School of Health Sciences, Purdue University, West Lafayette, Indiana 47907-2051.
Departments of African and African American Studies, Biology, Global Health, and Family Medicine and Community Health and Center on Genomics, Race, Identity, Difference, Duke University, Durham, North Carolina 27708.
Toxicol Sci. 2021 Apr 27;181(1):3-12. doi: 10.1093/toxsci/kfab022.
Environmental factors and gene-environment interactions modify the variable expressivity, progression, severity, and onset of some classic (monogenic) Mendelian-inherited genetic diseases. Cystic fibrosis, Huntington disease, Parkinson's disease, and sickle cell disease are examples of well-known Mendelian disorders that are influenced by exogenous exposures. Environmental factors may act by direct or indirect mechanisms to modify disease severity, timing, and presentation, including through epigenomic influences, protein misfolding, miRNA alterations, transporter activity, and mitochondrial effects. Because pathological features of early-onset Mendelian diseases can mimic later onset complex diseases, we propose that studies of environmental exposure vulnerabilities using monogenic model systems of rare Mendelian diseases have high potential to provide insight into complex disease phenotypes arising from multi-genetic/multi-toxicant interactions. Mendelian disorders can be modeled by homologous mutations in animal model systems with strong recapitulation of human disease etiology and natural history, providing an important advantage for study of these diseases. Monogenic high penetrant mutations are ideal for toxicant challenge studies with a wide variety of environmental stressors, because background genetic variability may be less able to alter the relatively strong phenotype driving disease-causing mutations. These models promote mechanistic understandings of gene-environment interactions and biological pathways relevant to both Mendelian and related sporadic complex disease outcomes by creating a sensitized background for relevant environmental risk factors. Additionally, rare disease communities are motivated research participants, creating the potential of strong research allies among rare Mendelian disease advocacy groups and disease registries and providing a variety of translational opportunities that are under-utilized in genetic or environmental health science.
环境因素和基因-环境相互作用改变了某些经典（单基因）孟德尔遗传疾病的表现度、进展、严重程度和发病时间。囊性纤维化、亨廷顿病、帕金森病和镰状细胞病是受外源性暴露影响的知名孟德尔疾病的例子。环境因素可能通过直接或间接机制来改变疾病的严重程度、发病时间和表现形式，包括通过表观遗传影响、蛋白质错误折叠、miRNA 改变、转运体活性和线粒体效应。由于早发性孟德尔疾病的病理特征可能模仿迟发性复杂疾病，因此我们提出，使用罕见孟德尔疾病的单基因模型系统研究环境暴露易感性，很有可能为多基因/多毒物相互作用引起的复杂疾病表型提供深入了解。可以通过动物模型系统中的同源突变来模拟孟德尔疾病，这些动物模型系统强烈重现了人类疾病的病因和自然史，这为这些疾病的研究提供了一个重要优势。单基因高外显率突变非常适合用各种环境应激源进行毒物挑战研究，因为背景遗传变异性可能不太能够改变导致疾病的突变所驱动的相对强烈的表型。这些模型通过为相关环境风险因素创造敏感的背景，促进了孟德尔和相关散发性复杂疾病结果的基因-环境相互作用和生物学途径的机制理解。此外，罕见疾病社区是积极的研究参与者，这在罕见孟德尔疾病倡导团体和疾病登记处之间创造了强大的研究联盟的潜力，并提供了遗传或环境健康科学中未充分利用的各种转化机会。
