Akemann Camille, Meyer Danielle N, Gurdziel Katherine, Baker Tracie R
Department of Pharmacology, Wayne State University, Detroit, 540 E. Canfield, Detroit, MI, 48201, USA.
Institute of Environmental Health Sciences, Wayne State University, Detroit, 5135 Woodward Ave. Detroit, MI, 48202, USA.
Environ Epigenet. 2020 Sep 27;6(1):dvaa010. doi: 10.1093/eep/dvaa010. eCollection 2020.
The legacy endocrine disrupting chemical and aryl hydrocarbon receptor agonist, 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD), is produced as a byproduct of industrial processes and causes adverse health effects ranging from skin irritation to cancer. TCDD endpoints are also observed in subsequent, unexposed generations; however, the mechanisms of these multi- and transgenerational effects are unknown. We hypothesized an epigenetic mechanism, specifically DNA methylation for the transgenerational, male-mediated reproductive effects of developmental TCDD exposure. Using whole genome bisulfite sequencing, we evaluated DNA methylation changes in three generations of zebrafish, the first of which was exposed to TCDD during sexual development at 50 ppt for 1 h at both 3- and 7-week post-fertilization. We discovered that TCDD induces multi- and transgenerational methylomic changes in testicular tissue from zebrafish with decreased reproductive capacity, but most significantly in the indirectly exposed F1 generation. In comparing differentially methylated genes to concurrent transcriptomic changes, we identified several genes and pathways through which transgenerational effects of low level TCDD exposure are likely inherited. These include significant differential methylation of genes involved in reproduction, endocrine function, xenobiotic metabolism, and epigenetic processing. Notably, a number of histone modification genes were both differentially methylated and expressed in all generations, and many differentially methylated genes overlapped between multiple generations. Collectively, our results suggest that DNA methylation is a promising mechanism to explain male-mediated transgenerational reproductive effects of TCDD exposure in zebrafish, and these effects are likely inherited through integration of multiple epigenetic pathways.
传统的内分泌干扰化学物质和芳烃受体激动剂2,3,7,8-四氯二苯并-对-二恶英（TCDD）是工业生产过程中的副产物，会导致从皮肤刺激到癌症等不良健康影响。在随后未接触过TCDD的几代人中也观察到了其相关终点；然而，这些多代和跨代效应的机制尚不清楚。我们推测存在一种表观遗传机制，特别是DNA甲基化，它介导了发育过程中接触TCDD对雄性产生的跨代生殖影响。我们使用全基因组亚硫酸氢盐测序技术，评估了三代斑马鱼的DNA甲基化变化，其中第一代在受精后3周和7周时，于50 ppt的浓度下，在性发育期间接触TCDD 1小时。我们发现，TCDD会在生殖能力下降的斑马鱼睾丸组织中诱导多代和跨代甲基化组变化，但在间接接触的F1代中最为显著。在将差异甲基化基因与同时期的转录组变化进行比较时，我们确定了几个基因和途径，低水平TCDD暴露的跨代效应可能通过这些基因和途径遗传。这些基因包括参与生殖、内分泌功能、外源性物质代谢和表观遗传加工的基因发生了显著的差异甲基化。值得注意的是，许多组蛋白修饰基因在所有世代中都存在差异甲基化和表达，并且多个世代之间存在许多重叠的差异甲基化基因。总体而言，我们的结果表明，DNA甲基化是一种很有前景的机制，可以解释斑马鱼中TCDD暴露通过雄性介导的跨代生殖影响，并且这些影响可能通过多种表观遗传途径的整合而遗传。
