Leung Maxwell C K, Procter Andrew C, Goldstone Jared V, Foox Jonathan, DeSalle Robert, Mattingly Carolyn J, Siddall Mark E, Timme-Laragy Alicia R
Nicholas School of the Environment, Duke University, Durham, NC, United States.
Institute for Advanced Analytics, North Carolina State University, Raleigh, NC, United States.
Reprod Toxicol. 2017 Apr;69:174-186. doi: 10.1016/j.reprotox.2017.03.003. Epub 2017 Mar 4.
Evolutionary thinking continues to challenge our views on health and disease. Yet, there is a communication gap between evolutionary biologists and toxicologists in recognizing the connections among developmental pathways, high-throughput screening, and birth defects in humans. To increase our capability in identifying potential developmental toxicants in humans, we propose to apply evolutionary genetics to improve the experimental design and data interpretation with various in vitro and whole-organism models. We review five molecular systems of stress response and update 18 consensual cell-cell signaling pathways that are the hallmark for early development, organogenesis, and differentiation; and revisit the principles of teratology in light of recent advances in high-throughput screening, big data techniques, and systems toxicology. Multiscale systems modeling plays an integral role in the evolutionary approach to cross-species extrapolation. Phylogenetic analysis and comparative bioinformatics are both valuable tools in identifying and validating the molecular initiating events that account for adverse developmental outcomes in humans. The discordance of susceptibility between test species and humans (ontogeny) reflects their differences in evolutionary history (phylogeny). This synthesis not only can lead to novel applications in developmental toxicity and risk assessment, but also can pave the way for applying an evo-devo perspective to the study of developmental origins of health and disease.
进化思维不断挑战着我们对健康与疾病的看法。然而，在认识发育途径、高通量筛选与人类出生缺陷之间的联系方面，进化生物学家与毒理学家之间存在沟通障碍。为了提高我们识别人类潜在发育毒物的能力，我们建议应用进化遗传学来改进使用各种体外和全生物体模型的实验设计及数据解读。我们回顾了五个应激反应分子系统，并更新了18条公认的细胞间信号通路，这些通路是早期发育、器官发生和分化的标志；并根据高通量筛选、大数据技术和系统毒理学的最新进展重新审视了致畸学原理。多尺度系统建模在跨物种外推的进化方法中起着不可或缺的作用。系统发育分析和比较生物信息学都是识别和验证导致人类不良发育结果的分子起始事件的宝贵工具。试验物种与人类之间易感性的不一致（个体发生）反映了它们在进化历史（系统发育）上的差异。这种综合不仅可以在发育毒性和风险评估方面带来新的应用，还可以为将进化发育生物学观点应用于健康与疾病的发育起源研究铺平道路。
