Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Palmer Commons, Ann Arbor, MI, USA.
Epigenetics. 2024 Dec;19(1):2426952. doi: 10.1080/15592294.2024.2426952. Epub 2024 Nov 13.
Lead (Pb) is a neurotoxicant with early life exposure linked to long-term health effects. Piwi-interacting RNAs (piRNAs) are small non-coding RNAs that associate with PIWIL proteins to induce DNA methylation. It remains unknown whether Pb exposure influences piRNA expression. This study evaluated how perinatal Pb exposure (32 ppm in drinking water) impacts piRNA expression in adult mice and assessed piRNA dysregulation as a potential mechanism for Pb-induced toxicity. Pb exposure effects on piRNA expression and associated gene repression in the germline (testis/ovary) and soma (liver and brain) were evaluated. Small RNA sequencing was used to determine differentially expressed piRNAs, RT-qPCR to examine piRNA target expression, and whole genome bisulfite sequencing to evaluate target DNA methylation status. Three piRNAs (mmpiR-1500602, mmpiR-0201406, and mmpiR-0200026) were significant after multiple testing correction (all downregulated in the male Pb-exposed brain in comparison to control; FDR < 0.05). Within piOxiDB, TAO Kinase 3 was identified as a downstream mRNA target for one of the three Pb-sensitive piRNA. The Pb-exposed male brain exhibited increased expression ( < 0.05) and decreased DNA methylation (FDR < 0.01). The results demonstrate that perinatal Pb exposure stably influences longitudinal piRNA expression in a tissue- and sex-specific manner, potentially via DNA methylation-directed mechanisms.
铅（Pb）是一种神经毒素，其早期生命暴露与长期健康影响有关。Piwi 相互作用 RNA（piRNA）是一种与 PIWIL 蛋白结合诱导 DNA 甲基化的小非编码 RNA。目前尚不清楚 Pb 暴露是否会影响 piRNA 的表达。本研究评估了围产期 Pb 暴露（饮用水中 32ppm）如何影响成年小鼠的 piRNA 表达，并评估了 piRNA 失调是否是 Pb 诱导毒性的潜在机制。评估了 Pb 暴露对生殖细胞（睾丸/卵巢）和体细胞（肝脏和大脑）中 piRNA 表达和相关基因抑制的影响。使用小 RNA 测序确定差异表达的 piRNA，使用 RT-qPCR 检查 piRNA 靶基因表达，使用全基因组亚硫酸氢盐测序评估靶基因 DNA 甲基化状态。经过多重检验校正后，有 3 个 piRNA（mmpiR-1500602、mmpiR-0201406 和 mmpiR-0200026）显著上调（与对照组相比，雄性 Pb 暴露组大脑中的所有 piRNA 均下调；FDR<0.05）。在 piOxiDB 中，TAO 激酶 3 被确定为三个 Pb 敏感 piRNA 之一的下游 mRNA 靶标。Pb 暴露雄性大脑表现出 表达增加（<0.05）和 DNA 甲基化减少（FDR<0.01）。研究结果表明，围产期 Pb 暴露以组织和性别特异性的方式稳定地影响纵向 piRNA 表达，可能通过 DNA 甲基化导向机制。
