Torres Tiago, Barros Susana, Neuparth Teresa, Ruivo Raquel, Santos Miguel Machado
Group of Endocrine Disruptors and Emerging Contaminants, University of Porto, Avenida General Norton de Matos, 4450-208, Matosinhos, S/N, Portugal.
FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua Do Campo Alegre, 4169-007, Porto, Portugal.
Environ Sci Pollut Res Int. 2023 Feb;30(9):22913-22928. doi: 10.1007/s11356-022-23683-5. Epub 2022 Oct 29.
Contaminants of emerging concern have been increasingly associated with the modulation of the epigenome, leading to potentially inherited and persistent impacts on apical endpoints. Here, we address the performance of the OECD Test No. 236 FET (fish embryo acute toxicity) in the identification of chemicals able to modulate the epigenome. Using zebrafish (Danio rerio) embryos, acute and chronic exposures were performed with the pharmaceutical, simvastatin (SIM), a widely prescribed hypocholesterolemic drug reported to induce inter and transgenerational effects. In the present study, the epigenetic effects of environmentally relevant concentrations of SIM (from 8 ng/L to 2000 ng/L) were addressed following (1) an acute embryo assay based on OECD Test No. 236 FET, (2) a chronic partial life-cycle exposure using adult zebrafish (90 days), and (3) F1 embryos obtained from parental exposed animals. Simvastatin induced significant effects in gene expression of key epigenetic biomarkers (DNA methylation and histone acetylation/deacetylation) in the gonads of exposed adult zebrafish and in 80 hpf zebrafish embryos (acute and chronic parental intergenerational exposure), albeit with distinct effect profiles between biological samples. In the chronic exposure, SIM impacted particularly DNA methyltransferase genes in males and female gonads, whereas in F1 embryos SIM affected mostly genes associated with histone acetylation/deacetylation. In the embryo acute direct exposure, SIM modulated the expression of both genes involved in DNA methylation and histone deacetylase. These findings further support the use of epigenetic biomarkers in zebrafish embryos in a high throughput approach to identify and prioritize epigenome-modulating chemicals.
新出现的关注污染物越来越多地与表观基因组的调控相关联，从而对顶端终点产生潜在的遗传和持续影响。在此，我们探讨了经合组织第236号鱼类胚胎急性毒性试验（FET）在鉴定能够调控表观基因组的化学物质方面的性能。使用斑马鱼（Danio rerio）胚胎，对药物辛伐他汀（SIM）进行急性和慢性暴露，辛伐他汀是一种广泛处方的降胆固醇药物，据报道会诱导代内和跨代效应。在本研究中，针对环境相关浓度的SIM（8纳克/升至2000纳克/升）的表观遗传效应进行了以下研究：（1）基于经合组织第236号FET的急性胚胎试验；（2）使用成年斑马鱼进行的慢性部分生命周期暴露（90天）；以及（3）从亲代暴露动物获得的F1胚胎。辛伐他汀在暴露的成年斑马鱼性腺和80小时pf斑马鱼胚胎（急性和慢性亲代跨代暴露）的关键表观遗传生物标志物（DNA甲基化和组蛋白乙酰化/去乙酰化）的基因表达中诱导了显著影响，尽管生物样品之间的效应谱不同。在慢性暴露中，SIM特别影响雄性和雌性性腺中的DNA甲基转移酶基因，而在F1胚胎中，SIM主要影响与组蛋白乙酰化/去乙酰化相关的基因。在胚胎急性直接暴露中，SIM调节了参与DNA甲基化和组蛋白去乙酰化的基因的表达。这些发现进一步支持了在斑马鱼胚胎中使用表观遗传生物标志物，以高通量方法鉴定和优先排序调控表观基因组的化学物质。
