PDF(Pubmed)
Abstract：
Bisphenol A (BPA) is a common component in the manufacture of daily plastic consumer goods. Recent studies have suggested that prenatal exposure to BPA can increase the susceptibility of offspring to mental illness, although the underlying mechanisms remain unclear. In this study, we performed transcriptomic and epigenomic profiling in the adult mouse brain following prenatal exposure to low-dose BPA. We observed a sex-specific transcriptional dysregulation in the cortex, with more significant differentially expressed genes was observed in adult cortex from male offspring. Moreover, the upregulated genes primarily influenced neuronal functions, while the downregulated genes were significantly associated with energy metabolism pathways. More evidence supporting impaired mitochondrial function included a decreased ATP level and a reduced number of mitochondria in the cortical neuron of the BPA group. We further investigated the higher-order chromatin regulatory patterns of DEGs by incorporating published Hi-C data. Interestingly, we found that upregulated genes exhibited more distal interactions with multiple enhancers, while downregulated genes displayed relatively short-range interactions among adjacent genes. Our data further revealed decreased H3K9me3 signal on the distal enhancers of upregulated genes, whereas increased DNA methylation and H3K27me3 signals on the promoters of downregulated genes. In summary, our study provides compelling evidence for the potential health risks associated with prenatal exposure to BPA, and uncovers sex-specific transcriptional changes with a complex interplay of multiple epigenetic mechanisms.
摘要：
双酚A（BPA）是日常塑料消费品制造中的常见成分。最近的研究表明，产前暴露于BPA可以增加后代对精神疾病的易感性，尽管潜在的机制仍不清楚.在这项研究中,我们在产前暴露于低剂量BPA后的成年小鼠大脑中进行了转录组和表观基因组分析.我们在大脑皮层观察到性别特异性转录失调,在雄性后代的成年皮质中观察到更显著的差异表达基因。此外，上调的基因主要影响神经元功能，而下调的基因与能量代谢途径显著相关。支持线粒体功能受损的更多证据包括BPA组的皮质神经元中ATP水平降低和线粒体数量减少。通过结合已发表的Hi-C数据，我们进一步研究了DEGs的高阶染色质调控模式。有趣的是,我们发现上调的基因与多个增强子表现出更多的远端相互作用，而下调的基因在相邻基因之间表现出相对较短的相互作用。我们的数据进一步显示，上调基因的远端增强子上的H3K9me3信号降低，而DNA甲基化和H3K27me3信号在下调基因的启动子上增加。总之,我们的研究提供了与产前暴露于BPA相关的潜在健康风险的令人信服的证据，并通过多种表观遗传机制的复杂相互作用揭示性别特异性转录变化。
