Fish Trevor J, Benninghoff Abby D
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA.
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA; School of Veterinary Medicine, Utah State University, Logan, UT 84322, USA.
Food Chem Toxicol. 2017 Nov;109(Pt 1):703-713. doi: 10.1016/j.fct.2017.04.047. Epub 2017 May 2.
Polycyclic aromatic hydrocarbons (PAHs) comprise an important class of environmental pollutants that are known to cause lung cancer in animals and are suspected lung carcinogens in humans. Moreover, evidence from cell-based studies points to PAHs as modulators of the epigenome. The objective of this work was to assess patterns of genome-wide DNA methylation in lung tissues of adult offspring initiated in utero with the transplacental PAH carcinogens dibenzo [def,p]chrysene (DBC) or benzo [a]pyrene (BaP). Genome-wide methylation patterns for normal (not exposed), normal adjacent and lung tumor tissues obtained from adult offspring were determined using methylated DNA immunoprecipitation (MeDIP) with the NimbleGen mouse DNA methylation CpG island array. Lung tumor incidence in 45-week old mice initiated with BaP was 32%, much lower than that of the DBC-exposed offspring at 96%. Also, male offspring appeared more susceptible to BaP as compared to females. Distinct patterns of DNA methylation were associated with non-exposed, normal adjacent and adenocarcinoma lung tissues, as determined by principal components, hierarchical clustering and gene ontology analyses. From these methylation profiles, a set of genes of interest was identified that includes potential important targets for epigenetic modification during the process of lung tumorigenesis in animals exposed to environmental PAHs.
多环芳烃（PAHs）是一类重要的环境污染物，已知可导致动物肺癌，并且被怀疑是人类肺癌致癌物。此外，基于细胞的研究证据表明PAHs是表观基因组的调节剂。这项工作的目的是评估在子宫内通过胎盘接触PAH致癌物二苯并[def,p]芘（DBC）或苯并[a]芘（BaP）的成年后代肺组织中的全基因组DNA甲基化模式。使用NimbleGen小鼠DNA甲基化CpG岛阵列通过甲基化DNA免疫沉淀（MeDIP）确定从成年后代获得的正常（未暴露）、正常相邻和肺肿瘤组织的全基因组甲基化模式。用BaP启动的45周龄小鼠的肺肿瘤发生率为32%，远低于DBC暴露后代的96%。此外，与雌性相比，雄性后代似乎对BaP更敏感。通过主成分分析、层次聚类分析和基因本体分析确定，DNA甲基化的不同模式与未暴露、正常相邻和腺癌肺组织相关。从这些甲基化谱中，鉴定出一组感兴趣的基因，其中包括在暴露于环境PAHs的动物肺癌发生过程中可能作为表观遗传修饰重要靶点的基因。
