Morphometric analysis of developing zebrafish embryos allows predicting teratogenicity modes of action in higher vertebrates
Morphometric analysis of developing zebrafish embryos allows predicting teratogenicity modes of action in higher vertebrates
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DOI：
10.1016/j.reprotox.2020.08.004
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发表时间：
2020-09-01
影响因子：
3.3
通讯作者：
Terriente, Javier
中科院分区：
文献类型：
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作者：
Jarque, Sergio;Rubio-Brotons, Maria;Terriente, Javier
早期发现人类和动物中的致畸剂对于药物发现和开发是强制性的。斑马鱼已成为传统临床前模型的替代模型，用于预测致畸性和其他潜在的化学诱导毒性危害。为了证明其预测性，我们暴露斑马鱼胚胎0至96小时后受精的电池31分类为致畸剂或非致畸剂的哺乳动物的化合物。致畸性评分基于16个表型参数的测量，即心脏水肿、色素沉着、体长、眼睛大小、卵黄大小、卵黄囊水肿、耳泡缺陷、耳石缺陷、体轴缺陷、发育迟缓、尾部弯曲、脊柱侧凸、侧鳍缺失、孵化率、下颌畸形和组织坏死。在31种化合物中，20种被检测为致畸剂，11种被检测为非致畸剂，与啮齿动物相比，灵敏度为94.44%，特异性为90.91%，准确性为87.10%。当涉及人类时，这些百分比略有下降，灵敏度为87.50%，特异性为81.82%，准确性为74.19%，但允许啮齿动物报告的相同化合物的预测水平增加。阳性化合物的致畸参数之间表现出高度的相关性，指出在一般发育迟缓的主要原因，以解释生理/形态畸形。基于偏离主要趋势的更详细分析揭示了某些化合物的潜在特定作用模式，如视黄酸、DEAB、赭曲霉毒素A、氟哌啶醇、华法林、丙戊酸、对乙酰氨基酚、达沙替尼、伊马替尼、地塞米松、6-氨基烟酰胺和双酚A。高度的可预测性和应用机械方法的可能性使斑马鱼成为筛选致畸性的强大模型。
The early identification of teratogens in humans and animals is mandatory for drug discovery and development. Zebrafish has emerged as an alternative model to traditional preclinical models for predicting teratogenicity and other potential chemical-induced toxicity hazards. To prove its predictivity, we exposed zebrafish embryos from 0 to 96 h post fertilization to a battery of 31 compounds classified as teratogens or non-teratogens in mammals. The teratogenicity score was based on the measurement of 16 phenotypical parameters, namely heart edema, pigmentation, body length, eye size, yolk size, yolk sac edema, otic vesicle defects, otoliths defects, body axis defects, developmental delay, tail bending, scoliosis, lateral fins absence, hatching ratio, lower jaw malformations and tissue necrosis. Among the 31 compounds, 20 were detected as teratogens and 11 as non-teratogens, resulting in 94.44 % sensitivity, 90.91 % specificity and 87.10 % accuracy compared to rodents. These percentages decreased slightly when referred to humans, with 87.50 % sensitivity, 81.82 % specificity and 74.19 % accuracy, but allowed an increase in the prediction levels reported by rodents for the same compounds. Positive compounds showed a high correlation among teratogenic parameters, pointing out at general developmental delay as major cause to explain the physiological/morphological malformations. A more detailed analysis based on deviations from main trends revealed potential specific modes of action for some compounds such as retinoic acid, DEAB, ochratoxin A, haloperidol, warfarin, valproic acid, acetaminophen, dasatinib, imatinib, dexamethasone, 6-aminonicotinamide and bisphenol A. The high degree of predictivity and the possibility of applying mechanistic approaches makes zebrafish a powerful model for screening teratogenicity.