Sasagawa Shota, Nishimura Yuhei, Kon Tetsuo, Yamanaka Yukiko, Murakami Soichiro, Ashikawa Yoshifumi, Yuge Mizuki, Okabe Shiko, Kawaguchi Koki, Kawase Reiko, Tanaka Toshio
Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine Tsu, Japan.
Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of MedicineTsu, Japan; Mie University Medical Zebrafish Research CenterTsu, Japan; Department of Systems Pharmacology, Mie University Graduate School of MedicineTsu, Japan; Department of Omics Medicine, Mie University Industrial Technology Innovation InstituteTsu, Japan; Department of Bioinformatics, Mie University Life Science Research CenterTsu, Japan.
Front Pharmacol. 2016 Mar 14;7:57. doi: 10.3389/fphar.2016.00057. eCollection 2016.
Intestinal helminths cause iron-deficiency anemia in pregnant women, associated with premature delivery, low birth weight, maternal ill health, and maternal death. Although benzimidazole compounds such as mebendazole (MBZ) are highly efficacious against helminths, there are limited data on its use during pregnancy. In this study, we performed in vivo imaging of the retinas of zebrafish larvae exposed to MBZ, and found that exposure to MBZ during 2 and 3 days post-fertilization caused malformation of the retinal layers. To identify the molecular mechanism underlying the developmental toxicity of MBZ, we performed transcriptome analysis of zebrafish eyes. The analysis revealed that the DNA damage response was involved in the developmental toxicity of MBZ. We were also able to demonstrate that inhibition of ATM significantly attenuated the apoptosis induced by MBZ in the zebrafish retina. These results suggest that MBZ causes developmental toxicity in the zebrafish retina at least partly by activating the DNA damage response, including ATM signaling, providing a potential adverse outcome pathway in the developmental toxicity of MBZ in mammals.
肠道蠕虫会导致孕妇缺铁性贫血，这与早产、低出生体重、母亲健康状况不佳及母亲死亡有关。尽管苯并咪唑类化合物如甲苯达唑（MBZ）对蠕虫具有高效作用，但关于其在孕期使用的数据有限。在本研究中，我们对暴露于MBZ的斑马鱼幼体视网膜进行了体内成像，发现受精后第2天和第3天暴露于MBZ会导致视网膜层畸形。为了确定MBZ发育毒性的分子机制，我们对斑马鱼眼睛进行了转录组分析。分析表明，DNA损伤反应参与了MBZ的发育毒性。我们还能够证明，抑制ATM可显著减轻MBZ在斑马鱼视网膜中诱导的细胞凋亡。这些结果表明，MBZ至少部分通过激活包括ATM信号传导在内的DNA损伤反应，在斑马鱼视网膜中引起发育毒性，这为MBZ在哺乳动物中的发育毒性提供了一条潜在的不良结局途径。
