Department of Animal Science, Iowa State University, Ames, Iowa, USA.
Biol Reprod. 2024 Feb 10;110(2):419-429. doi: 10.1093/biolre/ioad140.
Histones are slowly evolving chromatin components and chromatin remodeling can incorporate histone variants differing from canonical histones as an epigenetic modification. Several identified histone variants are involved with the environmental stress-induced DNA damage response (DDR). Mechanisms of DDR in transcriptionally inactive, prophase-arrested oocytes and epigenetic regulation are under-explored in ovarian toxicology. The study objective was to identify ovarian proteomic and histone modifications induced by DMBA exposure and an influence of obesity. Post-pubertal wildtype (KK.Cg-a/a; lean) and agouti (KK.Cg-Ay/J; obese) female mice, were exposed to either corn oil (control; CT) or DMBA (1 mg/kg) for 7d via intraperitoneal injection (n = 10/treatment). Ovarian proteome analysis (LC-MS/MS) determined that obesity altered 225 proteins (P < 0.05) with histone 3 being the second least abundant (FC = -5.98, P < 0.05). Histone 4 decreased by 3.33-fold, histone variant H3.3 decreased by 3.05-fold, and H1.2, H1.4 and H1.1(alpha) variants increased by 1.59, 1.90 and 2.01-fold, respectively (P < 0.05). DMBA exposure altered 48 proteins in lean mice with no observed alterations in histones or histone variants. In obese mice, DMBA exposure altered 120 proteins and histone 2B abundance increased by 0.30-fold (P < 0.05). In DMBA-exposed mice, obesity altered the abundance of 634 proteins. Histones 4, 3 and 2A type 1-F decreased by 4.03, 3.71, 0.43-fold, respectively, whereas histone variant H1.2 and linker histone, H15 increased by 2.72- and 3.07-fold, respectively (P < 0.05). Thus, DMBA exposure alters histones and histone variants, and responsivity is more pronounced during obesity, potentially altering ovarian transcriptional regulation.
组蛋白是缓慢进化的染色质成分，染色质重塑可以将不同于经典组蛋白的组蛋白变体纳入表观遗传修饰。几种已鉴定的组蛋白变体参与了环境应激诱导的 DNA 损伤反应 (DDR)。在卵巢毒理学中，转录失活、前期阻滞的卵母细胞中的 DDR 机制和表观遗传调控仍未得到充分探索。本研究的目的是确定 DMBA 暴露诱导的卵巢蛋白质组和组蛋白修饰，以及肥胖的影响。青春期后，野生型 (KK.Cg-a/a；瘦) 和杂色 (KK.Cg-Ay/J；胖) 雌性小鼠分别经腹腔注射玉米油 (对照；CT) 或 DMBA (1mg/kg) 7d (n = 10/处理)。卵巢蛋白质组分析 (LC-MS/MS) 确定肥胖改变了 225 种蛋白质 (P < 0.05)，其中组蛋白 3 是第二丰富的 (FC = -5.98，P < 0.05)。组蛋白 4 减少了 3.33 倍，组蛋白变体 H3.3 减少了 3.05 倍，H1.2、H1.4 和 H1.1(alpha) 变体分别增加了 1.59、1.90 和 2.01 倍 (P < 0.05)。DMBA 暴露改变了瘦小鼠中的 48 种蛋白质，但组蛋白或组蛋白变体没有观察到变化。在肥胖小鼠中，DMBA 暴露改变了 120 种蛋白质，组蛋白 2B 的丰度增加了 0.30 倍 (P < 0.05)。在 DMBA 暴露的小鼠中，肥胖改变了 634 种蛋白质的丰度。组蛋白 4、3 和 2A 类型 1-F 分别减少了 4.03、3.71 和 0.43 倍，而组蛋白变体 H1.2 和连接组蛋白 H15 分别增加了 2.72 和 3.07 倍 (P < 0.05)。因此，DMBA 暴露改变了组蛋白和组蛋白变体，而在肥胖时反应更明显，可能改变了卵巢转录调控。
