表观遗传学机制与空气污染的健康效应

空气污染是一个全球性的问题,并且具有深远的环境影响。暴露于空气污染会对人体健康产生许多不同的影响,理解空气污染的健康效应又是一个复杂命题,既要考虑不同类型的污染物同时也要考虑相关疾病的复杂性。然而越来越多的研究表明,表观遗传学在空气污染相关疾病的发生、发展中发挥着重要的作用。空气污染物可引起DNA甲基化、组蛋白修饰和miRNA表达等表观遗传学改变,这种改变往往发生在疾病产生的早期,因此相关研究不仅可以了解疾病的发病机制,而且还为疾病早期诊断和预防筛选可能的标志物。本文综述了表观遗传学的几种修饰方式和空气污染物造成不良健康损伤机制的一些研究进展。     

Absence of metallothionein 3 expression in breast cancer is a rare but favorable marker that is under epigenetic control

Cadmium (Cd²⁺), a known carcinogen, mimics the effects of estrogen in the uterus and mammary gland suggesting its possible involvement in the development and progression of breast cancer. This lab showed through analysis of a small set of archival human diagnostic specimens that the third isoform of the classic Cd²⁺ binding protein metallothionein (MT-3) is not expressed in normal breast tissue, but is expressed in some breast cancers and that expression tends to correlate with a poor disease outcome. The goals of this study were to verify that overexpression of MT-3 in a large set of archival human diagnostic specimens tends to correlate with poor disease outcome and define the mechanism of MT-3 gene regulation in the normal breast epithelial cell. The results showed that MT-3 was expressed in approximately 90% of all breast cancers and was absent in normal breast epithelium. The lack of MT-3 staining in some cancers correlated with a favorable patient outcome. High frequency of MT-3 staining was also found for in situ breast cancer suggesting that MT-3 might be an early biomarker for breast cancer. The study also demonstrated that the MCF-10A cell line, an immortalized, non-tumorigenic model of human breast epithelial cells, displayed no basal expression of MT-3, nor was it induced by Cd²⁺. Treatment of the MCF-10A cells with the demethylation agent, 5-aza-2′-deoxycytidine, or the histone deacetylase inhibitor, MS-275, restored MT-3 mRNA expression. It was also shown that the MT-3 metal regulatory elements are potentially active binders of protein factors following treatment with these inhibitors suggesting that MT-3 expression may be subject to epigenetic regulation.     

PFOS对星形胶质细胞表观遗传调控作用初探

脑源性神经营养因子(BDNF)甲基化在全氟辛烷磺酸(PFOS)神经毒性中的作用已证实,但表观遗传修饰中其他调控因子在PFOS对星形胶质细胞毒性中的影响仍有待探索。本文以大鼠原代星形胶质细胞为体外生物体系,建立24 h PFOS(0、25、50和100μmol·L~(-1))暴露模型,通过观察PFOS暴露对星形胶质细胞表观遗传调控主要分子DNA甲基化酶(DNMTs)、组蛋白去乙酰化酶(HDACs)和小泛素化修饰物(SUMOs)的影响,初步明确表观遗传调控机制参与PFOS神经毒性作用。采用Hoechst 33258检测细胞凋亡,利用ELISA试剂盒检测HDACs含量,以实时荧光定量PCR考察DNMTs、HDACs和SUMOs基因表达。结果显示,星形胶质细胞暴露于一定浓度PFOS(≥25μmol·L~(-1))时产生凋亡现象(P0.05),HDACs含量升高(P0.05),且DNMT1、HDAC1/2/4与SUMO-1的基因表达显著升高(P0.05);而当PFOS浓度高于50μmol·L~(-1)时,可显著诱导DNMT3A、SUMO-2的基因表达(P0.05); DNMT3B在PFOS≥25μmol·L~(-1)时,其基因表达具有升高趋势,但不具统计学显著性(P0.05)。结果表明,PFOS可以影响星形胶质细胞的表观遗传修饰;表观遗传修饰可能是PFOS神经毒性作用机制之一。     

Prenatal diagnosis in monozygotic twins with Down syndrome who had different phenotypes

We report the case of monozygotic (MZ) male twin fetuses with different Down syndrome (DS) phenotypes. Prenatal fetal sonography showed a bichorial biamniotic pregnancy with increased nuchal translucency in twin A and a cervical cystic hygroma and heart defect in twin B. Cytogenetic analysis performed after double amniocentesis showed free and homogeneous trisomy 21 in both twins. Monozygosity was confirmed by molecular analysis. The pregnancy was terminated at 17 weeks of gestation (WG). Postmortem analysis confirmed the phenotypic discordance. To our knowledge, this is the first reported prenatal diagnosis of MZ male twins with different Down syndrome phenotypes but identical karyotypes. We discuss the mechanisms involved in phenotypic discordance of monozygotic twins and particularly the role of environmental factors. Copyright © 2007 John Wiley & Sons, Ltd.     

Toward an integrative molecular approach to wildlife disease

Pathogens pose serious threats to human health, agricultural investment, and biodiversity conservation through the emergence of zoonoses, spillover to domestic livestock, and epizootic outbreaks. As such, wildlife managers are often tasked with mitigating the negative effects of disease. Yet, parasites form a major component of biodiversity that often persist. This is due to logistical challenges of implementing management strategies and to insufficient understanding of host–parasite dynamics. We advocate for an inclusive understanding of molecular diversity in driving parasite infection and variable host disease states in wildlife systems. More specifically, we examine the roles of genetic, epigenetic, and commensal microbial variation in disease pathogenesis. These include mechanisms underlying parasite virulence and host resistance and tolerance, and the development, regulation, and parasite subversion of immune pathways, among other processes. Case studies of devil facial tumor disease in Tasmanian devils (Sarcophilus harrisii) and chytridiomycosis in globally distributed amphibians exemplify the broad range of questions that can be addressed by examining different facets of molecular diversity. For particularly complex systems, integrative molecular analyses present a promising frontier that can provide critical insights necessary to elucidate disease dynamics operating across scales. These insights enable more accurate risk assessment, reconstruction of transmission pathways, discernment of optimal intervention strategies, and development of more effective and ecologically sound treatments that minimize damage to the host population and environment. Such measures are crucial when mitigating threats posed by wildlife disease to humans, domestic animals, and species of conservation concern.     

苯急性暴露对Sprague-Dawley大鼠全基因组DNA甲基化的影响

现有文献表明,DNA甲基化异常与肿瘤的发生密切相关,其中全基因组DNA甲基化水平的改变已经被认为是癌症发生的生物标志物;同时,大量遗传毒理学实验证明苯可以引起DNA突变和断裂,然而苯暴露引起全基因组DNA甲基化异常的现象,目前鲜有文献报道。为了揭示苯引起全基因组DNA甲基化变化的致毒机制,本实验中,Sprague-Dawley（SD）雄性大鼠经口灌胃急性暴露于以500 mg.kg-1（以体质量计）的苯中,在暴露6、12、24、30 h后采集SD雄性大鼠体内血液、肝脏、肾脏和肺,利用高效液相色谱分析方法检测全基因组DNA甲基化水平。结果表明,SD雄性大鼠血液和肝脏的全基因组DNA甲基化水平显著下降,而在肾脏和肺中没有显著地变化,表现出组织特异性。本实验率先报道了苯的暴露可以引起全基因组DNA甲基化水平的异常,从表观遗传学的角度解释了苯影响人体健康的机制。