department of Molecular Diagnostics & Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
出版信息
Chemosphere. 2022 Dec;308(Pt 2):136354. doi: 10.1016/j.chemosphere.2022.136354. Epub 2022 Sep 7.
Recently, the potential toxic effects of various pharmaceuticals on the thyroid endocrine system have raised considerable concerns. In this study, we evaluated the adverse effects of sorafenib and sunitinib, two widely used anti-tumor drugs, on the developmental toxicities and thyroid endocrine disruption by using zebrafish (Danio rerio) model. Zebrafish embryos/larvae were exposed to different contentions (0, 10, 50 and 100 nM) of sorafenib and sunitinib for 96 hpf. The results revealed that waterborne exposure to sorafenib and sunitinib exhibited remarkable toxic effects on the survival and development in zebrafish embryos/larvae, which was accompanied by obvious disturbances of thyroid endocrine system (e.g., decreased T3 and T4 content, increased TSH content) and genes' transcription changes within the hypothalamus-pituitary-thyroid (HPT) axis. In addition, we verified a strikingly abnormal thyroid gland organogenesis in zebrafish larvae in response to sorafenib and sunitinib, by assessing the development of thyroid follicles using the WISH staining of tg, the Tg (tg:GFP) zebrafish transgenic line, and histopathological analysis. Taken together, our results indicated sorafenib and sunitinib exposure could induce obvious developmental toxicities and thyroid function disruption in zebrafish embryos/larvae, which might involve a regulatory mechanism, at least in part, by destroying the thyroid follicle structure, and by disturbing the balance of the HPT axis.
最近，各种药物对甲状腺内分泌系统的潜在毒性作用引起了相当大的关注。在这项研究中，我们使用斑马鱼（Danio rerio）模型评估了索拉非尼和舒尼替尼这两种广泛使用的抗肿瘤药物对发育毒性和甲状腺内分泌紊乱的不良影响。将斑马鱼胚胎/幼鱼暴露于不同浓度（0、10、50 和 100 nM）的索拉非尼和舒尼替尼中 96 hpf。结果表明，水基暴露于索拉非尼和舒尼替尼对斑马鱼胚胎/幼鱼的存活和发育表现出显著的毒性作用，伴随着甲状腺内分泌系统的明显紊乱（例如，T3 和 T4 含量降低，TSH 含量增加）和下丘脑-垂体-甲状腺（HPT）轴内基因转录变化。此外，我们通过评估 tg 染色的甲状腺滤泡发育，即 Tg（tg：GFP）斑马鱼转基因系，以及组织病理学分析，验证了索拉非尼和舒尼替尼对斑马鱼幼鱼甲状腺异常发生的显著影响。总之，我们的结果表明，索拉非尼和舒尼替尼暴露可引起斑马鱼胚胎/幼鱼明显的发育毒性和甲状腺功能紊乱，这可能涉及一种调节机制，至少部分是通过破坏甲状腺滤泡结构和扰乱 HPT 轴的平衡。
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