Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723, USA.
Am J Med Genet C Semin Med Genet. 2011 Aug 15;157C(3):215-26. doi: 10.1002/ajmg.c.30314. Epub 2011 Jul 15.
Birth defects remain the leading cause of infant death in US. The field of teratology has been focused on the causes and underlying mechanisms of birth defects for decades, yet our understanding of these critical issues remain unacceptably vague. Conclusions from years of animal and human studies made it clear that the vast majority of birth defects have multifactorial origins, with contributions from environmental and genetic factors. The environment comprises not only of the physical, biological, and chemical external environment surrounding the pregnant woman, but it also includes the internal environment of the woman's body that interact with the developing embryo in a complex fashion. The importance of maternal and embryonic genetic factors consisting of countless genetic variants/mutations that exist within every individual contribute to birth defect susceptibility is only now being more fully appreciated. This great complexity of the genome and its diversity within individuals and populations seems to be the principal reason why the same teratogenic exposure can induce severe malformation in one embryo, while fail to do so to other exposed embryos. As the interaction between genetic and environmental factors has long been recognized as the first "Principle of Teratology" by Wilson and Warkany [1965. Teratology: Principles and techniques. Chicago: University of Chicago Press], it is only recently that the appropriate investigative tools have been developed with which to fully investigate this fundamental principle. The introduction of high throughput technologies like whole genome sequencing or genome-wide association studies are promising to deliver an enormous amount of new data that will shed light on the genomic factors that contribute susceptibility to environmental teratogens. In this review, we attempt to summarize the epidemiological and experimental literature concerning birth defects whose phenotypic expression can be clearly related to the interactions between several select environmental factors and those genetic pathways in which they are most likely to have significant modifying effects. © 2011 Wiley-Liss, Inc.
出生缺陷仍然是美国婴儿死亡的主要原因。几十年来，畸形学领域一直专注于出生缺陷的原因和潜在机制，但我们对这些关键问题的理解仍然非常模糊。多年来的动物和人类研究的结论清楚地表明，绝大多数出生缺陷具有多因素的起源，涉及环境和遗传因素。环境不仅包括孕妇周围的物理、生物和化学外部环境，还包括女性身体的内部环境，这些环境以复杂的方式与发育中的胚胎相互作用。母体和胚胎遗传因素的重要性，包括每个个体中存在的无数遗传变异/突变，这些遗传因素有助于出生缺陷的易感性，现在才得到更充分的认识。基因组的这种复杂性及其在个体和人群中的多样性似乎是导致相同致畸暴露在一个胚胎中引起严重畸形，而在其他暴露胚胎中却没有引起畸形的主要原因。由于遗传和环境因素的相互作用长期以来一直被认为是威尔逊和瓦卡尼（Wilson and Warkany）提出的第一个“致畸学原理”[1965. Teratology: Principles and techniques. Chicago: University of Chicago Press]，直到最近才开发出适当的研究工具来全面研究这一基本原理。高通量技术的引入，如全基因组测序或全基因组关联研究，有望提供大量新数据，这些数据将揭示导致环境致畸物易感性的基因组因素。在这篇综述中，我们试图总结有关出生缺陷的流行病学和实验文献，这些文献的表型表达可以明确地与几个选定的环境因素与它们最有可能产生显著修饰作用的遗传途径之间的相互作用相关。©2011 威利-利希，公司。
