University of Navarra, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, E-31008, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, E-31008, Pamplona, Spain.
University of Navarra, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Nutrition, E-31008, Pamplona, Spain.
Food Chem Toxicol. 2019 Jan;123:337-348. doi: 10.1016/j.fct.2018.10.057. Epub 2018 Oct 25.
Ochratoxin A (OTA) is a potent rodent nephrocarcinogen; being males more sensitive than females. The objective was to study the response between sexes at gene expression level (whole genome transcriptomics) in kidneys of F344 rats treated with 0.21 or 0.50 mg/kg bw OTA for 21 days. DNA methylation analysis of selected genes was also studied (MALDI-TOF mass spectrometry). OTA-induced response was dose-dependent in males and females, although clearer in males. Females showed a higher number of altered genes than males but functional analysis revealed a higher number of significantly enriched toxicity lists in 0.21 mg/kg treated males. OTA modulated damage, signaling and metabolism related lists, as well as inflammation, proliferation and oxidative stress in both sexes. Eleven toxicity lists (damage, fibrosis, cell signaling and metabolism) were exclusively altered in males while renal safety biomarker and biogenesis of mitochondria lists were exclusively enriched in females. A high number of lists (39) were significantly enriched in both sexes. However, they contained many sex-biased OTA-modulated genes, mainly phase I and II, transporters and nuclear receptors, but also others related to cell proliferation/apoptosis. No biologically relevant changes were observed in the methylation of selected genes.
赭曲霉毒素 A（OTA）是一种强效的啮齿动物肾致癌物；雄性比雌性更敏感。本研究的目的是研究雄性和雌性 F344 大鼠在接受 0.21 或 0.50mg/kg bw OTA 21 天后，肾脏基因表达水平（全基因组转录组学）的性别反应。还研究了选定基因的 DNA 甲基化分析（基质辅助激光解吸电离飞行时间质谱）。在雄性和雌性中，OTA 诱导的反应呈剂量依赖性，尽管在雄性中更为明显。雌性表现出比雄性更多的改变基因，但功能分析显示，在 0.21mg/kg 处理的雄性中，具有显著富集毒性列表的数量更高。OTA 调节了损伤、信号和代谢相关列表，以及两性中的炎症、增殖和氧化应激。11 个毒性列表（损伤、纤维化、细胞信号和代谢）仅在雄性中改变，而肾脏安全生物标志物和线粒体生物发生列表仅在雌性中富集。大量列表（39 个）在两性中均显著富集。然而，它们包含许多性别偏向的 OTA 调节基因，主要是 I 期和 II 期、转运蛋白和核受体，但也有其他与细胞增殖/凋亡有关的基因。在选定基因的甲基化中未观察到生物学上相关的变化。
