塑化剂混合物暴露诱导的产卵前的发病因子:综合单细胞和批量转录组学,网络毒理学和分子对接洞察力
Chenwan Zu1, Min Li1, Sen Ren2
1Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, Anhui, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, Anhui, China.
概括
对ATBC,DEP,DMP和DOP等增塑剂的联合暴露可能通过影响BCL6,FLT1和INHA等关键点,导致孕前 (PE). 这些发现为PE病原体提供了新的见解.
科学领域:
- 环境毒理学环境毒理学
- 生殖医学是一种生殖医学.
- 分子生物学分子生物学
背景情况:
- 塑化剂是已知的孕前 (PE) 的风险因素.
- 在PE中,对特定塑化剂 (ATBC,DEP,DMP,DOP) 的联合暴露的确切机制在很大程度上是未知的.
- 了解这些机制对于开发有效的干预措施至关重要.
研究的目的:
- 阐明在产前症中联合暴露于ATBC,DEP,DMP和DOP的生物目标和致病机制.
- 为了确定关键的分子参与者和细胞途径参与塑化剂诱导的PE.
- 为了解PE发展提供分子基础.
主要方法:
- 对PE/毒素基因标的生物信息预测.
- 差异基因表达分析,机器学习和ROC分析用于生物标记物识别.
- 基因组丰富分析 (GSEA),免疫透分析,分子动力学模拟和单细胞RNA测序 (scRNA-seq),以探索机制和细胞子集.
- 用RT-qPCR和免疫组织化学 (IHC) 来验证标表达.
主要成果:
- 确定了三个关键标 (BCL6,FLT1,INHA),它们在核糖体路径中被丰富,并与激活的树突细胞相关联.
- 在FLT1中,DEP,DMP和DOP的结合能是最低的 (≤5.8 kcal/mol).
- scRNA-seq揭示了小细胞原体 (VCT) 作为一个关键的细胞类型,在分化过程中具有动态的BCL6和FLT1表达;这些标在PE胎盘组织中升级调节,并在VCT细胞中差异表达.
结论:
- 这项研究阐明了在PE的背景下塑化剂毒性机制.
- 提供了新的洞察力,了解塑化剂暴露导致的PE病原性.
- 这些发现为推进孕前的临床治疗提供了理论基础.
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